Lazertinib versus Platinum-Based Chemotherapy with Epidermal Growth Factor Receptor (EGFR)-Positive Non-Small-Cell Lung Cancer after Failing EGFR-Tyrosine Kinase Inhibitor: A Real-World External Comparator Study.

BACKGROUND: Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy. METHODS: We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes. RESULTS: The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; p < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; p < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; p < 0.001) compared to platinum-based chemotherapy. CONCLUSION: Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.

Accuracy assessment of patient safety incident (PSI) codes and present-on-admission (POA) indicators: a cross-sectional analysis using the Patient Safety Incidents Inquiry (PSII) in Korea.

BACKGROUND: Among the various methods used, administrative data collected for claims and billing purposes, such as diagnosis codes and present-on-admission (POA) indicators, can easily be employed to assess patient safety status. However, it is crucial that administrative data be accurate to generate valid estimates of adverse event (AE) occurrence. Thus, we aimed to evaluate the accuracy of diagnosis codes and POA indicators in patients with confirmed AEs in the hospital admission setting. METHODS: We analysed the diagnosis codes of 1,032 confirmed AE cases and 6,754 non-AE cases from the 2019 Patient Safety Incidents Inquiry, which was designed as a cross-sectional study, to determine their alignment with the Korean Patient Safety Incidents (PSIs) Code Classification System. The unit of analysis was the individual case rather than the patient, because two or more AEs may occur in one patient. We examined whether the primary and secondary diagnostic codes had PSIs codes matching the AE type and checked each PSI code for whether the POA indicator had an 'N' tag. We reviewed the presence of PSI codes in patients without identified AEs and calculated the correlation between the AE incidence rate and PSI code and POA indicator accuracy across 15 hospitals. RESULTS: Ninety (8.7%) of the AE cases had PSI codes with an 'N' tag on the POA indicator compared to 294 (4.4%) of the non-AE cases. Infection- (20.4%) and surgery/procedure-related AEs (13.6%) had relatively higher instances of correctly tagged PSI codes. We did not identify any PSI codes for diagnosis-related incidents. While we noted significant differences in AE incidence rates, PSI code accuracy, and POA indicator accuracy among the hospitals, the correlations between these variables were not statistically significant. CONCLUSION: Currently, PSI codes and POA indicators in South Korea appear to have low validity. To use administrative data in medical quality improvement activities such as monitoring patient safety levels, improving the accuracy of administrative data should be a priority. Possible strategies include targeted education on PSI codes and POA indicators and introduction of new evaluation indicators regarding the accuracy of administrative data.

Kaempferol Inhibits Cervical Cancer Cells by Inducing Apoptosis and Autophagy via Inactivation of the PI3K/AKT/mTOR Signaling Pathway.

BACKGROUND/AIM: Kaempferol, a natural flavonoid, occurs abundantly in fruits and vegetables. It has various bioactivities, with antioxidant, anti-inflammatory, and other beneficial properties. The aim of this study was to investigate the in vitro effects of kaempferol on the proliferation, apoptosis, and autophagy of KB cells, a human cervical cancer cell line, and the corresponding action mechanisms. MATERIALS AND METHODS: The inhibitory efficacy of kaempferol on KB cervical cancer cells was investigated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration assay, 4',6-diamidino-2-phenylindole staining, flow cytometry, acridine orange staining and western blotting. RESULTS: Kaempferol reduced KB cell viability and migration in a dose-dependent manner. Additionally, kaempferol-induced apoptosis was confirmed, and kaempferol treatment influenced levels of apoptotic proteins. Autophagy was detected upon visualization of characteristic autophagic vacuoles and acidic vesicular organelles, and verified using western blotting, which revealed elevated levels of autophagy-related proteins. Kaempferol-mediated apoptosis and autophagy were evidently attributable to reduced phosphorylation in the phosphoinositide 3-kinase (PI3K)/serine/threonine kinase 1 (AKT)/mammalian target of rapamycin (mTOR) pathway. This finding was validated using a pharmacological inhibition assay with the PI3K pathway inhibitor LY294002, which promoted KB cell apoptosis and autophagy. CONCLUSION: Our results suggest that kaempferol induces apoptosis and autophagy by inhibiting the PI3K/AKT/mTOR pathway in human cervical cancer cells, empirically showing the anticancer effects of kaempferol, and thereby presenting it as a potential anticancer therapeutic agent.

Long-Term Antioxidant Metal-Organic Frameworks.

Free radicals produced during metabolism induce effects, such as cell damage and cancer, because of their high reactivity. Although antioxidants in food products can eliminate free radicals, they are expelled within a relatively short period of time after serving their function. In this study, we investigated the possibility of using metal-organic frameworks (MOFs) with antioxidants as their ligands. Metal-organic frameworks are crystalline polymers with repetitively coordinated ligands and metal centers. We assume that once antioxidant-based MOFs are ingested, ligands are released on a long-term basis during the process of chemical and physical disintegration. To evaluate their eligibility, we established criteria for biocompatibility, particle size, and long-term antioxidant effects. For biocompatibility, we treated cells with various concentrations of MOFs and their precursors followed by a water-soluble tetrazolium 8 (WST-8) assay. The particle size distribution was analyzed using TEM and ImageJ software, and the antioxidant release was quantified using UV-vis spectroscopy. We concluded that Fe-based FeTHQ with the antioxidant tetrahydroxy-1,4-benzoquinone (THQ) as its ligand is the most effective long-term antioxidant with its effect lasting up to 7 days. Furthermore, microwave synthesis of FeTHQ was conducted to produce more suitable particles for in vivo antioxidant applications.

An accurate and rapidly calibrating speech neuroprosthesis.

Brain-computer interfaces can enable rapid, intuitive communication for people with paralysis by transforming the cortical activity associated with attempted speech into text on a computer screen. Despite recent advances, communication with brain-computer interfaces has been restricted by extensive training data requirements and inaccurate word output. A man in his 40's with ALS with tetraparesis and severe dysarthria (ALSFRS-R = 23) was enrolled into the BrainGate2 clinical trial. He underwent surgical implantation of four microelectrode arrays into his left precentral gyrus, which recorded neural activity from 256 intracortical electrodes. We report a speech neuroprosthesis that decoded his neural activity as he attempted to speak in both prompted and unstructured conversational settings. Decoded words were displayed on a screen, then vocalized using text-to-speech software designed to sound like his pre-ALS voice. On the first day of system use, following 30 minutes of attempted speech training data, the neuroprosthesis achieved 99.6% accuracy with a 50-word vocabulary. On the second day, the size of the possible output vocabulary increased to 125,000 words, and, after 1.4 additional hours of training data, the neuroprosthesis achieved 90.2% accuracy. With further training data, the neuroprosthesis sustained 97.5% accuracy beyond eight months after surgical implantation. The participant has used the neuroprosthesis to communicate in self-paced conversations for over 248 hours. In an individual with ALS and severe dysarthria, an intracortical speech neuroprosthesis reached a level of performance suitable to restore naturalistic communication after a brief training period.

Inhibition of Immunoproteasome Attenuates NLRP3 Inflammasome Response by Regulating E3 Ubiquitin Ligase TRIM31.

Excessive secretion of pro-inflammatory cytokines leads to the disruption of intestinal barrier in inflammatory bowel disease (IBD). The inflammatory cytokine tumor necrosis factor alpha (TNFα) induces the assembly of the NLRP3 inflammasome, resulting in the augmented secretion of inflammatory cytokines implicated in the pathogenesis of inflammatory bowel disease (IBD). TNFα has also been known to induce the formation of immunoproteasome (IP), which incorporates immunosubunits LMP2, LMP7, and MECL-1. Inhibition of IP activity using the IP subunit LMP2-specific inhibitor YU102, a peptide epoxyketone, decreased the protein levels of NLRP3 and increased the K48-linked polyubiquitination levels of NLRP3 in TNFα-stimulated intestinal epithelial cells. We observed that inhibition of IP activity caused an increase in the protein level of the ubiquitin E3 ligase, tripartite motif-containing protein 31 (TRIM31). TRIM31 facilitated K48-linked polyubiquitination and proteasomal degradation of NLRP3 with an enhanced interaction between NLRP3 and TRIM31 in intestinal epithelial cells. In addition, IP inhibition using YU102 ameliorated the symptoms of colitis in the model mice inflicted with dextran sodium sulfate (DSS). Administration of YU102 in the DSS-treated colitis model mice caused suppression of the NLRP3 protein levels and accompanied inflammatory cytokine release in the intestinal epithelium. Taken together, we demonstrated that inhibiting IP under inflammatory conditions induces E3 ligase TRIM31-mediated NLRP3 degradation, leading to attenuation of the NLRP3 inflammatory response that triggers disruption of intestinal barrier.

Perception gaps of patient engagement for patient safety between healthcare professionals and the public in Korea.

BACKGROUND: To ensure effective patient engagement, patients' efforts, partnerships with healthcare professionals, and the organisation's role in providing safe healthcare settings must be emphasised. Perception gaps regarding patient engagement between the public and healthcare professionals could prevent healthy partnerships from forming and hinder patient engagement activities. This study examined healthcare professionals' perception of patient engagement and compared the findings with that determined for the public in a previous study. METHODS: An anonymous online survey was conducted in February 2020 among 1,007 healthcare professionals (physicians, nurses). The questionnaire comprised five parts regarding the perception of patient engagement. Descriptive analysis and Chi-squared/Fisher's exact tests determined the frequency and significant differences among the public from previous study and healthcare professionals in this study. RESULTS: The perception of the importance of patient safety was high among healthcare professionals and the public. However, statistically significant differences in perceptions were observed among the public and healthcare professionals in all categories. The perception gaps were substantial between the groups in sub-categories of engagement for patient safety during medical treatment; 86% of physicians and 90% of nurses agreed that patients participate in the decision-making for the treatment process. Conversely, 58% of the public agreed. Only 22% of the public agreed with confirming healthcare professionals' hand washing to prevent infection, versus 57% of physicians and 65% of nurses. More than 89% of healthcare professionals positively perceived medical dispute mediation versus only half of the public. In certain areas such as "medical dispute mediation and arbitration programs", "fall prevention", and "infection prevention", there was a statistically significant difference in the perception of patient involvement among healthcare professionals, with nurses' perception being particularly more positive than that of physicians. CONCLUSIONS: The healthcare professionals' perception of patient engagement was more positive than that of the public. To narrow the perception gaps and enhance the public's perception, strategies involving changes in healthcare systems, promotional efforts, and educational initiatives should be developed. Additionally, strategies should be formulated for healthcare professionals to better engage as partners in patient care.

Importance of Quality of Medical Record: Differences in Patient Safety Incident Inquiry Results According to Assessment for Quality of Medical Record.

BACKGROUND: Medical record review is the gold standard method of identifying adverse events. However, the quality of medical records is a critical factor that can affect the accuracy of adverse event detection. Few studies have examined the impact of medical record quality on the identification of adverse events. OBJECTIVES: In this study, we analyze whether there were differences in screening criteria and characteristics of adverse events according to the quality of medical records evaluated in the patient safety incident inquiry in Korea. METHODS: Patient safety incident inquiry was conducted in 2019 on 7500 patients in Korea to evaluate their screening criteria, adverse events, and preventability. Furthermore, medical records quality judged by reviewers was evaluated on a 4-point scale. The χ 2 test was used to examine differences in patient safety incident inquiry results according to medical record quality. RESULTS: Cases with inadequate medical records had higher rates of identified screening criteria than those with adequate records (88.8% versus 55.7%). Medical records judged inadequate had a higher rate of confirmed adverse events than those judged adequate. "Drugs, fluids, and blood-related events," "diagnosis-related events," and "patient care-related events" were more frequently identified in cases with inadequate medical records. There was no statistically significant difference in the preventability of adverse events according to the medical record quality. CONCLUSIONS: Lower medical record quality was associated with higher rates of identified screening criteria and confirmed adverse events. Patient safety incident inquiry should specify medical record quality evaluation questions more accurately to more clearly estimate the impact of medical record quality.

The Effect of Bimatoprost Implant on Glaucoma Patients: An Observational Study.

PRCIS: In this retrospective study of glaucoma patients receiving the bimatoprost implant at Duke Eye Center, the number of topical intraocular pressure-lowering medications was significantly reduced through 12 months after the implant. PURPOSE: To study the effects of the bimatoprost implant on intraocular pressure (IOP) and the need for topical IOP-lowering medications in glaucoma patients in the clinical practice setting. PATIENTS AND METHODS: Patients who received the bimatoprost implant at Duke Eye Center from November 2020 to October 2021 were identified. Exclusion criteria included addition of other IOP-lowering medications concurrent with the implant and <1 month of follow-up. The change in IOP and number of topical IOP-lowering medications from baseline to months 1, 3, 6, 9, and 12 after the implant was calculated. Subgroup analysis was performed for different glaucoma severities. RESULTS: A total of 63 patients and 92 eyes were included (mean age 77.8 ± 10.1 years). Glaucoma severity ranged from mild (11%), moderate (30%), to severe (54%). There was a nonsignificant decrease in IOP at all timepoints. The mean number of topical IOP-lowering medications significantly decreased by 0.81, 0.75, 0.63, 0.70, and 0.67 at month 1, 3, 6, 9, and 12, respectively (all P < 0.001). There was no significant change in the total number of medications, including the bimatoprost implant. When divided by glaucoma severity, the reduction in the number of topical medications was significant at 1, 3, and 6 months for mild/moderate disease and at 1 month for severe disease. During the follow-up period, 19 eyes underwent additional laser or surgical procedures, 68% of which had a history of prior incisional glaucoma surgery. CONCLUSIONS: The bimatoprost implant may reduce the need for topical IOP-lowering agents over a 1-year period, especially in mild to moderate-stage glaucoma. The efficacy of the implant may be more limited in severe glaucoma, and further work is needed to characterize its long-term effects.

Risk Factors for the Mortality of Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation in a Non-Centralized Setting: A Nationwide Study.

BACKGROUND: Limited data are available on the mortality rates of patients receiving extracorporeal membrane oxygenation (ECMO) support for coronavirus disease 2019 (COVID-19). We aimed to analyze the relationship between COVID-19 and clinical outcomes for patients receiving ECMO. METHODS: We retrospectively investigated patients with COVID-19 pneumonia requiring ECMO in 19 hospitals across Korea from January 1, 2020 to August 31, 2021. The primary outcome was the 90-day mortality after ECMO initiation. We performed multivariate analysis using a logistic regression model to estimate the odds ratio (OR) of 90-day mortality. Survival differences were analyzed using the Kaplan-Meier (KM) method. RESULTS: Of 127 patients with COVID-19 pneumonia who received ECMO, 70 patients (55.1%) died within 90 days of ECMO initiation. The median age was 64 years, and 63% of patients were male. The incidence of ECMO was increased with age but was decreased after 70 years of age. However, the survival rate was decreased linearly with age. In multivariate analysis, age (OR, 1.048; 95% confidence interval [CI], 1.010-1.089; P = 0.014) and receipt of continuous renal replacement therapy (CRRT) (OR, 3.069; 95% CI, 1.312-7.180; P = 0.010) were significantly associated with an increased risk of 90-day mortality. KM curves showed significant differences in survival between groups according to age (65 years) (log-rank P = 0.021) and receipt of CRRT (log-rank P = 0.004). CONCLUSION: Older age and receipt of CRRT were associated with higher mortality rates among patients with COVID-19 who received ECMO.

Anticancer Effects of α-Pinene in AGS Gastric Cancer Cells.

Gastric cancer is the fifth most common cancer globally and the third leading cause of cancer-related mortality. Existing treatment strategies for gastric cancer often present numerous side effects. Consequently, recent studies have shifted toward devising new treatments grounded in safer natural substances. α-Pinene, a natural terpene found in the essential oils of various plants, such as Lavender angustifolia and Satureja myrtifolia, displays antioxidant, antibiotic, and anticancer properties. Yet, its impact on gastric cancer remains unexplored. This research assessed the effects of α-pinene in vitro using a human gastric adenocarcinoma cell-line (AGS) human gastric cancer cells and in vivo via a xenograft mouse model. The survival rate of AGS cells treated with α-pinene was notably lower than that of the control group, as revealed by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. This decline in cell viability was linked to apoptosis, as verified by 4',6-diamidino-2-phenylindole and annexin V/propidium iodide staining. The α-pinene-treated group exhibited elevated cleaved-poly (ADP-ribose) polymerase and B cell lymphoma 2 (Bcl-2)-associated X (Bax) levels and reduced Bcl-2 levels compared with the control levels. Moreover, α-pinene triggered the activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 within the mitogen-activated protein kinase (MAPK) pathway. In the xenograft mouse model, α-pinene induced apoptosis through the MAPK pathway, devoid of toxicity. These findings position α-pinene as a promising natural therapeutic for gastric cancer.

Multitask Deep Learning for Joint Detection of Necrotizing Viral and Noninfectious Retinitis From Common Blood and Serology Test Data.

Purpose: Necrotizing viral retinitis is a serious eye infection that requires immediate treatment to prevent permanent vision loss. Uncertain clinical suspicion can result in delayed diagnosis, inappropriate administration of corticosteroids, or repeated intraocular sampling. To quickly and accurately distinguish between viral and noninfectious retinitis, we aimed to develop deep learning (DL) models solely using noninvasive blood test data. Methods: This cross-sectional study trained DL models using common blood and serology test data from 3080 patients (noninfectious uveitis of the posterior segment [NIU-PS] = 2858, acute retinal necrosis [ARN] = 66, cytomegalovirus [CMV], retinitis = 156). Following the development of separate base DL models for ARN and CMV retinitis, multitask learning (MTL) was employed to enable simultaneous discrimination. Advanced MTL models incorporating adversarial training were used to enhance DL feature extraction from the small, imbalanced data. We evaluated model performance, disease-specific important features, and the causal relationship between DL features and detection results. Results: The presented models all achieved excellent detection performances, with the adversarial MTL model achieving the highest receiver operating characteristic curves (0.932 for ARN and 0.982 for CMV retinitis). Significant features for ARN detection included varicella-zoster virus (VZV) immunoglobulin M (IgM), herpes simplex virus immunoglobulin G, and neutrophil count, while for CMV retinitis, they encompassed VZV IgM, CMV IgM, and lymphocyte count. The adversarial MTL model exhibited substantial changes in detection outcomes when the key features were contaminated, indicating stronger causality between DL features and detection results. Conclusions: The adversarial MTL model, using blood test data, may serve as a reliable adjunct for the expedited diagnosis of ARN, CMV retinitis, and NIU-PS simultaneously in real clinical settings.

Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity.

Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.

Kaempferol induces apoptosis through the MAPK pathway and regulates JNK-mediated autophagy in MC-3 cells.

This study sought to determine the anticancer effect of kaempferol, a glycone-type flavonoid glycoside with various pharmacological benefits, on human oral cancer MC-3 cells. In vitro studies comprised a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, annexin V and propidium iodide staining, western blotting analysis, and acridine orange staining, while the in vivo studies entailed a xenograft model, hematoxylin and eosin staining, and TdT-mediated dUTP-biotin nick end labelling. In vitro, kaempferol reduced the rate of survival of MC-3 cells, mediated intrinsic apoptosis, increased the number of acidic vesicular organelles, and altered the expression of autophagy-related proteins. Further, treatment with the autophagy inhibitors revealed that the induced autophagy had a cytoprotective effect on apoptosis in kaempferol-treated MC-3 cells. Kaempferol also decreased the expression of phosphorylated extracellular signal-regulated kinase and increased that of phosphorylated c-Jun N-terminal kinase (p-JNK) and phosphorylated p38 kinase in MC-3 cells, suggesting the occurrence of mitogen-activated protein kinase-mediated apoptosis and JNK-mediated autophagy. In vivo, kaempferol reduced tumor growth inducing apoptosis and autophagy. These results showed that kaempferol has the potential use as an adjunctive agent in treating oral cancer.

Neighborhood Social Environment and Dementia: The Mediating Role of Social Isolation.

OBJECTIVES: Despite the potential importance of the neighborhood social environment for cognitive health, the connection between neighborhood characteristics and dementia remains unclear. This study investigated the association between the prospective risk of dementia and three distinct aspects of neighborhood social environment: socioeconomic deprivation, disorder, and social cohesion. We also examined whether objective and subjective aspects of individual-level social isolation may function as mediators. METHODS: Leveraging data from the Health and Retirement Study (2006-2018; N = 9,251), we used Cox proportional hazards models to examine the association between time-to-dementia incidence and each neighborhood characteristic, adjusting for covariates and the propensity to self-select into disadvantaged neighborhoods. We used inverse odds weighting to decompose significant total effects of neighborhood characteristics into mediational effects of objective and subjective social isolation. RESULTS: The risk of dementia was associated with deprivation and disorder but not low cohesion. In deprived neighborhoods, individuals had an 18% increased risk of developing dementia (cause-specific hazard ratio [CHR] = 1.18, 95% CI: 1.02 to 1.38), and those in disordered areas had a 27% higher risk (CHR = 1.27, 95% CI: 1.03 to 1.59). 20% of the disorder's effects were mediated by subjective social isolation, while the mediational effects of objective isolation were nonsignificant. Deprivation's total effects were not partitioned into mediational effects given its nonsignificant associations with the mediators. DISCUSSION: Neighborhood deprivation and disorder may increase middle to older adults' risks of dementia. The disorder may adversely affect cognitive health through increasing loneliness. Our results suggest a clear need for dementia prevention targeting upstream neighborhood contexts, including the improvement of neighborhood conditions to foster social integration among residents.

Innate Immune Training Initiates Efferocytosis to Protect against Lung Injury.

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.

NIPBL::NACC1 Fusion Hepatic Carcinoma.

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of cholangiocarcinoma and have unique characteristics, namely immunoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin-positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma.

Longitudinal Associations of Neighborhood Social Cohesion With Self-Perceptions of Aging and Loneliness.

OBJECTIVES: One's aging experience is structurally embedded in the social aspects of the residential environment. However, it is largely unknown how this upstream contextual factor may shape self-perceptions of aging (SPA) and loneliness, critical aspects of later-life psychological well-being with profound health implications. This study examines the longitudinal association of neighborhood social cohesion with SPA and -loneliness, as well as the potential bidirectional associations between outcomes. METHODS: This study used 8-year data from the Health and Retirement Study, with an analytic sample of 9,299 U.S. adults aged 50 or older. Latent growth curve models were implemented to assess the associations of baseline neighborhood social cohesion with trajectories of SPA and loneliness. Path analysis was conducted to examine the longitudinal mediation mechanisms connecting neighborhood social cohesion with SPA and loneliness. RESULTS: Respondents from cohesive neighborhoods at baseline started with and maintained more positive initial SPA over time, but their positive perceptions decreased faster over time. Cohesive neighborhoods were associated with lower levels of loneliness over an 8-year study period, but also with slower rates of decline in loneliness. Path analysis revealed that neighborhood social cohesion indirectly affected SPA and loneliness, via bidirectional mechanisms. DISCUSSION: This study demonstrates the significant role of environmental factors beyond individual predictors and advocates for the potential of neighborhood environments as a target for interventions to foster positive aging perception and tackle loneliness. Furthermore, it indicates that loneliness and SPA could reciprocally influence each other in the context of neighborhood social cohesion, enriching our understanding of their dynamics.

Effect of nitro-conjugated linoleic acid on the inflammatory response of murine macrophages activated with lipopolysaccharide derived from Prevotella intermedia.

Nitro-conjugated linoleic acid (NO2-CLA) has been observed to manifest salutary signaling responses, including anti-inflammatory and antioxidant properties. Here, the authors have explored the influence and underlying mechanisms of NO2-CLA on the proinflammatory reaction of murine macrophages that were challenged with lipopolysaccharide (LPS) derived from Prevotella intermedia, a putative periodontopathic bacterium. Treatment of LPS-activated RAW264.7 cells with NO2-CLA notably dampened the secretion of iNOS-derived NO, IL-1ß and IL-6 as well as their gene expressions and significantly enhanced the markers for M2 macrophage polarization. NO2-CLA promoted the HO-1 expression in cells challenged with LPS, and tin protoporphyrin IX, an HO-1 inhibitor, significantly reversed the NO2-CLA-mediated attenuation of NO secretion, but not IL-1ß or IL-6. We found that cells treated with NO2-CLA significantly increased mRNA expression of PPAR-γ compared to control cells, and NO2-CLA significantly reverted the decrease in PPAR-γ mRNA caused by LPS. Nonetheless, antagonists to PPAR-γ were unable to reverse the NO2-CLA-mediated suppression of inflammatory mediators. In addition, NO2-CLA did not alter the p38 and JNK activation elicited by LPS. Both NF-κB reporter activity and IκB-α degradation caused by LPS were notably diminished by NO2-CLA. NO2-CLA was observed to interrupt the nuclear translocation and DNA binding of p50 subunits caused by LPS with no obvious alterations in p65 subunits. Further, NO2-CLA attenuated the phosphorylation of STAT1/3 elicited in response to LPS. We propose that NO2-CLA could be considered as a possible strategy for the therapy of periodontal disease, although additional researches are certainly required to confirm this.