Recombinant Human IL-32θ Induces Polarization Into M1-like Macrophage in Human Monocytic Cells.

The tumor microenvironment (TME) is formed by several immune cells. Notably, tumor-associated macrophages (TAMs) are existed in the TME that induce angiogenesis, metastasis, and proliferation of cancer cells. Recently, a point-mutated variant of IL-32θ was discovered in breast cancer tissues, which suppressed migration and proliferation through intracellular pathways. Although the relationship between cancer and IL-32 has been previously studied, the effects of IL-32θ on TAMs remain elusive. Recombinant human IL-32θ (rhIL-32θ) was generated using an Escherichia coli expression system. To induce M0 macrophage polarization, THP-1 cells were stimulated with PMA. After PMA treatment, the cells were cultured with IL-4 and IL-13, or rhIL-32θ. The mRNA level of M1 macrophage markers (IL-1ß, TNFα, inducible nitric oxide synthase) were increased by rhIL-32θ in M0 macrophages. On the other hand, the M2 macrophage markers (CCL17, CCL22, TGFß, CD206) were decreased by rhIL-32θ in M2 macrophages. rhIL-32θ induced nuclear translocation of the NF-κB via regulation of the MAPK (p38) pathway. In conclusion, point-mutated rhIL-32θ induced the polarization to M1-like macrophages through the MAPK (p38) and NF-κB (p65/p50) pathways.

Trends in Hospital Stay, Complication Rate, and Mortality in Hip Fracture Patients: A Two-Decade Comparison at a National Tertiary Referral Center.

Background: Since the turn of the century, the age-adjusted incidence of proximal femoral fractures has caused a plateau or fall. However, it was anticipated that the number of patients with proximal femoral fractures would rise as life expectancy rose and the population over 80 years old expanded. The aim of this study was to compare the length of hospital stay, complication rate, and mortality in patients with proximal femoral fractures between two different time periods: 20 years ago and the present. Methods: We conducted a retrospective review of medical records of patients aged 65 years and above who underwent surgery for proximal femoral fractures between January 2000 and December 2001 and between January 2020 and December 2021. We collected information on age, gender, fracture type, length of hospital stay, and complication rate. Dates of death were obtained from the Ministry of the Interior and Safety. Results: We included 136 patients who were operated on between 2000 and 2001 and 134 patients between 2020 and 2021. The average age increased significantly from 71.6 years to 79.0 years (p < 0.001). The length of hospital stay decreased dramatically from 15.1 days to 6.0 days (p < 0.001). There was no statistically significant difference in delirium, urinary tract infection, or pneumonia. No difference was found in 30-day or 1-year mortality between the two groups. Conclusions: The complication rate and mortality between the two time periods appeared comparable, although the length of hospital stay decreased substantially. Therefore, we recommend considering expedited discharge from the acute care hospital for elderly hip fracture patients while implementing an individualized approach for better outcomes.

Mitral Valve Repair with Leaflet Resection versus Preservation for Degenerative Posterior Leaflet Prolapse.

OBJECTIVES: The optimal technique for repairing posterior mitral valve (MV) leaflet (PMVL) prolapse remains undetermined. We aimed to compare leaflet resection and neo-chordae implantation in patients undergoing MV repair for posterior leaflet prolapse, focusing on trans-mitral pressure gradient (PG) and recurrence of mitral regurgitation (MR). METHODS: We enrolled patients undergoing MV repair using either leaflet resection or neo-chordae implantation for single-segment prolapse of PMVL between 2000 and 2021 at our institution. Longitudinal outcomes were evaluated after adjustments with inverse-probability-of-treatment weighting (IPTW). Repeat echocardiographic measurements (n=3,473, 5.4/patient) of trans-mitral PG and significant (moderate or severe) MR recurrence were estimated using nonlinear mixed-effect models. Subgroup analyses were conducted based on the size and type of prosthesis. RESULTS: Among 639 patients, leaflet resection was used in 479 (75.0%) and neo-chordae implantation in 160 (25.0%). In the IPTW-adjusted cohort, the risk of death (P=0.623) and MV reoperation (P=0.340) did not significantly differ between the two groups during a median follow-up of 97.3 months. Echocardiographic data showed comparable mean (at 5 years, 3.8 vs. 4.0 mmHg; P=0.442) and peak (9.6 vs. 10.4mmHg; P=0.131) PGs between groups, which persisted in most subgroup analyses. However, neo-chordae implantation was associated with a higher probability of significant MR recurrence compared to leaflet resection (at 5 years, 16.1% vs. 7.0%; P<0.001). CONCLUSIONS: Leaflet resection yielded similar clinical outcomes and trans-mitral PGs compared to neo-chordae implantation after MV repair, with a lower MR recurrence rate. These findings underscore the need to reassess the efficacy of neo-chordae implantation relative to leaflet resection.

The prognostic role of aspartate transaminase to platelet ratio index on outcomes after nonemergent major hepatectomy.

INTRODUCTION: Noninvasive screening methods to identify patients preoperatively with abnormal liver texture remain limited. Aspartate transaminase to platelet ratio index has been validated to predict fibrosis in patients with hepatitis C; however, its use as a predictor of postoperative outcomes in patients without viral hepatitis remains unknown. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program dataset to identify patients who underwent a major hepatectomy between 2014 and 2021. We excluded patients who underwent emergent operations, patients with viral hepatitis, and patients with ascites. Aspartate transaminase to platelet ratio index was calculated using the following equation: (aspartate transaminase/40)/(platelet count) × 100. An aspartate transaminase to platelet ratio index ≥0.7 was used to identify patients with significant fibrosis. Univariable analysis was performed to identify factors associated with aspartate transaminase to platelet ratio index ≥0.7, perioperative transfusion, serious morbidity, overall morbidity, and 30-day mortality. Multivariable logistic regression analysis was performed to identify adjusted predictors of these outcomes. RESULTS: Of the 8,933 patients who met inclusion criteria, 1,170 (13.1%) patients had an aspartate transaminase to platelet ratio index ≥0.7. A perioperative blood transfusion was administered to 2,497 (28.0%). The number of patients who experienced overall morbidity, serious morbidity, and mortality were 3,195 (35.8%), 2,665 (29.8%), and 238 (2.7%), respectively. Aspartate transaminase to platelet ratio index ≥0.7 was an independent predictor of transfusion (odds ratio: 1.51 [1.32-1.72], P < .001), overall morbidity (1.16 [1.01-1.33], P = .032), and mortality (1.56 [1.12-2.13], P = .006). Transfusion was an independent predictor of overall morbidity (2.50 [2.26-2.76], P < .001), serious morbidity (2.51 [2.26-2.79], P < .001), and mortality (3.28 [2.49-4.33], P < .001). CONCLUSION: An aspartate transaminase to platelet ratio index ≥0.7 is associated with perioperative transfusion, overall morbidity, and 30-day mortality. The aspartate transaminase to platelet ratio index may serve as a noninvasive tool to risk stratify patients before elective major hepatectomy.

Clinical Utility of Tumor-Naïve Pre-surgical ctDNA Detection in Early-stage NSCLC.

PURPOSE: The use of tumor-informed circulating tumor DNA (ctDNA) testing in early-stage patients before surgery is limited mainly due to restricted tissue access and extended turnaround times. This study aimed to evaluate the clinical value of a tumor-naïve, methylation-based cell-free DNA assay in a large cohort of patients with resected non-small cell lung cancer (NSCLC). METHOD: We analyzed pre-surgical plasma samples from 895 patients with EGFR and ALK-wild-type, clinical stage I or II NSCLC. The ctDNA status was evaluated for its prognostic significance in relation to tumor volume, metabolic activity, histology, histological subtypes, and clinical-to-pathological TNM upstaging. RESULTS: Pre-surgical ctDNA detection was observed in 55 out of 414 (13%) patients with clinical stage I lung adenocarcinoma (LUAD) and was associated with poor recurrence-free survival (RFS) (2-year RFS 69% versus 91%; log-rank P<0.001), approaching that of clinical stage II LUAD. Pre-surgical ctDNA detection was not prognostic in patients with clinical stage II LUAD or non-LUAD. Within LUAD, tumor volume and positron emission tomography avidity interacted to predict pre-surgical ctDNA detection. Moreover, pre-surgical ctDNA detection was predictive of the post-surgical discovery of IASLC G3 tumors (P<0.001) and pathological TNM upstaging (P<0.001). Notably, pre-surgical ctDNA detection strongly correlated with higher PD-L1 expression in tumors (positive rates 28% vs. 55%, P<0.001), identifying a subgroup likely to benefit from anti-PD-(L)-1 therapies. CONCLUSION: These findings support the integration of ctDNA testing into routine diagnostic workflows in early-stage NSCLC without the need of tumor tissue profiling. Furthermore, it is clinically useful in identifying high-risk patients who might benefit from innovative treatments, including neoadjuvant immune checkpoint inhibitors.

Factors Associated with Postoperative Recurrence in Stage I to IIIA Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation: Analysis of Korean National Population Data.

Purpose: Recent development in perioperative treatment of resectable non-small cell lung cancer (NSCLC) have changed the landscape of early lung cancer management. The ADAURA trial has demonstrated the efficacy of adjuvant osimertinib treatment in resectable NSCLC patients; however, studies are required to show which subgroup of patients are at a high risk of relapse and require adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. This study evaluated risk factors for postoperative relapse among patients who underwent complete resection. Materials and Methods: Data were obtained from the Korean Association for Lung Cancer Registry (KALC-R), a database created using a retrospective sampling survey by the Korean Central Cancer Registry (KCCR) and the Lung Cancer Registration Committee. Results: A total of 3,176 patients who underwent curative resection was evaluated. The mean observation time was approximately 35.4 months. Among stage I to IIIA NSCLC patients, the EGFR-mutant subgroup included 867 patients, and 75.2%, 11.2%, and 11.8% were classified as stage I, stage II, and stage III, respectively. Within the EGFR-mutant subgroup, 44 (5.1%) and 121 (14.0%) patients showed early and late recurrence, respectively. Multivariate analysis on association with postoperative relapse among the EGFR-mutant subgroup showed that age, pathologic N and TNM stages, pleural invasion status, and surgery type were independent significant factors. Conclusion: Among the population that underwent complete resection for early NSCLC with EGFR mutation, patients with advanced stage, pleural invasion, or limited resection are more likely to show postoperative relapse.

Impact of multidrug resistance on outcomes in hematologic cancer patients with bacterial bloodstream infections.

Despite the improved outcomes in patients with hematological malignancies, infections caused by multidrug-resistant organisms (MDROs) pose a new threat to these patients. We retrospectively reviewed the patients with hematological cancer and bacterial bloodstream infections (BSIs) at a tertiary hospital between 2003 and 2022 to assess the impact of MDROs on outcomes. Among 328 BSIs, 81 (24.7%) were caused by MDROs. MDRO rates increased from 10.3% (2003-2007) to 39.7% (2018-2022) (P < 0.001). The 30-day mortality rate was 25.0%, which was significantly higher in MDRO-infected patients than in non-MDRO-infected patients (48.1 vs. 17.4%; P < 0.001). The observed trend was more pronounced in patients with newly diagnosed diseases and relapsed/refractory disease but less prominent in patients in complete remission. Among MDROs, carbapenem-resistant Gram-negative bacteria exhibited the highest mortality, followed by vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and extended-spectrum ß-lactamase-producing Enterobacteriaceae. Multivariate analysis identified independent risk factors for 30-day mortality as age ≥ 65 years, newly diagnosed disease, relapsed/refractory disease, MDROs, polymicrobial infection, CRP ≥ 20 mg/L, and inappropriate initial antibiotic therapy. In conclusion, MDROs contribute to adverse outcomes in patients with hematological cancer and bacterial BSIs, with effects varying based on the underlying disease status and causative pathogens. Appropriate initial antibiotic therapy may improve patient outcomes.

Longitudinal multiomic profiling and corticosteroid modulation of the immediate innate immune response to an adenovirus-vector vaccine.

Among new vaccine technologies contributed to the control of the COVID-19 pandemic, ChAdOx1 nCoV-19, a chimpanzee adenovirus (ChAd)-vector vaccine expressing the SARS-CoV-2 spike protein, could be administered globally owing to its low production cost and lack of a requirement for frozen storage. Despite its benefits, most recipients have reported immediate inflammatory reactions after the initial dose vaccination. We comprehensively examined the immune landscape following ChAdOx1 nCoV-19 vaccination based on the single-cell transcriptomes of immune cells and epigenomic profiles of monocytes. Monocyte and innate-like activated T cell populations expressing interferon-stimulated genes (ISGs) increased 1 day post-vaccination with appearance of distinct subtype of ISG-activated cells, returning to baseline by day 14. Pre-treatment with oral corticosteroids effectively curtailed these ISG-associated inflammatory responses by decreasing chromatin accessibility of major ISGs, without hampering vaccine immunogenicity. Our findings provide insights into the human immune response following ChAd-based vaccination and propose a method to reduce inflammatory side effects.

Association between metabolic dysfunction-associated steatotic liver disease and myosteatosis measured by computed tomography.

BACKGROUND: In 2023, the concept of metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced as an alternative to non-alcoholic fatty liver disease (NAFLD). We aimed to assess the quantity and quality of skeletal muscle using each of these diagnostic classifications. METHODS: This cross-sectional study included 18 154 participants (11 551 [63.6%] men and 6603 [36.4%] women, mean age 53.0 ± 8.8). The participants were classified into four categories: neither steatotic liver disease (SLD), NAFLD only, MASLD only or both SLDs. An appendicular skeletal muscle mass adjusted for body mass index of <0.789 for men and <0.512 for women was defined as sarcopenia. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area and intermuscular/intramuscular adipose tissue. Myosteatosis was defined by a T-score < -1.0 of the NAMA/TAMA index, which was calculated by dividing the NAMA by the TAMA and multiplying by 100. RESULTS: Using subjects with neither SLD as a reference, the multivariable-adjusted odds ratios (ORs) for sarcopenia were significantly increased in those with MASLD, with adjusted ORs (95% confidence interval [CI]) of 2.62 (1.94-3.54) in the MASLD-only group and 2.33 (1.92-2.82) in the both SLDs group, while the association was insignificant in those with NAFLD only (adjusted OR [95% CI]: 2.16 [0.67-6.94]). The OR for myosteatosis was also elevated in the MASLD groups, with an OR (95% CI) of 1.75 (1.52-2.02) in subjects with MASLD only and 1.70 (1.57-1.84) in those with both SLDs, while it was slightly decreased in subjects with NAFLD only (0.52 [0.29-0.95]). CONCLUSIONS: Employing the MASLD concept rather than that of the NAFLD proved to be more effective in distinguishing individuals with reduced muscle mass and compromised muscle quality.

The Microbiological Characteristics of Acinetobacter Baumannii Associated With Early Mortality in Patients With Bloodstream Infection.

Background: Despite rapid deaths resulting from Acinetobacter baumannii bacteremia, the clinical impact of the microbiological characteristics of A baumannii strains on early mortality (EM) is unclear. We aimed to identify the microbiological characteristics of A baumannii strains associated with EM. Methods: Clinical information and isolates from patients with A baumannii bacteremia from January 2015 to December 2021 were collected. EM was defined as death within 3 days of the initial positive blood culture, whereas late mortality meant death within 5-30 days. The microbiological characteristics of A baumannii were analyzed using multilocus sequence typing, polymerase chain reactions, and a Galleria mellonella in vivo infection model. Results: Among 130 patients, 69 (53.1%) died within 30 days and EM occurred in 38 (55.1% of 30-day deaths). Sequence type 191 (ST191) strain was more prevalent in patients with EM than in 30-day survivors (31.6% vs 6.6%). Regarding virulence genes, bfmS was more frequent (92.1% vs 47.5%), whereas bauA was less frequent (13.2% vs 52.5%) in patients with EM than in 30-day survivors. Higher clinical severity, pneumonia, and ST191 infection were identified as independent risk factors for EM. In the G mellonella infection model, ST191, bfmS+, and bauA- isolates showed higher virulence than non-ST191, bfmS-, and bauA+ isolates, respectively. Conclusions: ST191 and bfmS were more frequently found in the EM group. ST191 infection was also an independent risk factor for EM and highly virulent in the in vivo model. Tailored infection control measures based on these characteristics are necessary for A baumannii bacteremia management.

Amplifying Photochromic Response in Tungsten Oxide Films with Titanium Oxide and Polyvinylpyrrolidone.

Tungsten oxide (WO3) is known for its photochromic properties, making it useful for smart windows, displays, and sensors. However, its small bandgap leads to rapid recombination of electron-hole pairs, resulting in poor photochromic performance. This study aims to enhance the photochromic properties of WO3 by synthesizing hexagonal tungsten oxide via hydrothermal synthesis, which increases surface area and internal hydrates. Titanium oxide (TiO2) was adsorbed onto the tungsten oxide to inject additional charges and reduce electron-hole recombination. Additionally, polyvinylpyrrolidone (PVP) was used to improve dispersion in organic solvents, allowing for the fabrication of high-quality films using the doctor blade method. Characterization confirmed the enhanced surface area, crystal structure, and dispersion stability. Reflectance and transmittance measurements demonstrated significant improvements in photochromic properties due to the composite structure. These findings suggest that the introduction of TiO2 and PVP to tungsten oxide effectively enhances its photochromic performance, broadening its applicability in various advanced photochromic applications.

Limited impact of bacterial virulence on early mortality risk factors in Acinetobacter baumannii bacteremia observed in a Galleria mellonella model.

Acinetobacter baumannii (AB) has emerged as a major pathogen in vulnerable and severely ill patients. It remains unclear whether early mortality (EM) due to AB bacteremia is because of worse clinical characteristics of the infected patients or the virulence of the pathogen. In this study, we aimed to investigate the effect of AB virulence on EM due to bacteremia. This retrospective study included 138 patients with AB bacteremia (age: ≥ 18 years) who were admitted to a tertiary care teaching hospital in South Korea between 2015 and 2019. EM was defined as death occurring within 7 days of bacteremia onset. The AB clinical isolates obtained from the patients' blood cultures were injected into 15 Galleria mellonella larvae each, which were incubated for 5 days. Clinical isolates were classified into high- and low-virulence groups based on the number of dead larvae. Patients' clinical data were combined and subjected to multivariate Cox regression analyses to identify the risk factors for EM. In total, 48/138 (34.8%) patients died within 7 days of bacteremia onset. The Pitt bacteremia score was the only risk factor associated with EM. In conclusion, AB virulence had no independent effect on EM in patients with AB bacteremia.

Practice pattern and risk of not receiving planned surgery after neoadjuvant chemoradiotherapy for locally advanced oesophageal squamous cell carcinoma.

OBJECTIVES: Unlike the initial plan, some patients with oesophageal squamous cell carcinoma cannot or do not receive surgery after neoadjuvant chemoradiotherapy (nCRT). This study aimed to report the epidemiology of patients not receiving surgery after nCRT and to evaluate the potential risk of refusing surgery. METHODS: We analysed patients with clinical stage T3-T4aN0M0 or T1-T4aN1-N3M0 oesophageal squamous cell carcinoma who underwent nCRT as an initial treatment intent between January 2005 and March 2020. Patients not receiving surgery were categorized using predefined criteria. To evaluate the risk of refusing surgery, a propensity-matched comparison with those who received surgery was performed. Recurrence-free (RFS) and overall survival (OS) was compared between groups, according to clinical response to nCRT. RESULTS: Among the study population (n = 715), 105 patients (14.7%) eventually failed to reach surgery. There were three major patterns of not receiving surgery: disease progression before surgery (n = 25), functional deterioration at reassessment (n = 47), and patient's refusal without contraindications (n = 33). After propensity-score matching, the RFS curves of the surgery group and the refusal group were significantly different (P < 0.001), while OS curves were not significantly different (P = 0.069). In patients who achieved clinical complete response on re-evaluation, no significant difference in the RFS curves (P = 0.382) and in the OS curves (P = 0.290) was observed between the surgery group and the refusal group. However, among patients who showed partial response or stable disease on re-evaluation, the RFS and OS curves of the refusal group were overall significantly inferior compared to those of the surgery group (both P < 0.001). The 5-year RFS rates were 10.3% for the refusal group and 48.2% for the surgery group, and the 5-year OS rates were 8.2% for the refusal group and 46.1% for the surgery group. CONCLUSIONS: Patient's refusal remains one of the major obstacles in completing the trimodality therapy for oesophageal squamous cell carcinoma. Refusing surgery when offered may jeopardize oncological outcome, particularly in those with residual disease on re-evaluation after nCRT. These results provide significant implications for consulting patients who are reluctant to oesophagectomy after nCRT.

Enhancing Identification of High-Risk cN0 Lung Adenocarcinoma Patients Using MRI-Based Radiomic Features.

Purpose: To develop an MRI-based radiomics model to predict high-risk pathologic features for lung adenocarcinoma: micropapillary and solid pattern (MPsol), spread through air space (STAS), and poorly differentiated patterns. Materials and Methods: As a prospective study, we screened clinical N0 lung cancer patients who were surgical candidates and had undergone both 18F-fluorodeoxyglucose (FDG) positron emission tomography-CT (PET/CT) and chest CT from August 2018 to January 2020. We recruited patients meeting our proposed imaging criteria indicating high-risk, that is, poorer prognosis of lung adenocarcinoma, using CT and FDG PET/CT. If possible, these patients underwent an MRI examination from which we extracted 77 radiomics features from T1-contrast-enhanced and T2-weighted images. Additionally, patient demographics, SUVmax (maximum standardized uptake value) on FDG PET/CT, and the mean ADC value on DWI, were considered together to build prediction models for high-risk pathologic features. Results: Among 616 patients, 72 patients met the imaging criteria for high-risk lung cancer and underwent lung MRI. The MR-eligible group showed a higher prevalence of nodal upstaging (29.2% vs. 4.2%, p<0.001), vascular invasion (6.5% vs. 2.1%, p=0.011), high-grade pathologic features (p<0.001), worse 4-year disease free survival (p<0.001) compared with non-MR-eligible group. The prediction power for MR-based radiomics model predicting high-risk pathologic features was good, with mean area under the receiver operating curve (AUC) value measuring 0.751-0.886 in test sets. Adding clinical variables increased the predictive performance for MPsol and the poorly differentiated pattern using the 2021 grading system (AUC 0.860 and 0.907, respectively). Conclusion: Our imaging criteria can effectively screen high-risk lung cancer patients and predict high-risk pathologic features by our MR-based prediction model using radiomics.

Comparative Analysis of Clinical Characteristics and Prognosis Between Primary Lung Cancers Identified as Screening Detected and Incidentally Detected Pulmonary Nodules.

BACKGROUND/AIM: Although the importance of low-dose computed tomography (LDCT) screening is increasingly emphasized and implemented, many lung cancers continue to be incidentally detected during routine medical practices, and data on incidentally detected lung cancer (IDLC) remain scarce. This study aimed to investigate the clinical characteristics and prognosis of IDLCs by comparing them with screening-detected lung cancers (SDLCs). PATIENTS AND METHODS: In this retrospective study, subjects with cT1 (≤3 cm) pulmonary nodules detected on baseline computed tomography (CT), later pathologically confirmed as primary lung cancer in 2015, were included. Patients were categorized into IDLC and SDLC groups based on the setting of the first pulmonary nodule detection. RESULTS: Out of 457 subjects, 129 (28.2%) were IDLCs and 328 (71.8%) were SDLCs. The IDLC group, consisted of older individuals with a higher prevalence of smokers and underlying pulmonary disease, compared to the SDLC group. Adenocarcinomas were more frequently detected in SDLCs (87.5%) than in IDLCs (76.7%, p<0.001). The time to treatment initiation (TTI) and 5-year overall survival (OS) rates were similar. Multivariate analyses revealed underlying interstitial lung disease, DLCO, solidity of nodules and TNM stage as independent risk factors associated with mortality. Less than 30% of study participants would have been eligible for the current lung cancer screening program. CONCLUSION: The IDLC group was associated with older age, higher rate of smokers, underlying pulmonary disease, and non-adenocarcinoma histology. However, prognosis was similar to that of the SDLC group, attributable to the similarity in TNM stage, strict adherence to guidelines, and short TTI. Furthermore, less than 30% of the participants would have been suitable for the existing lung cancer screening program, indicating a potential need to reconsider the scope for screening candidates.

The TOX-RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases.

Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.

Tumor-intrinsic and Cancer-associated Fibroblast Subtypes Independently Predict Outcomes in Pancreatic Cancer.

OBJECTIVE: To assess the utility of tumor-intrinsic and cancer-associated fibroblast (CAF) subtypes of pancreatic ductal adenocarcinoma (PDAC) in predicting response to neoadjuvant therapy (NAT) and overall survival. BACKGROUND: PDAC remains a deadly disease with limited treatment options, and both the tumor as well as the microenvironment play an important role in pathogenesis. Gene expression-based tumor-intrinsic subtypes (classical and basal-like) have been shown to predict outcomes, but tumor microenvironment subtypes are still evolving. METHODS: RNA-sequencing was performed on 114 deidentified resected PDAC tumors. Clinical data were collected by retrospective chart review. Single sample classifiers (SSCs) were used to determine classical and basal-like subtypes as well as tumor-permissive permCAF and tumor-restraining restCAF subtypes. Survival was analyzed using log-rank test. RESULTS: Patients who received NAT had an increase in overall survival (OS), with median survival of 27.9 months compared to 20.1 months for those who did not receive NAT, but the difference did not reach statistical significance (HR 0.64, P=0.076). Either tumor-intrinsic or CAF subtypes alone were associated with OS regardless of NAT or no NAT, and patients with classical or restCAF subtype had the best outcomes. When evaluated together, patients with classical-restCAF subtype had the best OS and basal-permCAF the worst OS (P<0.0001). NAT patients with classical-restCAF subtype demonstrated the longest OS compared to the other groups (P=0.00041). CONCLUSIONS: CAF subtypes have an additive effect over tumor-intrinsic subtypes in predicting survival with or without neoadjuvant FOLFIRINOX in PDAC. Molecular subtyping of both tumor and CAF compartments of PDAC may be important steps in selecting first-line systemic therapy.

Assessing the Reproducibility of the Structured Abstracts Generated by ChatGPT and Bard Compared to Human-Written Abstracts in the Field of Spine Surgery: Comparative Analysis.

BACKGROUND: Due to recent advances in artificial intelligence (AI), language model applications can generate logical text output that is difficult to distinguish from human writing. ChatGPT (OpenAI) and Bard (subsequently rebranded as "Gemini"; Google AI) were developed using distinct approaches, but little has been studied about the difference in their capability to generate the abstract. The use of AI to write scientific abstracts in the field of spine surgery is the center of much debate and controversy. OBJECTIVE: The objective of this study is to assess the reproducibility of the structured abstracts generated by ChatGPT and Bard compared to human-written abstracts in the field of spine surgery. METHODS: In total, 60 abstracts dealing with spine sections were randomly selected from 7 reputable journals and used as ChatGPT and Bard input statements to generate abstracts based on supplied paper titles. A total of 174 abstracts, divided into human-written abstracts, ChatGPT-generated abstracts, and Bard-generated abstracts, were evaluated for compliance with the structured format of journal guidelines and consistency of content. The likelihood of plagiarism and AI output was assessed using the iThenticate and ZeroGPT programs, respectively. A total of 8 reviewers in the spinal field evaluated 30 randomly extracted abstracts to determine whether they were produced by AI or human authors. RESULTS: The proportion of abstracts that met journal formatting guidelines was greater among ChatGPT abstracts (34/60, 56.6%) compared with those generated by Bard (6/54, 11.1%; P<.001). However, a higher proportion of Bard abstracts (49/54, 90.7%) had word counts that met journal guidelines compared with ChatGPT abstracts (30/60, 50%; P<.001). The similarity index was significantly lower among ChatGPT-generated abstracts (20.7%) compared with Bard-generated abstracts (32.1%; P<.001). The AI-detection program predicted that 21.7% (13/60) of the human group, 63.3% (38/60) of the ChatGPT group, and 87% (47/54) of the Bard group were possibly generated by AI, with an area under the curve value of 0.863 (P<.001). The mean detection rate by human reviewers was 53.8% (SD 11.2%), achieving a sensitivity of 56.3% and a specificity of 48.4%. A total of 56.3% (63/112) of the actual human-written abstracts and 55.9% (62/128) of AI-generated abstracts were recognized as human-written and AI-generated by human reviewers, respectively. CONCLUSIONS: Both ChatGPT and Bard can be used to help write abstracts, but most AI-generated abstracts are currently considered unethical due to high plagiarism and AI-detection rates. ChatGPT-generated abstracts appear to be superior to Bard-generated abstracts in meeting journal formatting guidelines. Because humans are unable to accurately distinguish abstracts written by humans from those produced by AI programs, it is crucial to exercise special caution and examine the ethical boundaries of using AI programs, including ChatGPT and Bard.

Computed Tomography Evaluation of Alumina Ceramic-on-Ceramic Total Hip Arthroplasty With More Than 20 years of Follow-Up: Is a Follow-Up Computed Tomography Scan Necessary?

BACKGROUND: Ceramic-on-ceramic (CoC) bearings have been increasingly used in total hip arthroplasty (THA) because of their superior wear resistance and biocompatibility. However, there is a scarcity of reports on the computed tomography (CT) evaluation of CoC bearings with more than 10 years. The aim of this study was to evaluate the long-term CT results of THA using CoC bearings for more than 20 years of follow-up. We hypothesized that there would be no wear, osteolysis, or ceramic fracture. METHODS: Between November 1997 and June 2003, 956 hips underwent THA using alumina-on-alumina bearings at a tertiary referral hospital. Among them, 107 hips were assessed, all of which underwent a CT examination more than 20 years after the index surgery. The mean age at the time of surgery was 41 years, and a CT scan was performed at an average of 22.0 years postoperatively (range, 20.0 to 25.1). The CT scans were thoroughly assessed for osteolysis, stem notching, and ceramic component fracture. RESULTS: No loosening was observed in the acetabular cup or femoral stem. Stem notching was observed in 3 hips (2.8%). In the CT scan taken after a minimum of 20 years of follow-up, 1 case (0.9%) of osteolysis around the cup and 2 cases (1.9%) of osteolysis around the femoral stem were noted. Suspected chip fractures of the ceramic insert were discovered in 4 cases (3.7%). Despite these findings, the patients remained asymptomatic, and no subsequent surgical intervention was needed after close follow-up. CONCLUSIONS: Routine CT examinations for patients who underwent THA using CoC bearings over 20 years ago revealed unexpected findings, such as osteolysis and suspected chip fractures of the ceramic liner. However, routine CT scans may not be universally necessary. The CT evaluation in this cohort should be selectively performed for patients who have relevant clinical symptoms. LEVEL OF EVIDENCE: Level III, Therapeutic study.