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Recent advances in technology for hyper-realistic visual and audio effects provoke the concern that deepfake videos of political speeches will soon be indistinguishable from authentic video. We conduct 5 pre-registered randomized experiments with N = 2215 participants to evaluate how accurately humans distinguish real political speeches from fabrications across base rates of misinformation, audio sources, question framings with and without priming, and media modalities. We do not find base rates of misinformation have statistically significant effects on discernment. We find deepfakes with audio produced by the state-of-the-art text-to-speech algorithms are harder to discern than the same deepfakes with voice actor audio. Moreover across all experiments and question framings, we find audio and visual information enables more accurate discernment than text alone: human discernment relies more on how something is said, the audio-visual cues, than what is said, the speech content.

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OBJECTIVES: To evaluate the treatment outcomes in patients with advanced-stage olfactory neuroblastoma (ONB) who received induction chemotherapy (IC). MATERIALS AND METHODS: The clinical data of 38 patients with advanced-stage ONB who received initial IC were retrospectively analyzed. The response was defined using the Response Evaluation Criteria in Solid Tumors version 1.1. Patients with complete remission or partial remission were defined as responders. RESULTS: Seventeen (44.7%) patients responded to IC. The response rate was higher in patients with high Hyams grade tumor (III/IV) compared to those with low-grade tumors (I/II) (60% vs. 22.2%, p = 0.038). Overall, the 5-year cancer-specific survival (CSS) rate was 76.0%. Among nonresponders to IC, a significant difference in 5-year CSS rates was observed between surgery with adjuvant radiotherapy (RT) (100%) versus definitive RT or chemoradiotherapy (CRT) (68.6%) (log-rank p = 0.006). However, for responders, there was no significant difference in 5-year CSS rates between surgery with adjuvant therapy (75%) and definitive RT or CRT (51.1%) (log-rank p = 0.536). When only high-grade tumors were considered among responders, the 5-year CSS rate was significantly higher in patients who received RT or CRT (51.4%) compared to those who underwent surgery with adjuvant therapy (0%) (log-rank p = 0.008). CONCLUSION: In advanced-stage ONB, RT or CRT may be preferable for high-grade tumor responding to IC. Higher response rate and a potential role for induction IC in determining the optimal definitive treatment modality suggest a positive role for advanced-stage high-grade ONB.

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Hip fractures remain a substantial health concern, particularly among elderly individuals with osteoporosis, leading to high global mortality rates. This study aimed to analyze the association between body mass index (BMI) and postoperative mortality in patients who underwent surgery for hip fractures. A total of 680 patients treated at a single institution between January 2018 and December 2022 were included. Factors such as age, BMI, sex, Charlson Comorbidity Index (CCI), preoperative hemoglobin levels, American Society of Anesthesiologists score, anesthesia method, duration of surgery, and time from injury to surgery were assessed. Underweight status, male sex, higher CCI, and general anesthesia were significantly associated with 1-year and in-hospital mortality. Notably, underweight individuals exhibited a higher risk of mortality than normal-weight individuals, and female patients had lower mortality rates. This study underscores the importance of considering BMI, along with other demographic and clinical factors, in predicting postoperative mortality among patients with hip fractures, aiding the development of tailored management strategies to improve outcomes and reduce complications in this vulnerable patient population.

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OBJECTIVES: Sinonasal squamous cell carcinoma (SqCC) often invades the orbit. The treatment approach for sinonasal cancer that has spread to the orbit varies across medical centers and depends on the extent of the invasion. The decision to preserve the orbit in the treatment strategy is made on a case-by-case basis and. RESULTS: in varying outcomes. Currently, a multimodal treatment regimen, which may include surgery, chemotherapy, radiotherapy (RT), or concurrent chemoradiotherapy (CCRT), is commonly adopted for managing sinonasal cancers. This study aims to assess the prognosis of sinonasal SqCC with orbital invasion from various perspectives. METHODS: We conducted a retrospective review of patients with primary sinonasal SqCC invading the orbit who were treated at Seoul National University Hospital and Seoul National University Bundang Hospital between 2009 and 2018. The extent of the tumor, orbital invasion, treatment strategies, recurrence rates, and survival rates were analyzed. RESULTS: Overall survival and disease-free survival (DFS) rates showed no significant differences based on the grade of orbital invasion. When tumor resection with orbit preservation was employed as the definitive treatment, DFS was significantly extended compared to cases where surgery was not the definitive treatment (RT or CCRT). Additionally, there was no significant difference in DFS between patients who underwent orbit exenteration and those who underwent tumor resection with orbit preservation as the definitive treatment. CONCLUSION: Tumor resection with orbit preservation as the definitive treatment appears to be the preferred approach, prolonging DFS and increasing the likelihood of longer-term survival in cases of SqCC with orbital invasion.

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Treatment assessment and patient outcome for sepsis depend predominantly on the timely administration of appropriate antibiotics1-3. However, the clinical protocols used to stratify and select patient-specific optimal therapy are extremely slow4. In particular, the major hurdle in performing rapid antimicrobial susceptibility testing (AST) remains in the lengthy blood culture procedure, which has long been considered unavoidable due to the limited number of pathogens present in the patient's blood. Here we describe an ultra-rapid AST method that bypasses the need for traditional blood culture, thereby demonstrating potential to reduce the turnaround time of reporting drug susceptibility profiles by more than 40-60 h compared with hospital AST workflows. Introducing a synthetic beta-2-glycoprotein I peptide, a broad range of microbial pathogens are selectively recovered from whole blood, subjected to species identification or instantly proliferated and phenotypically evaluated for various drug conditions using a low-inoculum AST chip. The platform was clinically evaluated by the enrolment of 190 hospitalized patients suspected of having infection, achieving 100% match in species identification. Among the eight positive cases, six clinical isolates were retrospectively tested for AST showing an overall categorical agreement of 94.90% with an average theoretical turnaround time of 13 ± 2.53 h starting from initial blood processing.

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Peptidoglycan DL-endopeptidases locally cleave the peptide stem of peptidoglycan in the bacterial cell wall. This process facilitates bacterial growth and division by loosening the rigid peptidoglycan layer. IseA binds to the active site of multiple DL-endopeptidases and inhibits excessive peptidoglycan degradation that leads to cell lysis. To better understand how IseA inhibits DL-endopeptidase activity, we determined the crystal structure of the peptidoglycan DL-endopeptidase CwlO/IseA complex and compared it with that of the peptidoglycan DL-endopeptidase LytE/IseA complex. Structural analyses showed significant differences between the hydrophobic pocket-binding residues of the DL-endopeptidases (F361 of CwlO and W237 of LytE). Additionally, binding assays showed that the F361 mutation of CwlO to the bulkier hydrophobic residue, tryptophan, increased its binding affinity for IseA, whereas mutation to alanine reduced the affinity. These analyses revealed that the hydrophobic pocket-binding residue of DL-endopeptidases determines IseA-binding affinity and is required for substrate-mimetic inhibition by IseA.

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Background: Kidney transplantation (KT) improves physical and psychological prognoses for patients with end-stage kidney disease (ESKD). However, few comparative studies have examined depression and suicide rates among patients with ESKD treated with dialysis versus KT. Methods: Data on 21,809 patients with ESKD were extracted from the Korean National Health Insurance Service database, extending from January 2002 to December 2018. These patients exhibited no history of depression or insomnia before starting renal replacement therapy. Outcomes were compared between dialysis and KT recipients using 1:2 propensity score matching (PSM). Results: Of the patients, 17,649 received dialysis (hemodialysis, 15,537; peritoneal dialysis, 2,112), while 4,160 underwent KT. Of those on dialysis, 45.04% (7,949) experienced insomnia, compared to 25.72% (1,070) of KT recipients (P<0.001). Depression was more frequent among dialysis recipients (22.77%, 4,019) than KT recipients (8.61%, 358; P<0.001). Additionally, those on dialysis had a higher incidence of suicide (0.19%, 33) than recipients of KT (0.12%, 5; P=0.047). After PSM, the hazard ratio (HR) for depression in patients on dialysis compared to KT recipients was 1.76 (95% confidence interval [CI], 1.56-1.99). In subgroup analysis, the relative likelihood of depression among dialysis recipients was particularly high for residents of urban areas (HR, 2.10; 95% CI, 1.80-2.44) and patients under 65 years old (HR, 1.82; 95% CI, 1.62-2.09). Conclusions: KT recipients exhibit a lower suicide rate than patients on dialysis. Furthermore, KT is associated with a lower prevalence of depression among Korean patients with ESKD, particularly urban residents and individuals under 65 years old.

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In gram-positive bacteria, phosphorylated arginine functions as a protein degradation signal in a similar manner as ubiquitin in eukaryotes. The protein-arginine phosphorylation is mediated by the McsAB complex, where McsB possesses kinase activity and McsA modulates McsB activity. Although mcsA and mcsB are regulated within the same operon, the role of McsA in kinase activity has not yet been clarified. In this study, we determined the molecular mechanism by which McsA regulates kinase activity. The crystal structure of the McsAB complex shows that McsA binds to the McsB kinase domain through a second zinc-coordination domain and the subsequent loop region. This binding activates McsB kinase activity by rearranging the catalytic site, preventing McsB self-assembly, and enhancing stoichiometric substrate binding. The first zinc-coordination and coiled-coil domains of McsA further activate McsB by reassembling the McsAB oligomer. These results demonstrate that McsA is the regulatory subunit for the reconstitution of the protein-arginine kinase holoenzyme. This study provides structural insight into how protein-arginine kinase directs the cellular protein degradation system.

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Nasal endoscopy is routinely performed to distinguish the pathological types of masses. There is a lack of studies on deep learning algorithms for discriminating a wide range of endoscopic nasal cavity mass lesions. Therefore, we aimed to develop an endoscopic-examination-based deep learning model to detect and classify nasal cavity mass lesions, including nasal polyps (NPs), benign tumors, and malignant tumors. The clinical feasibility of the model was evaluated by comparing the results to those of manual assessment. Biopsy-confirmed nasal endoscopic images were obtained from 17 hospitals in South Korea. Here, 400 images were used for the test set. The training and validation datasets consisted of 149,043 normal nasal cavity, 311,043 NP, 9,271 benign tumor, and 5,323 malignant tumor lesion images. The proposed Xception architecture achieved an overall accuracy of 0.792 with the following class accuracies on the test set: normal = 0.978 ± 0.016, NP = 0.790 ± 0.016, benign = 0.708 ± 0.100, and malignant = 0.698 ± 0.116. With an average area under the receiver operating characteristic curve (AUC) of 0.947, the AUC values and F1 score were highest in the order of normal, NP, malignant tumor, and benign tumor classes. The classification performances of the proposed model were comparable with those of manual assessment in the normal and NP classes. The proposed model outperformed manual assessment in the benign and malignant tumor classes (sensitivities of 0.708 ± 0.100 vs. 0.549 ± 0.172, 0.698 ± 0.116 vs. 0.518 ± 0.153, respectively). In urgent (malignant) versus nonurgent binary predictions, the deep learning model achieved superior diagnostic accuracy. The developed model based on endoscopic images achieved satisfactory performance in classifying four classes of nasal cavity mass lesions, namely normal, NP, benign tumor, and malignant tumor. The developed model can therefore be used to screen nasal cavity lesions accurately and rapidly.

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Therapeutic antibodies that block vascular endothelial growth factor (VEGF) show clinical benefits in treating nonsmall cell lung cancers (NSCLCs) by inhibiting tumor angiogenesis. Nonetheless, the therapeutic effects of systemically administered anti-VEGF antibodies are often hindered in NSCLCs because of their limited distribution in the lungs and their adverse effects on normal tissues. These challenges can be overcome by delivering therapeutic antibodies in their mRNA form to lung endothelial cells, a primary target of VEGF-mediated pulmonary angiogenesis, to suppress the NSCLCs. In this study, we synthesized derivatives of poly(ß-amino esters) (PBAEs) and prepared nanoparticles to encapsulate the synthetic mRNA encoding bevacizumab, an anti-VEGF antibody used in the clinic. Optimization of nanoparticle formulations resulted in a selective lung transfection after intravenous administration. Notably, the optimized PBAE nanoparticles were distributed in lung endothelial cells, resulting in the secretion of bevacizumab. We analyzed the protein corona on the lung- and spleen-targeting nanoparticles using proteomics and found distinctive features potentially contributing to their organ-selectivity. Lastly, bevacizumab mRNA delivered by the lung-targeting PBAE nanoparticles more significantly inhibited tumor proliferation and angiogenesis than recombinant bevacizumab protein in orthotopic NSCLC mouse models, supporting the therapeutic potential of bevacizumab mRNA therapy and its selective delivery through lung-targeting nanoparticles. Our proof-of-principle results highlight the clinical benefits of nanoparticle-mediated mRNA therapy in anticancer antibody treatment in preclinical models.

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OBJECTIVES: Due to the rarity of olfactory neuroblastoma (ONB), there is ongoing debate about optimal treatment strategies, especially for early-stage or locally advanced cases. Therefore, our study aimed to explore experiences from multiple centers to identify factors that influence the oncological outcomes of ONB. METHODS: We retrospectively analyzed 195 ONB patients treated at nine tertiary hospitals in South Korea between December 1992 and December 2019. Kaplan-Meier survival analysis was used to evaluate oncological outcomes, and a Cox proportional hazards regression model was employed to analyze prognostic factors for survival outcomes. Furthermore, we conducted 1:1 nearest-neighbor matching to investigate differences in clinical outcomes according to the use of neoadjuvant chemotherapy. RESULTS: In our cohort, the 5-year overall survival (OS) rate was 78.6%, and the 5-year disease-free survival (DFS) rate was 62.4%. The Cox proportional hazards model revealed that the modified Kadish (mKadish) stage and Dulguerov T status were significantly associated with DFS, while the mKadish stage and Hyams grade were identified as prognostic factors for OS. The subgroup analyses indicated a trend toward improved 5-year DFS with dural resection in mKadish A and B cases, even though the result was statistically insignificant. Induction chemotherapy did not provide a survival benefit in this study after matching for the mKadish stage and nodal status. CONCLUSION: Clinical staging and pathologic grading are important prognostic factors in ONB. Dural resection in mKadish A and B did not show a significant survival benefit. Similarly, induction chemotherapy also did not show a survival benefit, even after stage matching.

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SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor has aggressive nature with a poor prognosis. Patients with this disease were diagnosed by immunohistochemistry or next-generation sequencing. Those who were able to receive a surgery tended to be cured, while the others treated with chemotherapy, radiation therapy, or immune checkpoint inhibitor were often insensitive to these therapies. However, one having CD274 (PD-L1) amplification showed the response to immune checkpoint inhibitor and a good prognosis. We believed that this report could provide promising information for determining the optimal treatment option.

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Objectives: This study aimed to evaluate the characteristics and treatment outcomes of inverted papillomas involving the frontal sinus. Methods: Patients treated for inverted papilloma involving the frontal sinus between 2003 and 2020 were reviewed. Tumors were classified based on their extent (Extent 1: partially encroaching on the frontal sinus; Extent 2: completely filling the frontal sinus; Extent 3: eroding bony borders beyond the frontal sinus) and site of origin (Origin 1: originating outside the frontal sinus and prolapsing into the frontal sinus; Origin 2: originating from the frontal sinus walls medial to the vertical plane of the lamina papyracea; Origin 3: originating from the frontal sinus walls lateral to the vertical plane of the lamina papyracea). Treatment outcomes including tumor recurrence and patency of the frontal recess were analyzed according to tumor characteristics and surgical treatment modalities. Results: A total of 49 surgical cases were analyzed. Extent 1 were the most common type (n = 27), followed by Extent 2 (n = 15), and Extent 3 (n = 7). The most common sites of origin were Origin 1 (n = 23), followed by Origin 2 (n = 15), and Origin 3 (n = 11). Overall, there were nine recurrences (18.4%). Recurrence was not associated with tumor extent, whereas tumor origin, particularly Origin 3 was associated with higher recurrence; 1/23 (4.3%) for Origin 1, 3/15 (20.0%) for Origin 2, and 5/11 (45.5%) for Origin 3 (Log-rank p < .001). Draf III frontal sinusotomy was associated with in the highest patency rate (84.6%) during the follow-up. Conclusion: The recurrence rate of frontal sinus inverted papilloma depends on tumor origin rather than the extent of the tumor. In particular, lesions originating from the frontal sinus lateral to the lamina papyracea recur frequently. Draf III frontal sinusotomy can achieve patent frontal recess allowing active surveillance. Level of Evidence: IV.

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Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with ß-glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin-induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. ß-Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with ß-glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of ß-glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury-mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury-mediated disorders.

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Abstract Introduction Contact granulomas (CGs) and intubation granulomas (IGs) are known to have different clinical manifestations despite having the same pathological features. Objectives The purpose of the present study was to analyze the treatment results for CG and IG and to obtain clinical information. Methods We retrospectively reviewed the medical records of patients diagnosed with vocal process granuloma (VPG) between January 2015 and December 2018. The patient's age, sex, medical history, lesion size, lesion type, reflux finding score (RFS), response to treatment, duration of treatment, and follow-up period were compared. Results Eighteen patients with CG and 14 patients with IG were included in the study. The IG group had more female patients (p = 0.0009), showed better response to proton pump inhibitor (PPI) and steroid inhalation (SI) (p = 0.036), and had a shorter treatment period (p = 0.0029) than the CG group. Five patients who received botulinum toxin injections in their vocal cords had complete remission. Conclusions Compared with CG, IG was more responsive to treatment with PPI and SI and required a shorter duration of treatment.

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The gasdermins are a family of pore-forming proteins that has recently been suggested to play a central role in pyroptosis. In this study, we describe the novel roles of gasdermins in the biogenesis of apoptotic cell-derived exosomes. In apoptotic human HeLa and HEK293 cells, GSDMA, GSDMC, GSDMD, and GSDME increased the release of apoptotic exosomes. GSDMB and DFNB59, in contrast, negatively affected the release of apoptotic exosomes. GSDME at its full-length and cleaved forms was localized in the exosomes and exosomal membrane. Full-length and cleaved forms of GSDME are suggested to increase Ca2+ influx to the cytosol through endosomal pores and thus increase the biogenesis of apoptotic exosomes. In addition, the GSDME-mediated biogenesis of apoptotic exosomes depended on the ESCRT-III complex and endosomal recruitment of Ca2+-dependent proteins, that is, annexins A2 and A7, the PEF domain family proteins sorcin and grancalcin, and the Bro1 domain protein HD-PTP. Therefore, we propose that the biogenesis of apoptotic exosomes begins when gasdermin-mediated endosomal pores increase cytosolic Ca2+, continues through the recruitment of annexin-sorcin/grancalcin-HD-PTP, and is completed when the ESCRT-III complex synthesizes intraluminal vesicles in the multivesicular bodies of dying cells. Finally, we found that GSDME-bearing tumors released apoptotic exosomes to induce inflammatory responses in the in vivo mouse 4T1 orthotropic model of BALB/c breast cancer. The data indicate that the switch from apoptosis to pyroptosis could drive the transfer of mass signals to nearby or distant living cells and tissues by way of extracellular vesicles, and that gasdermins play critical roles in that process.

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Introduction Contact granulomas (CGs) and intubation granulomas (IGs) are known to have different clinical manifestations despite having the same pathological features. Objective The purpose of the present study was to analyze the treatment results for CG and IG and to obtain clinical information. Methods We retrospectively reviewed the medical records of patients diagnosed with vocal process granuloma (VPG) between January 2015 and December 2018. The patient's age, sex, medical history, lesion size, lesion type, reflux finding score (RFS), response to treatment, duration of treatment, and follow-up period were compared. Results Eighteen patients with CG and 14 patients with IG were included in the study. The IG group had more female patients ( p = 0.0009), showed better response to proton pump inhibitor (PPI) and steroid inhalation (SI) ( p = 0.036), and had a shorter treatment period ( p = 0.0029) than the CG group. Five patients who received botulinum toxin injections in their vocal cords had complete remission. Conclusion Compared with CG, IG was more responsive to treatment with PPI and SI and required a shorter duration of treatment.

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Imaging an object embedded within a scattering medium requires the correction of complex sample-induced wave distortions. Existing approaches have been designed to resolve them by optimizing signal waves recorded in each 2D image. Here, we present a volumetric image reconstruction framework that merges two fundamental degrees of freedom, the wavelength and propagation angles of light waves, based on the object momentum conservation principle. On this basis, we propose methods for exploiting the correlation of signal waves from volumetric images to better cope with multiple scattering. By constructing experimental systems scanning both wavelength and illumination angle of the light source, we demonstrated a 32-fold increase in the use of signal waves compared with that of existing 2D-based approaches and achieved ultrahigh volumetric resolution (lateral resolution: 0.41 [Formula: see text], axial resolution: 0.60 [Formula: see text]) even within complex scattering medium owing to the optimal coherent use of the broad spectral bandwidth (225 nm).

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BACKGROUND: The lateral pharyngeal wall (LPW) is a critical anatomic structure in patients with obstructive sleep apnea (OSA). Resolving the retropalatal circumferential (RC) narrowing caused by combination of both LPW collapse and antero-posterior (AP) narrowing holds promise for surgical treatment of OSA. We sought to determine the clinical characteristics and distinctive alterations in sleep parameters of patients with OSA who have RC narrowing and LPW collapse. METHODS: Drug-induced sleep endoscopy (DISE), polysomnography findings, and sleep questionnaires were reviewed retrospectively in patients with OSA. RESULTS: Of the 106 OSA patients examined, 48% showed RC narrowing and 44% showed AP narrowing at the oropharynx level during sleep while 8% of the patients showed only LPW collapse. Patients with RC narrowing with LPW collapse exhibited a higher BMI than those with AP narrowing only. In addition, patients with RC narrowing showed more aggravated sleep parameters including apneic events than patients with AP narrowing alone. The degree of RC narrowing correlated significantly with the severity of OSA as shown by a higher apnea index and lower oxygen desaturations. CONCLUSIONS: Our clinical findings suggest that the presence of RC narrowing with LPW collapse in OSA is closely related to increased apneic and oxygen desaturation events. RC narrowing with LPW collapse may be targets for surgical correction in patients with OSA to improve therapeutic outcomes.

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This study aimed to evaluate the alteration of PAP compliance after nasal surgery and to determine the optimal indications of nasal surgery in obstructive sleep apnea (OSA) subjects. Among OSA subjects using PAP devices, 29 subjects who underwent septoturbinoplasty due to nasal obstruction were included and their pre- and postoperative medical and PAP records were reviewed retrospectively. Postoperative autoPAP usage data was further assessed by grouping the compliance (the percentage of days with usage ≥ 4 h) data (group 1: the good compliance group; group 2: the poor compliance group). The data showed that 56% of subjects in group 1 complained of nasal obstruction as the only barrier to using a PAP device and about 89% reported experiencing the efficacy of PAP usage. Both the mean and peak average PAP pressures were significantly reduced in group 1 following nasal surgery. Group 2 had multiple subjective problems that interfered with wearing a PAP device and reported a lack of experiencing the efficacy of PAP usage. Preoperative nasal cavity volume values were smaller and absolute blood eosinophil counts were significantly lower in group 1. The current data demonstrate that nasal surgery might increase the compliance of PAP device wear in OSA subjects who complained of only nasal obstruction as a barrier to wearing PAP and who had small nasal cavity volumes combined with allergic inflammation.

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