Clinical Implications of Polypharmacy for Patients with New-Onset Atrial Fibrillation Based on Real-World Data: Observations from the Korea National Health Insurance Service Data.

Background: Polypharmacy is commonly observed in atrial fibrillation (AF) and is associated with poorer clinical outcomes. Our study aimed to elucidate the polypharmacy prevalence, its associated risk factors, and its relationship with adverse clinical outcomes using a 'real-world' database. Methods: This study included 451,368 subjects without prior history of AF (median age, 54 [interquartile range, 48.0-63.0] years; 207,748 [46.0%] female) from the Korea National Health Insurance Service-Health Screening (NHIS-HealS) database between 2002 and 2013. All concomitant medications prescribed were collected, and the intake of five or more concomitant drugs was defined as polypharmacy. During the follow-up, all-cause death, major bleeding events, transient ischemic attack (TIA) or ischemic stroke, and admission due to worsened heart failure were recorded. Results: Based on up to 7.7 (6.8-8.3) years of follow-up and 768,306 person-years, there were 12,241 cases of new-onset AF identified. Among patients with new-onset AF (40.0% females, median age 63.0 [54.0-70.0] years), the polypharmacy prevalence was 30.9% (3784). For newly diagnosed AF, factors, such as advanced age (with each increase of 10 years, odds ratios (OR) 1.32, 95% confidence interval (CI) 1.26-1.40), hypertension (OR 4.00, 95% CI 3.62-4.43), diabetes mellitus (OR 3.25, 95% CI 2.86-3.70), chronic obstructive pulmonary disease (COPD) (OR 3.00, 95% CI 2.51-3.57), TIA/ischemic stroke (OR 2.36, 95% CI 2.03-2.73), dementia history (OR 2.30, 95% CI 1.06-4.98), end-stage renal disease (ESRD) or chronic kidney disease (CKD) (OR 1.97, 95% CI 1.38-2.82), and heart failure (OR 1.95, 95% CI 1.69-2.26), were found to be independently correlated with the incidence of polypharmacy. Polypharmacy significantly increased the incidence and risk of major bleeding (adjusted hazard ratio (aHR) 1.26, 95% CI 1.12-1.41). The study observed a statistically significant increase in the incidence of all-cause mortality, however, the risk for all-cause mortality elevated but did not show significance (aHR 1.11, 95% CI 0.99-1.24). The risk of stroke and admission for heart failure did not change with polypharmacy. Conclusions: In our investigation using data from a nationwide database, polypharmacy was widespread in new-onset AF population and was related to major bleeding events. However, polypharmacy does not serve as an independent risk factor for adverse outcomes, with exception of major bleeding event. For AF patients, ensuring tailored medication for comorbidities as well as reducing polypharmacy are essential considerations.

Clinical Outcomes of Endoscopic Butterfly Inlay Cartilage Myringoplasty.

OBJECTIVE: To review a 3-year case series of endoscopic butterfly inlay cartilage myringoplasty performed by a single surgeon (W.S.K.) and analyze the clinical surgical outcomes. STUDY DESIGN: Retrospective study. SETTING: Tertiary care academic center. PATIENTS: We enrolled 60 ears with tympanic membrane (TM) perforation, receiving endoscopic inlay butterfly myringoplasty between 2019 and 2022. MAIN OUTCOMES AND MEASURES: We reviewed patients' demographics, size and location of TM perforation, operation time, complications, and postoperative pain evaluated by the numerical rating scale (NRS). We analyzed the graft uptake success rate in 5 weeks and the perforation closure rate in 4 months after surgery. We also compared the air-bone gap (ABG) before and after the surgery. RESULTS: Among the 60 ears included, the mean age was 57.0 years, and 78.3% (47 of 60) had small perforations. The average operation time was 48.9 ± 11.5 minutes, and the postoperative NRS was 2.0 ± 1.6. The immediate graft uptake success rate evaluated at postoperative 5 weeks was 96.7% (58 of 60), with myringitis occurring in three ears. Except for 11 patients lost to follow-up, the perforation closure rate evaluated at postoperative 4 months was 100% (49 of 49). The mean ABG significantly improved from preoperative status (8.87 ± 5.51 dB HL) to postoperative 4 months (6.22 ± 6.03 dB HL) ( p = 0.019). CONCLUSIONS: A single surgeon's success rate for endoscopic butterfly inlay cartilage myringoplasty was almost 100%. This surgical procedure is safe and effective, with a high graft success rate.

Tinnitus reduction after active bone-conduction implantation in patients with single-sided deafness: a prospective multicenter study.

PURPOSE: Single-sided deafness (SSD) presents significant challenges for patients, including compromised sound localization, reduced speech recognition, and often, tinnitus. These issues are typically addressed using interventions such as cochlear implantation (CI) and bone conduction implant (BCI). However, evidence regarding the efficacy of BCI in reducing tinnitus in SSD patients remains limited. This study explored the ability of a novel active transcutaneous BCI (Bonebridge BCI602) to alleviate tinnitus in SSD patients. STUDY DESIGN: Prospective cohort multicenter study. SETTING: Tertiary referral hospitals. METHODS: A prospective multicenter study of 30 SSD patients was conducted. The patients were divided into two groups: those with (n = 19) and without (n = 11) tinnitus. Audiometric assessments, subjective questionnaires including the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Bern Benefit in Single-Sided Deafness (BBSS), and tinnitus evaluations with the Tinnitus Handicap Inventory (THI) and tinnitogram were conducted before and after BCI surgery. RESULTS: THI scores after surgery were significantly reduced in SSD patients with tinnitus. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups; however, the former group exhibited a significantly greater improvement in the APHAB questionnaire score. According to tinnitograms, the loudness of tinnitus decreased, particularly in patients with ipsilateral tinnitus. Patients with residual hearing had greater reductions in their THI scores. However, three patients without residual hearing had a relative worsening of tinnitus after surgery. CONCLUSION: The Bonebridge BCI602 effectively reduced tinnitus in SSD patients, particularly in those with residual hearing. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups. These findings demonstrate the therapeutic potential of BCI for managing SSD and associated tinnitus.

Cortical volumetric changes after cochlear implantation in postlingually deaf adults: correlation with speech perception abilities.

This study aims to analyse the volumetric changes in brain MRI after cochlear implantation (CI), focusing on the speech perception in postlingually deaf adults. We conducted a prospective cohort study with 16 patients who had bilateral hearing loss and received unilateral CI. Based on the surgical side, patients were categorized into left and right CI groups. Volumetric T1-weighted brain MRI were obtained before and one year after the surgery. To overcome the artifact caused by the internal device in post-CI scan, image reconstruction method was newly devised and applied using the contralateral hemisphere of the pre-CI MRI data, to run FreeSurfer. We conducted within-subject template estimation for unbiased longitudinal image analysis, based on the linear mixed effect models. When analyzing the contralateral cerebral hemisphere before and after CI, a substantial increase in superior frontal gyrus and superior temporal gyrus (STG) volumes was observed in the left CI group. A positive correlation was observed in the STG and post-CI word recognition score in both groups. As far as we know, this is the first study attempting longitudinal brain volumetry based on post-CI MRI scans. We demonstrate that better auditory performance after CI is associated with structural restoration in central auditory structures.

Three-Dimensional Analysis of Bone Remodeling After Closed Treatment for Mandibular Condylar Head Fracture.

Closed treatment of mandibular condylar fractures has been used for its indications based on the fracture site, fracture status, and patient age. Posttreatment mandibular condyle size is associated with mandibular function; however, a few studies have reported bone remodeling patterns and volume changes in the condyle and glenoid fossa after mandibular condylar head fractures (CHFs). Therefore, volumetric changes in the mandibular condyle and glenoid fossa were analyzed in the present study, and bone remodeling patterns were evaluated after mandibular CHFs. The present study included 16 condyles from 12 patients who received closed treatment for CHF. After reconstruction of a 3-dimensional skull model, including the mandible, using computed tomography data taken immediately after injury and 6 months after treatment, volume changes in the mandibular condyle and glenoid fossa were analyzed. The condylar volume increased by 0.32±0.66 cm3 during the 6-month healing period without statistical significance (P=0.093). Regarding the glenoid fossa, the fossa showed a statistically significant volume increase of 0.41±0.59 cm3 (P=0.021), and 12 glenoid fossae (75%) showed downward bone apposition; however, no change or only mild bone resorption was observed in 4 glenoid fossae (25%). The results of this study indicated that the volume changes in the mandibular condyle after closed treatment of a mandibular CHF are not significant, and the glenoid fossa adapts to the displaced mandibular condyle through downward growth accompanied by volume increase.

The Role of Measuring Preoperative Social Maturation Score in Children With Additional Needs Who Underwent Cochlear Implantation.

BACKGROUND AND OBJECTIVES: Additional needs refer to specific requirements or support for individuals with disabilities or syndromes. Intellectual ability is a crucial outcome determinant of a cochlear implant. The social quotient (SQ) is an indirect predictor of intellectual capacity and social skills. This study aimed to investigate the clinical significance of the SQ on children with additional needs who received cochlear implants. Subjects and. METHODS: This study included 24 patients with diagnosed developmental delays and syndromes, who demonstrated SQ scores of <70. Preoperative social skills were evaluated using the SQ. All patients underwent cochlear implantation (CI) surgery before 7 years of age. Outcomes were evaluated using the Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) and Categories of Auditory Performance (CAP) scores. Data were collected through a retrospective chart review. RESULTS: Children were categorized into three groups based on their SQ. There were no correlations between the preoperative SQ and IT-MAIS or CAP scores at 2 and 5 years of follow-up postoperatively. The CI outcomes of children with low SQ (<70) differed from those with normal development (SQ>70). In the low-SQ group, inner ear anomalies were observed in 10 (41.7%) patients. Although not statistically significant, these children exhibited a trend of lower average outcomes than children without inner ear anomalies. CONCLUSIONS: CI outcomes in children with additional needs positively affected auditory performance. Postoperative auditory and language skills tended to improve slowly in children with additional needs and a lower SQ. Over time, development gradually became more comparable to the other groups of children. However, this improvement was less than that observed in children without additional needs. Our findings support CI for children with additional needs as part of long-term auditory rehabilitation following surgery.

Detection and diagnosis of automated breast ultrasound in patients with BI-RADS category 4 microcalcifications: a retrospective study.

BACKGROUND: Automated Breast Ultrasound (AB US) has shown good application value and prospects in breast disease screening and diagnosis. The aim of the study was to explore the ability of AB US to detect and diagnose mammographically Breast Imaging Reporting and Data System (BI-RADS) category 4 microcalcifications. METHODS: 575 pathologically confirmed mammographically BI-RADS category 4 microcalcifications from January 2017 to June 2021 were included. All patients also completed AB US examinations. Based on the final pathological results, analyzed and summarized the AB US image features, and compared the evaluation results with mammography, to explore the detection and diagnostic ability of AB US for these suspicious microcalcifications. RESULTS: 250 were finally confirmed as malignant and 325 were benign. Mammographic findings including microcalcifications morphology (61/80 with amorphous, coarse heterogeneous and fine pleomorphic, 13/14 with fine-linear or branching), calcification distribution (189/346 with grouped, 40/67 with linear and segmental), associated features (70/96 with asymmetric shadow), higher BI-RADS category with 4B (88/120) and 4 C (73/38) showed higher incidence in malignant lesions, and were the independent factors associated with malignant microcalcifications. 477 (477/575, 83.0%) microcalcifications were detected by AB US, including 223 malignant and 254 benign, with a significantly higher detection rate for malignant lesions (x2 = 12.20, P < 0.001). Logistic regression analysis showed microcalcifications with architectural distortion (odds ratio [OR] = 0.30, P = 0.014), with amorphous, coarse heterogeneous and fine pleomorphic morphology (OR = 3.15, P = 0.037), grouped (OR = 1.90, P = 0.017), liner and segmental distribution (OR = 8.93, P = 0.004) were the independent factors which could affect the detectability of AB US for microcalcifications. In AB US, malignant calcification was more frequent in a mass (104/154) or intraductal (20/32), and with ductal changes (30/41) or architectural distortion (58/68), especially with the both (12/12). BI-RADS category results also showed that AB US had higher sensitivity to malignant calcification than mammography (64.8% vs. 46.8%). CONCLUSIONS: AB US has good detectability for mammographically BI-RADS category 4 microcalcifications, especially for malignant lesions. Malignant calcification is more common in a mass and intraductal in AB US, and tend to associated with architectural distortion or duct changes. Also, AB US has higher sensitivity than mammography to malignant microcalcification, which is expected to become an effective supplementary examination method for breast microcalcifications, especially in dense breasts.

Necroptosis contributes to non-alcoholic fatty liver disease pathoetiology with promising diagnostic and therapeutic functions.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease. However, the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies. Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoetiology and suggest functional therapeutic and diagnostic options. Pyroptosis, ferroptosis, and necroptosis are the main subtypes of non-apoptotic regulated cell deaths (RCDs), each of which represents particular characteristics. Considering the complexity of the findings, the present study aimed to review these types of RCDs and their contribution to NAFLD progression, and subsequently discuss in detail the role of necroptosis in the pathoetiology, diagnosis, and treatment of the disease. The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer, hence it has potential in diagnostic and therapeutic approaches. Nevertheless, further studies are necessary.

Long-Term Educational and Occupational Status of Prelingually Deaf Children Who Have Received a Cochlear Implant.

OBJECTIVE: To investigate the long-term educational and occupational status of prelingually bilateral deaf children who received a cochlear implant (CI) before the age of 7, and to identify factors that influence these outcomes. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary care center. METHODS: Seventy-one children who underwent CI surgery from 2000 to 2007 were included. The latest education and occupation status and word recognition score (WRS) were analyzed. RESULTS: The mean age at the time of surgery and the current age was 3.9 and 22.4 years. The age at CI showed a negative correlation with WRS. All subjects had graduated from high school or obtained an equivalent educational qualification. General high school graduates showed a higher WRS than those who attended a special education high school. The college entrance rate of CI patients (74.6% %) was comparable to that of the general population (72.5%). Subjects who went to college had a significantly better WRS than those who did not (51.4% vs 19.3%). Excluding 30 subjects currently enrolled in college, 26 (62%) of the remaining 41 were currently employed and engaged in various vocational activities, of which most (21 out of 26, 81%) were employed through vocational training institutes, or via special recruitment policy for the disabled. CONCLUSION: The long-term use of CI in prelingually deaf children enables not only speech perception but also produces comparable levels of education and employment to those of the general population. A good WRS and supportive policy were related to these successful outcomes.

Transoral Endoscopy-Assisted Tongue-Lip Adhesion With Modified Tongue Base Suspension in a Pierre-Robin Sequence: A Safe and Effective Technique.

Life-threatening airway obstruction is a major concern in patients with Pierre-Robin sequence. Tongue-lip adhesion (TLA) has been used to manage airway obstruction. The authors present the case of a female neonate with Pierre-Robin sequence who presented with airway obstruction and a cleft palate. She underwent a TLA procedure with modified tongue base suspension (TBS). Endoscopy was used to check and control the traction of the tongue base to enable unobstructed self-ventilation. Positive outcomes including improved O2 saturation and weight gain were noted. The effectiveness of TLA was enhanced by using TBS with real-time endoscopy to evaluate the oropharyngeal airway space required to alleviate airway obstruction. The use of endoscopy enabled us to check and determine how much the tongue base should be tracted by manipulating the tongue anteriorly and posteriorly. The authors report transoral endoscopy-assisted TLA and modified TBS.

Model-based hypothesis tests for the causal mediation of semi-competing risks.

Analyzing the causal mediation of semi-competing risks has become important in medical research. Semi-competing risks refers to a scenario wherein an intermediate event may be censored by a primary event but not vice versa. Causal mediation analyses decompose the effect of an exposure on the primary outcome into an indirect (mediation) effect: an effect mediated through a mediator, and a direct effect: an effect not through the mediator. Here we proposed a model-based testing procedure to examine the indirect effect of the exposure on the primary event through the intermediate event. Under the counterfactual outcome framework, we defined a causal mediation effect using counting process. To assess statistical evidence for the mediation effect, we proposed two tests: an intersection-union test (IUT) and a weighted log-rank test (WLR). The test statistic was developed from a semi-parametric estimator of the mediation effect using a Cox proportional hazards model for the primary event and a series of logistic regression models for the intermediate event. We built a connection between the IUT and WLR. Asymptotic properties of the two tests were derived, and the IUT was determined to be a size [Formula: see text] test and statistically more powerful than the WLR. In numerical simulations, both the model-based IUT and WLR can properly adjust for confounding covariates, and the Type I error rates of the proposed methods are well protected, with the IUT being more powerful than the WLR. Our methods demonstrate the strongly significant effects of hepatitis B or C on the risk of liver cancer mediated through liver cirrhosis incidence in a prospective cohort study. The proposed method is also applicable to surrogate endpoint analyses in clinical trials.

Entelon150® (Vitis vinifera Seed Extract) Attenuates Degenerative Changes in Intravascular Valve Prostheses in Rabbits.

BACKGROUND AND OBJECTIVES: The therapeutic strategy for inflammation and degenerative calcification is of utmost importance for bioprosthetic heart valve (BHV) implanted patients. The purpose of this study was to compare the anti-inflammatory and anti-calcification effects of Entelon150® (grape seed extract), losartan, and rosuvastatin, in a rabbit model of intravascular BHV leaflet implantation in bovine pericardium. METHODS: A total of 28 rabbits were implanted with BHV leaflet in the external jugular veins. The Entelon150® group was administered 7.7 mg/kg Entelon150® twice daily for 6 weeks after surgery. The losartan and rosuvastatin groups received 5.14 mg/kg and 1 mg/kg, respectively, once per day. The control group received 1 ml of saline once daily. And then, calcium concentration was measured in the implanted BHV, and histological and molecular analyses were performed on the surrounding tissues. RESULTS: The calcium content of the implanted tissue in the Entelon150® group (0.013±0.004 mg/g) was lower than that in the control group (0.066±0.039 mg/g) (p=0.008). The losartan (0.024±0.016 mg/g, p=0.032) and rosuvastatin (0.022±0.011 mg/g, p=0.032) groups had lower calcium content than the control group, and higher tendency than the Entelon150® group. Immunohistochemistry revealed that the expressions of bone morphogenic protein 2 (BMP2), S-100, and angiotensin II type 1 receptor in the Entelon150® group showed lower tendency than those in the control group. The protein expression levels of BMP2 were reduced in the Entelon150® group compared with those in the control group. CONCLUSIONS: Entelon150® exhibited a significant effect, similar to other drugs, in reducing calcification and inflammation in the intravascular bovine pericardium.

Efficacy of the Bonebridge BCI602 for Adult Patients with Single-sided Deafness: A Prospective Multicenter Study.

OBJECTIVE: To investigate the safety and efficacy of a novel active transcutaneous bone conduction implant (BCI) device for patients with single-sided deafness (SSD). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral hospitals. METHODS: This prospective multicenter study was conducted at 15 institutions nationwide. Thirty adult (aged ≥19 years) SSD patients were recruited. They underwent implantation of an active transcutaneous BCI device (Bonebridge BCI602). Objective outcomes included aided pure-tone thresholds, aided speech discrimination scores (SDSs), and the Hearing in Noise Test (HINT) and sound localization test results. The Bern Benefit in Single-Sided Deafness (BBSS) questionnaire, the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire, and the Tinnitus Handicap Inventory (THI) were used to measure subjective benefits. RESULTS: The mean aided pure-tone threshold was 34.2 (11.3), mean (SD), dB HL at 500 to 4000 Hz. The mean total BBSS score was 27.5 (13.8). All APHAB questionnaire domain scores showed significant improvements: ease of communication, 33.6 (23.2) versus 22.6 (21.3), P = .025; reverberation, 44.8 (16.6) versus 32.8 (15.9), P = .002; background noise, 55.5 (23.6) versus 35.2 (18.1), P < .001; and aversiveness, 36.7 (22.8) versus 25.8 (21.4), P = .028. Moreover, the THI scores were significantly reduced [47.4 (30.1) versus 31.1 (27.0), P = .003]. Congenital SSD was a significant factor of subjective benefit (-11.643; 95% confidence interval: -21.946 to -1.340). CONCLUSION: The BCI602 active transcutaneous BCI device can provide functional hearing gain without any adverse effects and is a feasible option for acquired SSD patients with long-term deafness.

Comparison of blinatumomab and CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia: a systematic review and meta-analysis.

OBJECTIVES: This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies. RESULTS: The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy. CONCLUSIONS: The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT, and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥3 hematological toxicity, CRS, and neurological events.

Impact of Guideline-Directed Management Strategies for Low-Density Lipoprotein Cholesterol Control in Patients Who Underwent Percutaneous Coronary Intervention.

There are little direct comparative evidences of strategies between ≥50% and the absolute target goal of low-density lipoprotein cholesterol (LDL-C) level <55 mg/100 ml for the patients who underwent percutaneous coronary intervention (PCI). This study aimed to investigate the clinical impact of different strategies between 2 groups of patients who underwent PCI. A total of 3,104 patients with previous PCI were retrospectively enrolled from 2014 to 2020 at Yeungnam University Medical Center. The study population was stratified into 2 groups based on whether the LDL-C level was <55 mg/100 ml at the 1-year mark or not. Furthermore, the 50% reduction rate of LDL-C was also categorized based on whether it had decreased by ≥50% from the initial LDL-C level at the 1-year mark. The primary end point was 3-year major adverse cardiovascular events (MACEs) which were defined as a composite of cardiovascular death, nonfatal myocardial infarction, target lesion revascularization, hospitalization for heart failure, or nonfatal stroke. There was no significant difference between the LDL <55 mg/100 ml group and the LDL ≥55 mg/100 ml group in the risk of MACEs (hazard ratio 1.06, 95% confidence interval 0.81 to 1.38, p = 0.690) after propensity score matching. However, the group that achieved ≥50% reduction of LDL-C from baseline LDL-C level showed a significant reduction in the occurrence of MACEs in the subgroup of LDL-C level ≥55 mg/100 ml (hazard ratio 0.41, 95% confidence interval 0.19 to 0.89, p = 0.025) compared with the group with <50% reduction of LDL-C. In all patients, the achievement rate of target LDL-C <55 mg/100 ml and more than 50% reduction from baseline was 17.2%. In conclusion, guideline-directed management strategy of ≥50% reduction of LDL-C from the baseline will be needed to reduce the incidence of MACEs in patients with LDL-C ≥55 mg/100 ml who underwent PCI. Additional efforts to increase the target goal achievement rate of LDL-C are warranted.

Generation of Fibrotic Liver Organoids Using Hepatocytes, Primary Liver Sinusoidal Endothelial Cells, Hepatic Stellate Cells, and Macrophages.

Liver organoids generated with single or multiple cell types have been used to investigate liver fibrosis development, toxicity, pathogenesis, and drug screening. However, organoid generation is limited by the availability of cells isolated from primary tissues or differentiated from various stem cells. To ensure cell availability for organoid formation, we investigated whether liver organoids could be generated with cell-line-based Huh-7 hepatocellular carcinoma cells, macrophages differentiated from THP-1 monocytes, and LX-2 hepatic stellate cells (HSCs) and primary liver sinusoidal endothelial cells (LSECs). In liver organoids, hepatocyte-, LSEC-, macrophage-, and HSC-related gene expression increased relative to that in two-dimensional (2D)-cultured Huh-7/LSEC/THP-1/LX-2 cells without Matrigel. Thioacetamide (TAA) increased α-smooth muscle actin expression in liver organoids but not in 2D-cultured cells, whereas in TAA-treated organoids, the expression of hepatic and LSEC markers decreased and that of macrophage and HSC markers increased. TAA-induced fibrosis was suppressed by treatment with N-acetyl-L-cysteine or tumor-necrosis-factor-stimulated gene 6 protein. The results showed that liver toxicants could induce fibrotic and inflammatory responses in liver organoids comprising Huh-7/LSEC/macrophages/LX-2 cells, resulting in fibrotic liver organoids. We propose that cell-line-based organoids can be used for disease modeling and drug screening to improve liver fibrosis treatment.

Condylar volume and positional changes following a bilateral sagittal split ramus osteotomy in skeletal class II and III malocclusions.

BACKGROUND: Mandibular condyle remodeling and displacement are post-orthognathic surgery concerns that can potentially lead to occlusal issues after bilateral sagittal split ramus osteotomy. This retrospective study examined the relationship between condylar volume changes and position alterations after surgery in patients with skeletal class II and III malocclusions using cone-beam CT. METHODS: The study included 16 patients (6 with Class II malocclusion, 10 with Class III malocclusion) who underwent bilateral sagittal split ramus osteotomy at Chonnam National University Hospital. Cone-beam CT data were collected at three specific time points: before surgery, immediately after surgery, and approximately 6 months post-surgery. Mandibular movement was measured using InVivoDental 5.4.6. ITK-SNAP 3.8.0 was used to assessed condylar volume changes post-surgery. Condyle positions were evaluated in four parts with RadiAnt DICOM Viewer 4.6.9. Statistical analyses were performed using the SPSS version 23. RESULTS: Considering both Class II and III malocclusion, a 2.91% volume reduction was noted immediately and at 6 months after surgery. Both Class II and III cases demonstrated a decrease in superior joint space by -0.59 mm and medial joint space by -1.09 mm. No significant correlation was found between this process and condylar volume change. CONCLUSIONS: The mandibular condyle volume decreased, and superior-medial movement of the condyle was detected in patients with Class II and III malocclusion immediately and at 6 months after surgery with no volume-position correlation.

Incidence and risk of stroke in Korean patients with congenital heart disease.

OBJECTIVES: The incidence and risk of ischemic stroke (IS) and hemorrhagic stroke (HS) in Korean patients with CHD have not been reported, therefore, we aimed to investigate this. MATERIALS AND METHODS: Participants were selected from the Korean National Health Insurance Service benefit records from 2006-2017. Cases were extracted using diagnosis codes related to CHD. Controls without CHD were selected through age- and sex-matched random sampling at a 1:10 ratio. RESULTS: The case and control groups included 232,203 and 3,024,633 participants, respectively. The median (interquartile range) follow-up period was 7.28 (3.59-8.73) years. The incidence rates of IS and HS per 100,000 person-years were much higher in cases than in controls (IS: 135 vs. 47; HS: 41.7 vs. 24.9). After adjusting for confounders, CHD was a risk factor for IS and HS (subdistribution HR; 1.96 and 1.71, respectively). In patients with CHD, the following risk factors were identified: diabetes, heart failure, and atrial fibrillation for any stroke; hypertension, atrial septal defects, and use of antiplatelet agents for IS only; and coronary artery bypass graft surgery for HS only. CONCLUSIONS: Korean patients with CHD have a high risk of stroke. A personalized preventive approach is needed to reduce the incidence of stroke in this population.

Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells.

Reactive oxygen species (ROS)-sensitive polymer nanoparticles were synthesized for tumor targeting of an anticancer drug, doxorubicin (DOX). For this purpose, chitosan-methoxy poly(ethylene glycol) (mPEG) (ChitoPEG)-graft copolymer was synthesized and then DOX was conjugated to the backbone of chitosan using a thioketal linker. Subsequently, the chemical structure of the DOX-conjugated ChitoPEG copolymer (ChitoPEGthDOX) was confirmed via 1H nuclear magnetic resonance (NMR) spectra. Nanoparticles of the ChitoPEGthDOX conjugates have spherical shapes and a size of approximately 100 nm. Transmission electron microscopy (TEM) has shown that ChitoPEGthDOX nanoparticles disintegrate in the presence of hydrogen peroxide and the particle size distribution also changes from a monomodal/narrow distribution pattern to a multi-modal/wide distribution pattern. Furthermore, DOX is released faster in the presence of hydrogen peroxide. These results indicated that ChitoPEGthDOX nanoparticles have ROS sensitivity. The anticancer activity of the nanoparticles was evaluated using AT84 oral squamous carcinoma cells. Moreover, DOX-resistant AT84 cells were prepared in vitro. DOX and its nanoparticles showed dose-dependent cytotoxicity in both DOX-sensitive and DOX-resistant AT84 cells in vitro. However, DOX itself showed reduced cytotoxicity against DOX-resistant AT84 cells, while the nanoparticles showed almost similar cytotoxicity to DOX-sensitive and DOX-resistant AT84 cells. This result may be due to the inhibition of intracellular delivery of free DOX, while nanoparticles were efficiently internalized in DOX-resistant cells. The in vivo study of a DOX-resistant AT84 cell-bearing tumor xenograft model showed that nanoparticles have higher antitumor efficacy than those found in free DOX treatment. These results may be related to the efficient accumulation of nanoparticles in the tumor tissue, i.e., the fluorescence intensity in the tumor tissue was stronger than that of any other organs. Our findings suggest that ChitoPEGthDOX nanoparticles may be a promising candidate for ROS-sensitive anticancer delivery against DOX-resistant oral cancer cells.

CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway.

CXCL8-CXCR1/CXCR2 signaling pathways might form complex crosstalk among different cell types within the ovarian tumor microenvironment, thereby modulating the behaviors of different cells. This study aimed to investigate the expression pattern of CXCL8 in the ovarian tumor microenvironment and its impact on both endothelial-to-mesenchymal transition (EndMT) and ferroptosis of endothelial cells. The human monocytic cell line THP-1 and the human umbilical vein endothelial cell line PUMC-HUVEC-T1 were used to conduct in vitro studies. Erastin was used to induce ferroptosis. Results showed that tumor-associated macrophages are the major source of CXCL8 in the tumor microenvironment. CXCL8 treatment promoted the nucleus entrance of NF-κB p65 and p65 phosphorylation via CXCR2 in endothelial cells, suggesting activated NF-κB signaling. Via the NF-κB signaling pathway, CXCL8 enhanced TGF-ß1-induced EndMT of PUMC-HUVEC-T1 cells and elevated their expression of SLC7A11 and GPX4. These trends were drastically weakened in groups with CXCR2 knockdown or SB225002 treatment. TPCA-1 reversed CXCL8-induced upregulation of SLC7A11 and GPX4. CXCL8 protected endothelial cells from erastin-induced ferroptosis. However, these protective effects were largely canceled when CXCR2 was knocked down. In summary, CXCL8 can activate the NF-κB signaling pathway in endothelial cells in a CXCR2-dependent manner. The CXCL8-CXCR2/NF-κB axis can enhance EndMT and activate SLC7A11 and GPX4 expression, protecting endothelial cells from ferroptosis.