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Sarcopenia burdens the older population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are lacking. The glucocorticoid prednisone remodels muscle metabolism on the basis of frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone administration rescued muscle quality in aged 24-month-old mice to a level comparable to that seen in young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and its cofactor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1α, which was required for the treatmentdriven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed myocyte-specific Lipin1 as a nonredundant factor coaxing PGC1α upregulation to the stimulation of both oxidative and anabolic effects. Our study unveils an aging-resistant druggable program in myocytes for the coordinated rescue of energy and mass in sarcopenia. [ABSTRACT FROM AUTHOR]

The fusion of autophagosomes and lysosomes is essential for the prevention of nonalcoholic fatty liver disease (NAFLD). Here, we generate a hepatocyte-specific CHIP knockout (H-KO) mouse model that develops NAFLD more rapidly in response to a high-fat diet (HFD) or high-fat, high-fructose diet (HFHFD). The accumulation of P62 and LC3 in the livers of H-KO mice and CHIP-depleted cells indicates the inhibition of autophagosome-lysosome fusion. AAV8-mediated overexpression of CHIP in the murine liver slows the progression of NAFLD induced by HFD or HFHFD feeding. Mechanistically, CHIP induced K63- and K27-linked polyubiquitination at the lysine 198 residue of STX17, resulting in increased STX17-SNAP29-VAMP8 complex formation. The STX17 K198R mutant was not ubiquitinated by CHIP; it interfered with its interaction with VAMP8, rendering STX17 incapable of inhibiting steatosis development in mice. These results indicate that a signaling regulatory mechanism involving CHIP-mediated non-degradative ubiquitination of STX17 is necessary for autophagosome-lysosome fusion., (© 2024. The Author(s).)

A 4-year-old female Maltese dog was referred to our veterinary hospital with uveitis and conjunctivitis of the right eye. An ophthalmological evaluation revealed an intraocular mass that appeared to originate from the anterior uvea. Metastasis and regional invasion were not detected with CT examination. Enucleation of the right eye was recommended; however, the owner declined treatment. Six months later, the dog was re-presented with a right facial mass. At presentation, superficial lymph node enlargement was not appreciated, and no apparent alterations were noted on blood analysis or urinalysis. Computed tomography revealed an intraocular mass that invaded the surrounding tissues, including the frontal sinus. Presumed solitary ocular lymphoma with a large B-cell phenotype and Mott cell change was diagnosed via histopathological and immunohistochemical examination of a biopsy of the lesion. As the mass was too large for complete excision, neoadjuvant chemotherapy was administered. Complete remission was achieved using the L-COAP protocol and successful exenteration of the right eye. However, the dog was returned with enlargement of the right retropharyngeal lymph nodes. To the best of our knowledge, this is the first case report of presumed solitary ocular lymphoma with a large B-cell phenotype displaying Mott cell change in a dog. Key clinical message: This is the first reported case of a presumed solitary ocular lymphoma with a large B-cell phenotype and Mott cell change. Although systemic involvement was observed 6 mo after the initial visit, neoadjuvant chemotherapy and exenteration were effective., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Background: Gastric neuroendocrine carcinomas (NECs) are rare cancers with highly aggressive behavior. Although tertiary lymphoid structures (TLSs) are well-known prognostic factors in various cancers, their role in gastric NECs remain unexplored. Unique immunohistochemical subtypes of pulmonary NECs have been discovered, however, their feasibility in gastric NECs is unknown., Methods: The presence and maturation of TLSs (lymphoid aggregates, primary and secondary follicles) were assessed in 48 surgically resected gastric NECs and were compared with immunohistochemical subtypes, using a panel of ASCL1, NeuroD1, POU2F3, YAP1, and DLL3 with three neuroendocrine (NE) markers., Results: Patients with secondary follicles had significantly better overall survival (OS) and recurrence-free survival (RFS; both, p = 0.004) than those without them. Based on the hierarchical clustering, gastric NECs were classified into all low/negative (31%), high-YAP1 (19%), high-DLL3/low-NE (29%), and high-NE (21%) expression groups. The high-DLL3/low-NE group was associated with absent TLSs (p = 0.026) and showed the worst OS (p = 0.026). Distant metastasis and a lack of secondary follicles were poor independent prognostic factors of OS and RFS., Conclusion: The assessment of TLSs is a feasible and potent biomarker for gastric NECs, thus enabling better prognosis and more effective immunotherapy. Furthermore, gastric NECs can be categorized as four immunohistochemically distinct groups, of which the high-DLL3/low-NE group has the worst OS with lack of TLSs., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Methotrexate (MTX) is an antifolate agent widely used for treating conditions such as rheumatoid arthritis and hematologic cancer. This study aimed to quantitatively interpret the drug-drug interactions (DDIs) of MTX mediated by drug transporters using physiologically-based pharmacokinetic (PBPK) modeling. An open-label, randomized, 4-treatment, 6-sequence, 4-period crossover study was conducted to investigate the effects of rifampicin (RFP), an inhibitor of organic anionic transporting peptides (OATP) 1B1/3, and febuxostat (FBX), an inhibitor of breast cancer resistance protein (BCRP), on the pharmacokinetics of MTX in healthy volunteers. PBPK models of MTX, RFP, and FBX were developed based on in vitro and in vivo data, and the performance of the simulation results for final PBPK models was validated in a clinical study. In the clinical study, when MTX was co-administered with RFP or FBX, systemic exposure of MTX increased by 33% and 17%, respectively, compared with that when MTX was administered alone. When MTX was co-administered with RFP and FBX, systemic exposure increased by 52% compared with that when MTX was administered alone. The final PBPK model showed a good prediction performance for the observed clinical data. The PBPK model of MTX was well developed in this study and can be used as a potential mechanistic model to predict and evaluate drug transporter-mediated DDIs of MTX with other drugs., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Although hyponatremia and salt wasting are common in patients with HIV/AIDS, the understanding of their contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the sodium-chloride cotransporter (which is responsible for sodium reabsorption in distal nephron segments), single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr transgenic (Vpr Tg) mice. The percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05); in Vpr Tg mice, Slc12a3 expression was not significantly different in DCT cells. The Pvalb +  DCT1 subcluster had fewer cells in Vpr Tg mice compared with those in WT mice (P < 0.01). Immunohistochemistry revealed fewer Slc12a3 + Pvalb +  DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT samples in the DCT cluster showed down-regulation of the Ier3 gene, which is an inhibitor of apoptosis. The in vitro knockdown of Ier3 by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by Ier3 down-regulation in DCT1 cells and loss of Slc12a3 + Pvalb +  DCT1 segments., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. All rights reserved.)

Introduction: GB-5001 is an intramuscular (IM) formulation of donepezil under development for the treatment of Alzheimer's disease. The objective of this study was to develop a population pharmacokinetic (PK) model for donepezil in both IM and oral formulations, and to optimize the IM dosage of GB-5001 using bioequivalence (BE) simulation., Methods: A population PK model of donepezil was developed using NONMEM. It was based on plasma concentration data from a Phase 1 dose escalation study, which involved a single administration of donepezil IM formulation at doses of 70, 140, and 280 mg, and the oral formulation at 10 mg. The model was evaluated based on goodness-of-fit plots, conditional weighted residuals, visual predictive checks, and bootstrapping. BE simulations were conducted using a parallel design between various doses of the IM formulation and the 10-mg dose of oral formulation., Results: The PKs of donepezil were best described by a two-compartment model, which incorporated distinct absorption compartments for the IM (dual first-order absorption and simultaneous zero-order absorption with lag time) and oral (first-order absorption with lag time) formulations. Based on the simulation results, an IM dosage range of 210-215 mg in a sample size of over 92 was estimated to achieve a success rate of approximately 80% for BE., Conclusion: The population PK model well explained the PKs of donepezil following administration of both the IM and oral formulations. This model could be applied for the design and dose selection of future BE trials., Trial Registration: ClinicalTrials.gov identifier, NCT05525780., (© 2024. The Author(s).)

Introduction: This study was conducted to assess the systemic pharmacokinetic profiles of half-dose verteporfin photodynamic therapy (PDT) using concentration data from a previous clinical trial, and to subsequently suggest the safety precaution guidelines., Methods: Coefficients for the bi-exponential model were obtained from published data on post-infusion plasma verteporfin concentrations within a period of 0.17-4 h. Using the extrapolative forecasting method, we plotted the 48 h post-verteporfin plasma concentration model. The time required to achieve a comparable level of verteporfin 48 h after a conventional -dose (6 mg/m2 body surface area, BSA) infusion was calculated for a half-dose infusion (3 mg/m2 BSA)., Results: At 24 and 48 hours post-verteporfin infusion, the plasma concentration following the conventional dose was 1.28 × 10⁻⁴ µg/mL and 5.06 × 10⁻⁸ µg/mL, compared to 3.57 × 10⁻⁵ µg/mL and 7.54 × 10⁻⁹ µg/mL for the half-dose PDT, representing concentrations that were 3.6 times and 6.7 times higher, respectively. The estimated time required to attain the same level of verteporfin 48 h after a conventional -dose was calculated as 42 h post- half-dose PDT., Conclusions: The study results of this study indicate that it is advisable to take necessary precautionary measures should be taken to avoid sunlight following both half and conventional doses of PDT. Nevertheless, given the substantially higher plasma concentration levels associated with conventional-dose PDT as compared withto the half-dose, systemic safety should be given duecarefully consideredation whenwhile administering conventional-dose PDT., (The Author(s). Published by S. Karger AG, Basel.)

This study aimed to estimate individual pharmacokinetic (PK) parameters in an obese hemodialysis (HD) patient receiving gentamicin and to assess the impact of obesity on gentamicin clearance (CL). A 53-year-old obese Korean woman underwent HD and received gentamicin. To estimate individual PK parameters, we employed the POSTHOC option using NONMEM ® 7.4.4. A priori model contained HD as a covariate for CL during HD, and creatinine CL (CrCL), normalized by the group mean value from the a priori model, as a covariate for non-HD CL (CLNHD). Individual CLNHD exhibited a substantial reduction from the population CLNHD, with the value corresponding to 36% of the a priori model's population PK (popPK) parameter. The patient's CrCL exceeded the group maximum of the a priori information, suggesting inaccurate renal function representation. After adjusting CrCL to the group mean from the a priori model, the patient's CLNHD was 138% of the population's typical value. The objective function value for each run was 0.53 and -4.49, respectively. The patient's CLNHD was greater than the popPK parameter value but less than the popPK parameter value when estimated using the patient's original CrCL. Meanwhile, another software (Monolix ® ; version 2024R1) gave similar results. This study shows the importance of individualized PK parameter estimation, particularly in obese HD patients, and highlights the potential impact of factors including obesity on gentamicin CL., Competing Interests: Conflict of Interest: - Authors: Nothing to declare - Reviewers: Nothing to declare - Editors: Nothing to declare, (Copyright © 2024 Translational and Clinical Pharmacology.)

Importance: Developing clinical skills is an essential element of veterinary education to ensure the competency of veterinary graduates. Although the Korean Veterinary Education Graduation Competencies were established in 2016, reflecting domestic needs and international trends in competency-based veterinary education, they have yet to be implemented in Korean veterinary education., Objective: This study aimed to establish the basic veterinary clinical skills required to ensure graduates of Korean veterinary universities have the day-one competency to independently perform their professional duties., Methods: The Education Committee of the Korean Association of Veterinary Medical Colleges, composed of veterinary school professors and an experienced veterinarian in the clinic, reviewed domestic and international veterinary education-related materials to define basic clinical skills., Results: The Korean Veterinarian Entrustable Professional Activities (KVEPA) was introduced, followed by the subsequent development of 54 essential clinical skills based on the KVEPA., Conclusions and Relevance: The veterinary basic clinical skills established through this study can be used as a specific guide for clinical education in Korean veterinary school, and is expected to play an important role in meeting the needs of the educational sector of the veterinary education accreditation standards., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Korean Society of Veterinary Science.)

Background: Hindfoot malalignment can cause various foot and ankle problems. For better surgical performance and correction of hindfoot malalignments, reliable intraoperative determination of hindfoot alignment is essential. However, there is no standard method for the intraoperative assessment of hindfoot alignment. We devised an intraoperative modified Méary posteroanterior (IOPPA) view to assess intraoperative hindfoot alignment. This study aimed to compare this intraoperative method with other radiographic hindfoot alignment measurements., Methods: Thirty-seven patients (47 feet) with various foot and ankle conditions scheduled to undergo surgery were prospectively recruited. Before surgery, the Saltzman, long axial, and modified Méary views were taken in a controlled and standardized fashion. IOPPA views were obtained under simulated weight bearing conditions using C-arm fluoroscopy in the operating room before surgery. The relationship between the IOPPA view and the three radiographic hindfoot alignments was evaluated using Pearson's correlation., Results: The mean hindfoot alignment angle was varus 3.50° (CI, varus 1.91 to 5.08) on the Saltzman view, varus 2.00° (CI, varus 0.60 to 3.39) on the long axial view, varus 0.13° (CI, valgus 1.41 to varus 1.67) on the modified Méary view, and varus 1.32° (CI, valgus 0.02 to varus 2.65) on IOPPA view. The IOPPA view and the three other hindfoot alignment views were found to be significantly correlated (r = 0.60 for the Saltzman view, r = 0.50 for the long axial view, r = 0.71 for the modified Méary view, P < .05). The intraobserver ICC (Intraclass Correlation Coefficient) value was 0.974 and interobserver ICC (Intraclass Correlation Coefficient) value was 0.988 for the IOPPA view (P < .001)., Conclusion: There was a statistically significant correlation between the IOPPA view and the other three hindfoot alignment views. We also found that interobserver and intraobserver ICC values were excellent. This study proposes that the IOPPA view can be used as a reliable intraoperative assessment tool for hindfoot alignment., Level of Evidence: Prospective study., Competing Interests: Declaration of competing interest The authors received no financial support for the research, authorship, and/or publication of this article., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Purpose: Brain Injury Guidelines (BIG) have been established to guide management related to TBI in adults. Here, BIG criteria were applied to pediatric TBI patients to evaluate reliability, safety, and resource utilization., Methods: A retrospective study was performed on all pediatric TBI patients aged 18 years or younger from January 2012 to July 2023 at a Level 1 Pediatric Trauma Center. The severity of TBI (BIG 1/2/3) was rated by review of initial cranial imaging by two independent observers. Inter-observer reliability was assessed. Predictions based on BIG criteria regarding repeat cranial imaging, ICU admission, and neurosurgical consultation were compared with observations from the cohort. Outcome data was collected, including neurosurgical intervention and mortality rate., Results: Three hundred fifty-nine patients were included with mean age of 5.3 years. Injury severity included 44 BIG 1 (12.2%), 170 BIG 2 (47.4%), and 145 BIG 3 injuries (40.4%). Inter-rater reliability was 96.4%. Neurosurgical consultation was obtained in all patients, though only predicted by guidelines in 40.4%. Repeat imaging was obtained in 166 BIG 1/2 patients, with an average of 1.3 CT scans and 0.8 MRIs/rapid MRIs per patient. ICU was utilized in 104 (77.6%) patients not recommended per BIG criteria. Ultimately, 37 patients, all BIG 3, required neurosurgical intervention; no neurosurgical interventions were required in those classified as BIG 1/2., Conclusions: BIG criteria can be applied to pediatric TBI with high inter-observer reliability and without formal neurosurgical training. Retrospective application of BIG predicted fewer imaging studies, ICU admissions, and neurosurgical consults without overlooking patients requiring neurosurgical intervention., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives : Acute heart failure (AHF) is a life-threatening condition frequently encountered in the emergency department (ED). Identifying reliable prognostic indicators for in-hospital mortality is crucial for risk stratification and the appropriate management of AHF patients. This study aimed to assess the most effective method for predicting in-hospital mortality among various physiological parameters in patients with AHF presenting to the ED. Additionally, the study evaluated the effectiveness of the RAM index-respiratory rate (RR), age, and mean arterial pressure (MAP)-derived from the shock index (SI) by replacing heart rate with RR, as a novel prognostic tool. This was compared with the SI and its other derivatives to predict in-hospital mortality in adult patients with AHF presenting to the ED. Materials and Methods : This is a retrospective study conducted in the ED of an urban medical center, enrolling adult patients with signs and symptoms of AHF, who met the epidemiological diagnosis criteria, between January 2017 and December 2021. Baseline physiological parameters, including the RR, heart rate, systolic blood pressure, and diastolic blood pressure, were recorded upon ED admission. The RAM index was calculated as the RR multiplied by the age divided by the MAP. Statistical analysis was performed, including univariate analysis, logistic regression, and receiver operating characteristic (ROC) curve analysis. Results : A total of 2333 patients were included in the study. A RAM index > 18.6 (area under ROC curve (AUROC): 0.81; 95% confidence interval (CI): 0.79-0.83) had a superior mortality discrimination ability compared to an SI > 0.77 (AUROC: 0.75; 95% CI: 0.72-0.77), modified shock index > 1.11 (AUROC: 0.75; 95% CI: 0.73-0.77), age shock index > 62.7 (AUROC: 0.74; 95% CI: 0.72-0.76), and age-modified shock index > 79.9 (AUROC: 0.75; 95% CI: 0.73-0.77). A RAM index > 18.6 demonstrated a 7.36-fold higher risk of in-hospital mortality with a sensitivity of 0.80, specificity of 0.68, and negative predictive value of 0.97. Conclusions : The RAM index is an effective tool to predict mortality in AHF patients presenting to the ED. Its superior performance compared to traditional SI-based parameters suggests that the RAM index can aid in risk stratification and the early identification of high-risk patients, facilitating timely and aggressive treatment strategies.

This paper presents the introduction, design, and experimental validation of two small helical antennae. These antennae are a component of the surface acoustic wave (SAW) sensor interrogation system, which has been miniaturized to operate at 915 MHz and aims to improve the performance of wireless passive SAW temperature-sensing applications. The proposed antenna designs are the normal-mode cylindrical helical antenna (CHA) and the hemispherical helical antenna (HSHA); both designed structures are developed for the ISM band, which ranges from 902 MHz to 928 MHz. The antennae exhibit resonance at 915 MHz with an operational bandwidth of 30 MHz for the CHA and 22 MHz for the HSHA. A notch occurs in the operating band, caused by the characteristics of the SAW sensor. The presence of this notch is crucial for the temperature measurement by aiding in calculating the frequency shifting of that notch. The decrement in the resonance frequency of the SAW sensor is about 66.67 kHz for every 10 °C, which is obtained by conducting the temperature measurement of the system model across temperature environments ranging from 30 °C to 90 °C to validate the variation in system performance.

Background: Traumatic brain injury (TBI) poses a significant health burden, particularly among pediatric populations, leading to long-term cognitive, physical, and psychosocial impairments. Timely transfer to specialized trauma centers is crucial for optimal management, yet the influence of socioeconomic factors, such as the Area Deprivation Index (ADI), on transfer patterns remains understudied., Methods: A retrospective study was conducted on pediatric TBI patients presenting to a Level I Pediatric Trauma Center between January 2012 and July 2023. Transfer status, distance, mode of transport, and clinical outcomes were analyzed in relation to ADI. Statistical analyses were performed using Student t-test and analysis of variance., Results: Of 359 patients, 53.5% were transferred from outside hospitals, with higher ADI scores observed in transfer patients (P<0.01). Air transport was associated with greater distances traveled and higher ADI compared to ground ambulance (P<0.01). Despite similarities in injury severity, intensive care unit admission rates differed between transfer modes, with no significant impact on mortality., Conclusions: High ADI patients were more likely to be transferred, suggesting disparities in access to specialized care. Differences in transfer modes highlight the influence of socioeconomic factors on logistical aspects. While transfer did not independently impact outcomes, disparities in intensive care unit admission rates were observed, possibly influenced by injury severity. Integrating socioeconomic data into clinical decision-making processes can inform targeted interventions to optimize care delivery and improve outcomes for all pediatric TBI patients. Prospective, multicenter studies are warranted to further elucidate these relationships., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have profoundly reshaped the treatment paradigm for non-small cell lung cancer (NSCLC). Despite these advancements, primary and secondary resistance to ICIs remain prevalent challenges in managing advanced NSCLC. Recent studies have highlighted the significant role of the tumor microenvironment (TME) in modulating treatment responses. This review aims to comprehensively examine the interactive roles of immune/stromal cells-such as T cells, B cells, neutrophils, macrophages, and CAFs within the TME, elucidating how these diverse cellular interactions contribute to immunotherapy resistance. It focuses on the dynamic interactions among diverse cell types such as the varying states of T cells under the influence of TME constituents like immune cells and cancer-associated fibroblasts (CAFs). By exploring the mechanisms involved in the complex cellular interactions, we highlight novel therapeutic targets and strategies aimed at overcoming resistance, thereby enhancing the efficacy of ICIs in NSCLC. Our synthesis of recent research provides critical insights into the multifaceted mechanisms of resistance and paves the way for the development of more effective, personalized treatment approaches., 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.)

(1) Background: Identifying acute aortic syndrome (AAS) and thoracic aortic aneurysm (TAA) in busy emergency departments (EDs) is crucial due to their life-threatening nature, necessitating timely and accurate diagnosis. (2) Methods: This retrospective case-control study was conducted in the ED of three hospitals. Adult patients visiting the ED between 1 January 2010 and 1 January 2020 with a chief complaint of chest or back pain were enrolled in the study. The collected chest radiography (CXRs) data were divided into training (80%) and testing (20%) datasets. The training dataset was trained by four different convolutional neural network (CNN) models. (3) Results: A total of 1625 patients were enrolled in this study. The InceptionV3 model achieved the highest F1 score of 0.76. (4) Conclusions: Analysis of CXRs using a CNN-based model provides a novel tool for clinicians to interpret ED patients with chest pain and suspected AAS and TAA. The integration of such imaging tools into ED could be considered in the future to enhance the diagnostic workflow for clinically fatal diseases.

Exfoliation of two-dimensional (2D) nanosheets from three-dimensional (3D) non-layered, non-van der Waals crystals represents an emerging strategy for materials engineering that could significantly increase the library of 2D materials. Yet, the exfoliation mechanism in which nanosheets are derived from crystals that are not intrinsically layered remains unclear. Here, we show that planar defects in the starting 3D boron material promote the exfoliation of 2D boron sheets-by combining liquid-phase exfoliation, aberration-corrected scanning transmission electron microscopy, Raman spectroscopy, and density functional theory calculations. We demonstrate that 2D boron nanosheets consist of a planar arrangement of icosahedral sub-units cleaved along the {001} planes of β-rhombohedral boron. Correspondingly, intrinsic stacking faults in 3D boron form parallel layers of faulted planes in the same orientation as the exfoliated nanosheets, reducing the {001} cleavage energy. Planar defects represent a potential engineerable pathway for exfoliating 2D sheets from 3D boron and, more broadly, the other covalently bonded materials., (© 2024. The Author(s).)

Glypican-3 (GPC3) is overexpressed in hepatocellular carcinomas and hepatoblastomas and represents an important therapeutic target but the biologic importance of GPC3 in liver cancer is unclear. To date, there are limited data characterizing the biological implications of GPC3 knockout (KO) in liver cancers that intrinsically express this target. Here, we report on the development and characterization of GPC3-KO liver cancer cell lines and compare to them to parental lines. GPC3-KO variants were established in HepG2 and Hep3B liver cancer cell lines using a lentivirus-mediated CRISPR/Cas9 system. We assessed the effects of GPC3 deficiency on oncogenic properties in vitro and in murine xenograft models. Downstream cellular signaling pathway changes induced by GPC3 deficiency were examined by RNAseq and western blot. To confirm the usefulness of the models for GPC3-targeted drug development, we evaluated the target engagement of a GPC3-selective antibody, GC33, conjugated to the positron-emitting zirconium-89 ( 89 Zr) in subcutaneous murine xenografts of wild type (WT) and KO liver cancer cell lines. Deletion of GPC3 significantly reduced liver cancer cell proliferation, migration, and invasion compared to the parental cell lines. Additionally, the tumor growth of GPC3-KO liver cancer xenografts was significantly slower compared with control xenografts. RNA sequencing analysis also showed GPC3-KO resulted in a reduction in the expression of genes associated with cell cycle regulation, invasion, and migration. Specifically, we observed the downregulation of components in the AKT/NFκB/WNT signaling pathways and of molecules related to cell cycle regulation with GPC3-KO. In contrast, pMAPK/ERK1/2 was upregulated, suggesting an adaptive compensatory response. KO lines demonstrated increased sensitivity to ERK (GDC09994), while AKT (MK2206) inhibition was more effective in WT lines. Using antibody-based positron emission tomography (immunoPET) imaging, we confirmed that 89 Zr-GC33 accumulated exclusively in GPC3-expression xenografts but not in GPC3-KO xenografts with high tumor uptake and tumor-to-liver signal ratio. We show that GPC3-KO liver cancer cell lines exhibit decreased tumorigenicity and altered signaling pathways, including upregulated pMAPK/ERK1/2, compared to parental lines. Furthermore, we successfully distinguished between GPC3+ and GPC3- tumors using the GPC3-targeted immunoPET imaging agent, demonstrating the potential utility of these cell lines in facilitating GPC3-selective drug development., Competing Interests: None., (AJCR Copyright © 2024.)

van der Waals heterojunctions based on transition-metal dichalcogenides (TMDs) offer advanced strategies for manipulating light-emitting and light-harvesting behaviors. A crucial factor determining the light-material interaction is in the band alignment at the heterojunction interface, particularly the distinctions between type-I and type-II alignments. However, altering the band alignment from one type to another without changing the constituent materials is exceptionally difficult. Here, utilizing Bi 2 O 2 Se with a thickness-dependent band gap as a bottom layer, we present an innovative strategy for engineering interfacial band configurations in WS 2 /Bi 2 O 2 Se heterojunctions. In particular, we achieve tuning of the band alignment from type-I (Bi 2 O 2 Se straddling WS 2 ) to type-II and finally to type-I (WS 2 straddling Bi 2 O 2 Se) by increasing the thickness of the Bi 2 O 2 Se bottom layer from monolayer to multilayer. We verified this band architecture conversion using steady-state and transient spectroscopy as well as density functional theory calculations. Using this material combination, we further design a sophisticated band architecture incorporating both type-I (WS 2 straddles Bi 2 O 2 Se, fluorescence-quenched) and type-I (Bi 2 SeO 5 straddles WS 2 , fluorescence-recovered) alignments in one sample through focused laser beam (FLB). By programming the FLB trajectory, we achieve a predesigned localized fluorescence micropattern on WS 2 without changing its intrinsic atomic structure. This effective band architecture design strategy represents a significant leap forward in harnessing the potential of TMD heterojunctions for multifunctional photonic applications.

Objective: This study aimed to propose treatment protocol and identify patterns of tillaux fractures using three-dimensional (3D) computed tomography (CT) analysis and to describe an effective reduction technique., Methods: Forty-two juvenile patients with tillaux fractures were evaluated with 3D-CT scan for fracture displacement pattern and received surgical treatment. Tillaux fragment was reduced by pushing the superomedial quadrant part of the fragment slightly downward towards the ankle joint from anterolateral to posteromedial through 5-mm skin incisions with mosquito forceps. A 4.0 cannulated screw was subsequently inserted from the anterolateral to the posteromedial side parallel to the ankle joint. We analysed the distance and direction of fracture displacement with 3D-CT before the surgery. Pre-operative and post-operative plain radiographs were evaluated., Results: Pre-operative 3D-CT analysis revealed a common fracture pattern, varus tilt, and external rotation of fragment. We achieved satisfactory reduction with residual fracture gaps less than 2 mm in 42 cases. Two cases had a 13-mm anterior gap that was reduced by mini-open reduction because of periosteal impingement. No significant clinical complications were found., Conclusion: The closed reduction technique developed based on the fracture pattern identified by 3D-CT anatomical analysis is safe and effective in treating tillaux fractures., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Acute lung injury is an acute inflammation disorder that disrupts the lung endothelial and epithelial barriers. In this study, we investigated the extracellular vesicles (EVs) obtained via priming inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ on canine adipose mesenchymal stem cells in improving their anti-inflammatory and/or immunosuppressive potential, and/or their ability to alleviate lipopolysaccharide-induced lung injury in vitro . We also explored the correlation between epithelial-to-mesenchymal transition and the inflammatory repressive effect of primed EVs. Using small RNA-Seq, we confirmed that miR-16 and miR-502 significantly increased in EVs from TNF-α and IFN-γ-primed canine adipose mesenchymal stem cells. The pro and anti-inflammatory cytokines were analyzed in a lipopolysaccharide-induced lung injury model and we found that the EV anti-inflammatory effect improved on priming with inflammatory cytokines. EVs obtained from primed stem cells effectively suppress endothelial-to-mesenchymal transition in a lung injury model. Our results suggest a potential therapeutic approach utilizing EVs obtained from adipose mesenchymal stem cells primed with TNF-α and IFN-γ against lung inflammation and endothelial to mesenchymal transition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lee, Jeong, Kim, Yun, Ahn, Chung and An.)

Aims: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM)., Methods: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL)., Results: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438)., Conclusions: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m 2 ) in a subsequent larger study., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: Results of initial endoscopic biopsy of gastric lesions often differ from those of the final pathological diagnosis. We evaluated whether an artificial intelligence-based gastric lesion detection and diagnostic system, ENdoscopy as AI-powered Device Computer Aided Diagnosis for Gastroscopy (ENAD CAD-G), could reduce this discrepancy., Materials and Methods: We retrospectively collected 24,948 endoscopic images of early gastric cancers (EGCs), dysplasia, and benign lesions from 9,892 patients who underwent esophagogastroduodenoscopy between 2011 and 2021. The diagnostic performance of ENAD CAD-G was evaluated using the following real-world datasets: patients referred from community clinics with initial biopsy results of atypia (n=154), participants who underwent endoscopic resection for neoplasms (Internal video set, n=140), and participants who underwent endoscopy for screening or suspicion of gastric neoplasm referred from community clinics (External video set, n=296)., Results: ENAD CAD-G classified the referred gastric lesions of atypia into EGC (accuracy, 82.47%; 95% confidence interval [CI], 76.46%-88.47%), dysplasia (88.31%; 83.24%-93.39%), and benign lesions (83.12%; 77.20%-89.03%). In the Internal video set, ENAD CAD-G identified dysplasia and EGC with diagnostic accuracies of 88.57% (95% CI, 83.30%-93.84%) and 91.43% (86.79%-96.07%), respectively, compared with an accuracy of 60.71% (52.62%-68.80%) for the initial biopsy results (P<0.001). In the External video set, ENAD CAD-G classified EGC, dysplasia, and benign lesions with diagnostic accuracies of 87.50% (83.73%-91.27%), 90.54% (87.21%-93.87%), and 88.85% (85.27%-92.44%), respectively., Conclusions: ENAD CAD-G is superior to initial biopsy for the detection and diagnosis of gastric lesions that require endoscopic resection. ENAD CAD-G can assist community endoscopists in identifying gastric lesions that require endoscopic resection., Competing Interests: Jinbae Park and Jiwoon Jeon are employees of Ainex Co., LTD. The other authors have no conflict of interest or financial arrangement that could potentially influence the presented research., (Copyright © 2024. Korean Gastric Cancer Association.)

This study developed a molecular classification model for cervical cancer using machine learning, integrating prognosis related biomarkers with clinical features. Analyzing 281 specimens, 27 biomarkers were identified, associated with recurrence and treatment response. The model identified four molecular subgroups: group 1 (OALO) with Overexpression of ATP5H and LOw risk; group 2 (LASIM) with low expression of ATP5H and SCP, indicating InterMediate risk; group 3 (LASNIM) characterized by Low expression of ATP5H, SCP, and NANOG, also at InterMediate risk; and group 4 (LASONH), with Low expression of ATP5H, and SCP, Over expression of NANOG, indicating High risk, and potentially aggressive disease. This classification correlated with clinical outcomes such as tumor stage, lymph node metastasis, and response to treatment, demonstrating that combining molecular and clinical factors could significantly enhance the prediction of recurrence and aid in personalized treatment strategies for cervical cancer., Competing Interests: None., (AJCR Copyright © 2024.)

Background : Research on the impact of reduced time to emergent surgery in trauma patients has yielded inconsistent results. Therefore, this study investigated the relationship between waiting emergent surgery time (WEST) and outcomes in trauma patients. Methods : This retrospective, multicenter study used data from the Tzu Chi Hospital trauma database. The primary clinical outcomes were in-hospital mortality, intensive care unit (ICU) admission, and prolonged hospital length of stay (LOS) of ≥30 days. Results : A total of 15,164 patients were analyzed. The median WEST was 444 min, with an interquartile range (IQR) of 248-848 min for all patients. Patients who died in the hospital had a shorter median WEST than did those who survived (240 vs. 446 min, p < 0.001). Among the trauma patients with a WEST of <2 h, the median time was 79 min (IQR = 50-100 min). No significant difference in WEST was observed between the survival and mortality groups for patients with a WEST of <120 min (median WEST: 85 vs. 78 min, p < 0.001). Multivariable logistic regression analysis revealed that WEST was not associated with an increased risk of in-hospital mortality (adjusted odds ratio [aOR] = 1.05, 95% confidence interval [CI] = 0.17-6.35 for 30 min ≤ WEST < 60 min; aOR = 1.12, 95% CI = 0.22-5.70 for 60 min ≤ WEST < 90 min; and aOR = 0.60, 95% CI = 0.13-2.74 for WEST ≥ 90 min). Conclusions : Our findings do not support the "golden hour" concept because no association was identified between the time to definitive care and in-hospital mortality, ICU admission, and prolonged hospital stay of ≥30 days.

The heterogeneity of etiology may serve as a crucial factor in the challenges of treatment, including the low response rate and the delay in establishing therapeutic effect. In the present study, we examined whether social experience since early life is one of the etiologies, with the involvement of the 5-HT1A receptors, and explored the potentially therapeutic action of the subchronic administration of buspirone, a partial 5-HT1A agonist. Rats were isolation reared (IR) since their weaning, and the depressive profile indexed by the forced-swim test (FST) was examined in adulthood. Nonspecific locomotor activity was used for the IR validation. Buspirone administration (1 mg/kg/day) was introduced for 14 days (week 9-11). The immobility score of the FST was examined before and after the buspirone administration. Tissue levels of serotonin (5-HT) and its metabolite 5-HIAA were measured in the hippocampus, the amygdala, and the prefrontal cortex. Efflux levels of 5-HT, dopamine (DA), and norepinephrine (NE) were detected in the hippocampus by brain dialysis. Finally, the full 5-HT1A agonist 8-OH-DPAT (0.5 mg/kg) was acutely administered in both behavioral testing and the dialysis experiment. Our results showed (i) increased immobility time in the FST for the IR rats as compared to the social controls, which could not be reversed by the buspirone administration; (ii) IR-induced FST immobility in rats receiving buspirone was corrected by the 8-OH-DPAT; and (iii) IR-induced reduction in hippocampal 5-HT levels can be reversed by the buspirone administration. Our data indicated the 5-HT1A receptor-linked early life social experience as one of the mechanisms of later life depressive mood.

Purpose: This study assesses the clinical performance of BTXBrain-Amyloid, an artificial intelligence-powered software for quantifying amyloid uptake in brain PET images., Methods: 150 amyloid brain PET images were visually assessed by experts and categorized as negative and positive. Standardized uptake value ratio (SUVR) was calculated with cerebellum grey matter as the reference region, and receiver operating characteristic (ROC) and precision-recall (PR) analysis for BTXBrain-Amyloid were conducted. For comparison, same image processing and analysis was performed using Statistical Parametric Mapping (SPM) program. In addition, to evaluate the spatial normalization (SN) performance, mutual information (MI) between MRI template and spatially normalized PET images was calculated and SPM group analysis was conducted., Results: Both BTXBrain and SPM methods discriminated between negative and positive groups. However, BTXBrain exhibited lower SUVR standard deviation (0.06 and 0.21 for negative and positive, respectively) than SPM method (0.11 and 0.25). In ROC analysis, BTXBrain had an AUC of 0.979, compared to 0.959 for SPM, while PR curves showed an AUC of 0.983 for BTXBrain and 0.949 for SPM. At the optimal cut-off, the sensitivity and specificity were 0.983 and 0.921 for BTXBrain and 0.917 and 0.921 for SPM12, respectively. MI evaluation also favored BTXBrain (0.848 vs. 0.823), indicating improved SN. In SPM group analysis, BTXBrain exhibited higher sensitivity in detecting basal ganglia differences between negative and positive groups., Conclusion: BTXBrain-Amyloid outperformed SPM in clinical performance evaluation, also demonstrating superior SN and improved detection of deep brain differences. These results suggest the potential of BTXBrain-Amyloid as a valuable tool for clinical amyloid PET image evaluation., Competing Interests: Conflict of InterestSeung Kwan Kang, Seong A Shin, and Jae Sung Lee are Brightonix Imaging Inc.’s employees. Mina Heo, Ji Yeon Chung, Daewoon Kim, Hongyoon Choi, Ari Chong, Jung-Min Ha, and Hoowon Kim declare that they have no conflict of interest., (© The Author(s) 2024.)

The CRISPR/Cas system has been introduced as an innovative tool for therapy, however achieving specific delivery to the target has been a major challenge. Here, an antibody-CRISPR/Cas conjugate platform that enables specific delivery and target gene editing in HER2-positive cancer is introduced. The CRISPR/Cas system by replacing specific residues of Cas9 with an unnatural amino acid is engineered, that can be complexed with a nanocarrier and bioorthogonally functionalized with a monoclonal antibody targeting HER2. The resultant antibody-conjugated CRISPR/Cas nanocomplexes can be specifically delivered and induce gene editing in HER2-positive cancer cells in vitro. It is demonstrated that the in vivo delivery of the antibody-CRISPR/Cas nanocomplexes can effectively disrupt the plk1 gene in HER2-positive ovarian cancer, resulting in substantial suppression of tumor growth. The current study presents a useful therapeutic platform for antibody-mediated delivery of CRISPR/Cas for the treatment of various cancers and genetic diseases., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background: Biomarkers that predict the treatment response in patients with knee osteoarthritis are scarce. This study aimed to investigate the potential role of synovial fluid cell counts and their ratios as biomarkers of primary knee osteoarthritis., Methods: This retrospective study investigated 96 consecutive knee osteoarthritis patients with knee effusion who underwent joint fluid aspiration analysis and received concomitant intra-articular corticosteroid injections and blood tests. The monocyte-to-lymphocyte ratio (MLR) and neutrophil-to-lymphocyte ratio (NLR) were calculated. After 6 months of treatment, patients were divided into two groups: the responder group showing symptom resolution, defined by a visual analog scale (VAS) score of ≤ 3, without additional treatment, and the non-responder group showing residual symptoms, defined by a VAS score of > 3 and requiring further intervention, such as additional medication, repeated injections, or surgical treatment. Unpaired t-tests and univariate and multivariate logistic regression analyses were conducted between the two groups to predict treatment response after conservative treatment. The predictive value was calculated using the area under the receiver operating characteristic curve, and the optimal cutoff value was determined., Results: Synovial fluid MLR was significantly higher in the non-responder group compared to the responder group (1.86 ± 1.64 vs. 1.11 ± 1.37, respectively; p = 0.02). After accounting for confounding variables, odds ratio of non-responder due to increased MLR were 1.63 (95% confidence interval: 1.11-2.39). The optimal MLR cutoff value for predicting patient response to conservative treatment was 0.941., Conclusions: MLR may be a potential biomarker for predicting the response to conservative treatment in patients with primary knee osteoarthritis., (© 2024. The Author(s).)

Importance: The portal vein to aorta (PV/Ao) ratio is used to assess the clinical significance of extrahepatic portosystemic shunt (EHPSS). Previous studies using computed tomography (CT) were conducted in dogs but not in cats., Objective: This study aimed to establish normal reference values for PV indices (PV/Ao ratio and PV diameter) in cats and determine the usefulness of these for predicting symptomatic EHPSS., Methods: This study included 95 dogs and 114 cats that underwent abdominal CT. The canine normal (CN) group included dogs without EHPSS. The cats were classified into feline normal (FN, 88/114), feline asymptomatic (FA, 16/114), and feline symptomatic (FS, 10/114) groups. The PV and Ao diameters were measured in axial cross-sections., Results: The group FN had a higher PV/Ao ratio than the group CN ( p < 0.001). Within the feline groups, the PV indices were in the order FN > FA > FS (both p < 0.001). The mean PV diameter and PV/Ao ratio for group FN were 5.23 ± 0.77 mm and 1.46 ± 0.19, respectively. The cutoff values between groups FN and FS were 4.115 mm for PV diameter (sensitivity, 100%; specificity, 97.7%) and 1.170 for PV/Ao ratio (90%, 92.1%). The cutoff values between group FA and FS were 3.835 mm (90%, 93.8%) and 1.010 (70%, 100%), respectively., Conclusions and Relevance: The results demonstrated significant differences in PV indices between dogs and cats. In cats, the PV/Ao ratio demonstrated high diagnostic performance for symptomatic EHPSS. The PV diameter also performed well, in contrast to dogs., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Korean Society of Veterinary Science.)

Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (C max,ss ) and area under plasma concentration-time curve over dosing interval at steady state (AUC τ,ss ) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in C max , 19% in AUC τ,ss ) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for C max,ss and AUC τ,ss was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Objectives : The Taiwan Triage and Acuity Scale (TTAS) is reliable for triaging patients in emergency departments in Taiwan; however, most triage decisions are still based on chief complaints. The reverse-shock index (SI) multiplied by the simplified motor score (rSI-sMS) is a more comprehensive approach to triage that combines the SI and a modified consciousness assessment. We investigated the combination of the TTAS and rSI-sMS for triage compared with either parameter alone as well as the SI and modified SI. Materials and Methods : We analyzed 13,144 patients with trauma from the Taipei Tzu Chi Trauma Database. We investigated the prioritization performance of the TTAS, rSI-sMS, and their combination. A subgroup analysis was performed to evaluate the trends in all clinical outcomes for different rSI-sMS values. The sensitivity and specificity of rSI-sMS were investigated at a cutoff value of 4 (based on previous study and the highest score of the Youden Index) in predicting injury severity clinical outcomes under the TTAS system were also investigated. Results : Compared with patients in triage level III, those in triage levels I and II had higher odds ratios for major injury (as indicated by revised trauma score < 7 and injury severity score [ISS] ≥ 16), intensive care unit (ICU) admission, prolonged ICU stay (≥14 days), prolonged hospital stay (≥30 days), and mortality. In all three triage levels, the rSI-sMS < 4 group had severe injury and worse outcomes than the rSI-sMS ≥ 4 group. The TTAS and rSI-sMS had higher area under the receiver operating characteristic curves (AUROCs) for mortality, ICU admission, prolonged ICU stay, and prolonged hospital stay than the SI and modified SI. The combination of the TTAS and rSI-sMS had the highest AUROC for all clinical outcomes. The prediction performance of rSI-sMS < 4 for major injury (ISS ≥ 16) exhibited 81.49% specificity in triage levels I and II and 87.6% specificity in triage level III. The specificity for mortality was 79.2% in triage levels I and II and 87.4% in triage level III. Conclusions : The combination of rSI-sMS and the TTAS yielded superior prioritization performance to TTAS alone. The integration of rSI-sMS and TTAS effectively enhances the efficiency and accuracy of identifying trauma patients at a high risk of mortality.

Templating is essential in hip arthroplasty preparation, facilitating implant size prediction and surgical rehearsal. It ensures the selection of suitable implants according to patient anatomy and disease, aiming to minimize post-operative complications. Various templating methods exist, including traditional acetate templating on both analog and digital images, alongside digital templating on digital images, which is categorized into 2D and 3D approaches. Despite the popularity of acetate templating on digital images, challenges such as the requirement for physical templates and result preservation persist. To address these limitations, digital templating with software like OrthoSize and Orthoview has been suggested, although not universally accessible. This technical note advocates for Microsoft PowerPoint as an effective alternative for 2D digital templating, highlighting its user-friendly features for image manipulation without needing specialized software. The described method involves scanning acetate templates, adjusting the images in PowerPoint 365 for size, position, and calibration on patient radiographs, and demonstrating reliability through preliminary assessments, with intraclass correlation coefficient (ICC) values indicating a high level of agreement for cup and stem size (ICC = 0.860, 0.841, respectively) but moderate for neck length (ICC = 0.592). We have introduced a method for performing 2D digital templating in the clinical field without the need for specialized software dedicated to digital templating. We believe this method significantly improves the accessibility to 2D digital templating, which was previously limited by the need for digital templating software. Additionally, it enables surgeons to easily establish arthroplasty plans and share them, overcoming the limitations of acetate templates.

Medical images are acquired through diverse imaging systems, with each system employing specific image reconstruction techniques to transform sensor data into images. In MRI, sensor data (i.e., k-space data) is encoded in the frequency domain, and fully sampled k-space data is transformed into an image using the inverse Fourier Transform. However, in efforts to reduce acquisition time, k-space is often subsampled, necessitating a sophisticated image reconstruction method beyond a simple transform. The proposed approach addresses this challenge by training a model to learn domain transform, generating the final image directly from undersampled k-space input. Significantly, to improve the stability of reconstruction from randomly subsampled k-space data, folded images are incorporated as supplementary inputs in the dual-input ETER-net. Moreover, modifications are made to the formation of inputs for the bi-RNN stages to accommodate non-fixed k-space trajectories. Experimental validation, encompassing both regular and irregular sampling trajectories, validates the method's effectiveness. The results demonstrated superior performance, measured by PSNR, SSIM, and VIF, across acceleration factors of 4 and 8. In summary, the dual-input ETER-net emerges as an effective both regular and irregular sampling trajectories, and accommodating diverse acceleration factors., 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 Ltd.. All rights reserved.)

Competing Interests: The authors have no conflict of interest to declare and no prior presentation.

Background: This study aimed to investigate the clinical outcomes of fixed-bearing medial unicompartmental knee arthroplasty (UKA) for tibia vara knees and the associated changes in joint space malalignment (JSM) and joint line obliquity (JLO)., Methods: We retrospectively analyzed a consecutive group of 100 patients who underwent fixed-bearing medial UKA with a preoperative medial proximal tibia angle (MPTA) ≥86° (n = 50) and MPTA <86° (n = 50) and who had a minimum 5-year follow-up. Radiological parameters, including the hip-knee-ankle angle, MPTA, and the postoperative JSM and JLO, were measured. Functional evaluation was performed using the range of motion, visual analog scale, Knee Society Knee Score, Knee Society Function Score, and Western Ontario and McMaster Universities Osteoarthritis Index score., Results: The MPTA <86° group showed significantly higher postoperative JLO (91.8 versus 90.4°, respectively; P = .002) and JSM (6.1 versus 4.2°, respectively; P = .026) compared to the MPTA ≥86° group. Functional outcomes, including range of motion, visual analog scale, Knee Society Knee Score, Knee Society Function Score, and Western Ontario and McMaster Universities Osteoarthritis Index scores, were not significantly different between the 2 groups., Conclusions: Fixed-bearing medial UKA is a safe and effective surgical option for patients who have tibia vara knees, as an increase in JLO and JSM postoperatively does not have a clinically relevant impact, even after a minimum 5-year follow-up., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Genetic variants affect drug responses, making pre-emptive genotyping crucial for averting serious adverse events (SAEs) and treatment failure. However, assessing the benefits of pre-emptive genotyping based on genetic distribution, drug exposure, and demographics is challenging. This study aimed to estimate the population-level benefits of pre-emptive genotyping in the Korean population using nationwide cohort data. We reviewed actionable gene-drug combinations recommended by both the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) as of February 2022, identifying high-risk phenotypes. We collected reported risk reduction from genotyping and standardized it into population attributable risks. Healthcare reimbursement costs for SAEs and treatment failures were obtained from the Health Insurance Review and Assessment Service Statistics in 2021. The benefits of pre-emptive genotyping for a specific group were determined by multiplying drug exposure from nationwide cohort data by individual genotyping benefits. We identified 31 gene-drug-event pairs, with CYP2D6 and CYP2C19 demonstrating the greatest benefits for both male and female patients. Individuals aged 65-70 years had the highest individual benefit from pre-emptive genotyping, with $84.40 for men and $100.90 for women. Pre-emptive genotyping, particularly for CYP2D6 and CYP2C19, can provide substantial benefits., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1β) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1β activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI., (© Andreia Morais et al., 2024; Published by Mary Ann Liebert, Inc.)

Cyclophilin B (CypB), encoded by peptidylprolyl isomerase B ( PPIB ), is involved in cellular transcriptional regulation, immune responses, chemotaxis, and proliferation. Recent studies have shown that PPIB/CypB is associated with tumor progression and chemoresistance in various cancers. However, the clinicopathologic significance and mechanism of action of PPIB/CypB in non-small cell lung cancer (NSCLC) remain unclear. In this study, we used RNA in situ hybridization to examine PPIB expression in 431 NSCLC tissue microarrays consisting of 295 adenocarcinomas (ADCs) and 136 squamous cell carcinomas (SCCs). Additionally, Ki-67 expression was evaluated using immunohistochemistry. The role of PPIB/CypB was assessed in five human NSCLC cell lines. There was a significant correlation between PPIB/CypB expression and Ki-67 expression in ADC (Spearman correlation r =0.374, P <0.001) and a weak correlation in SCC ( r =0.229, P =0.007). In ADCs, high PPIB expression (PPIB high ) was associated with lymph node metastasis ( P =0.023), advanced disease stage ( P =0.014), disease recurrence ( P =0.013), and patient mortality ( P =0.015). Meanwhile, high Ki-67 expression (Ki-67 high ) was correlated with male sex, smoking history, high pT stage, lymph node metastasis, advanced stage, disease recurrence, and patient mortality in ADC (all P <0.001). However, there was no association between either marker or clinicopathological factors, except for old age and PPIB high ( P =0.038) in SCC. Survival analyses revealed that the combined expression of PPIB high /Ki-67 high was an independent prognosis factor for poor disease-free survival (HR 1.424, 95% CI 1.177-1.723, P <0.001) and overall survival (HR 1.266, 95% CI 1.036-1.548, P =0.021) in ADC, but not in SCC. Furthermore, PPIB/CypB promoted the proliferation, colony formation, and migration of NSCLC cells. We also observed the oncogenic properties of PPIB/CypB expression in human bronchial epithelial cells. In conclusion, PPIB/CypB contributes to tumor growth in NSCLC, and elevated PPIB/Ki-67 levels are linked to unfavorable survival, especially in ADC., Competing Interests: None., (AJCR Copyright © 2024.)

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising immunotherapy for solid cancers; however, their effectiveness against pancreatic cancer is limited by the immunosuppressive tumor microenvironment. In particular, low NK cell infiltration poses a major obstacle that reduces cytotoxicity. The current study aimed to enhance the tumor-homing capacity of CAR-NK cells by targeting the chemokine-chemokine receptor axis between NK and pancreatic cancer cells. To this end, data from a chemokine array and The Cancer Genome Atlas pan-cancer cohort were analyzed. Pancreatic cancer cells were found to secrete high levels of ligands for C-X-C motif receptor 1 (CXCR1) and CXCR2. Subsequently, we generated anti-mesothelin CAR-NK cells incorporating CXCR1 or CXCR2 and evaluated their tumor-killing abilities in 2D cancer cell co-culture and 3D tumor-mimetic organoid models. CAR-NK cells engineered with CXCR2 demonstrated enhanced tumor killing and strong infiltration of tumor sites. Collectively, these findings highlight the potential of CXCR2-augmented CAR-NK cells as a clinically relevant modality for effective pancreatic cancer treatment. By improving their infiltration and tumor-killing capabilities, these CXCR2-augmented CAR-NK cells have the potential to overcome the challenges posed by the immunosuppressive tumor microenvironment, providing improved therapeutic outcomes., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Intermediate phase shifting is a footprint- and cost-reduction technique for reconfigurable feed networks. These feed networks are utilized in antenna arrays to perform electrical beam steering. In intermediate phase shifting, a phase shifter is shared between two adjacent antennas. Conventionally, antennas only have individual phase shifters. With shared phase shifters, we reduce the number of components and the footprint by 25%. Consequently, this decreases the price and enables designs at millimeter-wave frequencies where space is limited due to frequency-dependent antenna spacing. This intermediate phase shifting is demonstrated by designing a reconfigurable feed network for the Ka -band that generates a continuous phase shift profile for beam steering. Due to the use of varactors and a novel biasing method, it does not require expensive beamformer integrated chips or lumped components for biasing. The feed network is combined with a 4 × 4 antenna array to demonstrate its beam-steering capabilities. The result is a high-density and minimalistic design that fits in a small volume of 25.6 × 25.6 × 0.95 mm 3 . With this small antenna array, the main beam is steered at ±40∘ broadside, providing full 1D and restricted 2D steering. It is a potential candidate for wireless sensor and mobile networks.

Background: The reverse shock index (rSI) combined with the Simplified Motor Score (sMS), that is, the rSI-sMS, is a novel and efficient prehospital triage scoring system for patients with COVID-19. In this study, we evaluated the predictive accuracy of the rSI-sMS for general ward and intensive care unit (ICU) admission among patients with COVID-19 and compared it with that of other measures, including the shock index (SI), modified SI (mSI), rSI combined with the Glasgow Coma Scale (rSI-GCS), and rSI combined with the GCS motor subscale (rSI-GCSM)., Methods: All patients who visited the emergency department of Taipei Tzu Chi Hospital between January 2021 and June 2022 were included in this retrospective cohort. A diagnosis of COVID-19 was confirmed through a SARS-CoV-2 reverse-transcription polymerase chain reaction test or SARS-CoV-2 rapid test with oropharyngeal or nasopharyngeal swabs and was double confirmed by checking International Classification of Diseases, Tenth Revision, Clinical Modification codes in electronic medical records. In-hospital mortality was regarded as the primary outcome, and sepsis, general ward or ICU admission, endotracheal intubation, and total hospital length of stay (LOS) were regarded as secondary outcomes. Multivariate logistic regression was used to determine the relationship between the scoring systems and the three major outcomes of patients with COVID-19, including. The discriminant ability of the predictive scoring systems was investigated using the area under the receiver operating characteristic curve, and the most favorable cutoff value of the rSI-sMS for each major outcome was determined using Youden's index., Results: After 74,183 patients younger than 20 years (n = 11,572) and without COVID-19 (n = 62,611) were excluded, 9,282 patients with COVID-19 (median age: 45 years, interquartile range: 33-60 years, 46.1% men) were identified as eligible for inclusion in the study. The rate of in-hospital mortality was determined to be 0.75%. The rSI-sMS scores were significantly lower in the patient groups with sepsis, hyperlactatemia, admission to a general ward, admission to the ICU, total length of stay ≥ 14 days, and mortality. Compared with the SI, mSI, and rSI-GCSM, the rSI-sMS exhibited a significantly higher accuracy for predicting general ward admission, ICU admission, and mortality but a similar accuracy to that of the rSI-GCS. The optimal cutoff values of the rSI-sMS for predicting general ward admission, ICU admission, and mortality were calculated to be 3.17, 3.45, and 3.15, respectively, with a predictive accuracy of 86.83%, 81.94%%, and 90.96%, respectively., Conclusions: Compared with the SI, mSI, and rSI-GCSM, the rSI-sMS has a higher predictive accuracy for general ward admission, ICU admission, and mortality among patients with COVID-19., (© 2024. The Author(s).)

Background and Objectives : The coronavirus disease 2019 (COVID-19) pandemic has profoundly impacted healthcare systems worldwide. To assess the effects of the pandemic on pediatric emergency department (ED) visits in Taiwan, we conducted a study to evaluate changes in pediatric ED visits during the COVID-19 pandemic. Materials and Methods : This retrospective study included pediatric patients (age ≤ 18) who visited the ED between 21 January 2019 and 30 April 2019, at three hospitals of the Cathay Health System, and compared them with a corresponding period in 2020. Basic information, including mode of arrival, triage level, disposition, chief complaints, and incidence rates, were analyzed before and during the pandemic. Results : A total of 10,116 patients, with 6009 in the pre-pandemic group and 4107 in the pandemic group, were included in this study. The mean number of daily pediatric ED visits decreased from 60.09 before the pandemic to 40.66 during the pandemic, while ambulance use increased significantly by 2.56%. The percentage of patients with high acuity triage levels (levels 1 and 2) was significantly lower during the pandemic period (0.63% and 10.18%, respectively) than the pre-pandemic period (0.7% and 10.9%, respectively). Additionally, a significantly higher proportion of patients were discharged during the pandemic period (89.36%) than during the pre-pandemic period (88.33%). The proportion of COVID-19-related complaints, such as fever and respiratory tract infections, as well as other complaints including gastrointestinal issues, trauma, and psychological problems, significantly increased during the pandemic. Conclusions : In preparation for future pandemics, we recommend increasing emergency medical service capacity, establishing a non-contagious route for obtaining chronic medication prescriptions, optimizing staff allocation in pediatric emergency departments, and increasing the number of hospital social workers for enhanced support.