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Abstract Background Access to sterile syringes is a proven means of reducing the transmission of human immunodeficiency virus (HIV), viral hepatitis, and bacterial infections among injection drug users. In many U.S. states and territories, drug paraphernalia and syringe prescription laws are barriers to syringe access for injection drug users (IDUs): pharmacists may be reluctant to sell syringes to suspected IDUs, and police may confiscate syringes or arrest IDUs who cannot demonstrate a "legitimate" medical need for the syringes they possess. These barriers can be addressed by physician prescription of syringes. This study evaluates physicians' willingness to prescribe syringes, using the theory of planned behavior to identify key behavioral influences. Methods We mailed a survey to a representative sample of physicians from the American Medical Association physician database. Non-responding physicians were then called, faxed, or re-sent the survey, up to four times. Results Twenty percent responded to the survey. Although less than 1 percent of respondents had ever prescribed syringes to a known injection drug user, more than 60% of respondents reported that they would be willing to do so. Physicians' willingness to prescribe syringes was best predicted by the belief that it was a feasible and effective intervention, but individual and peer attitudes were also significant. Conclusion This was the first nationwide survey of the physician willingness to prescribe syringes to IDUs. While the majority of respondents were willing to consider syringe prescription in their clinical practices, multiple challenges need to be addressed in order to improve physician knowledge and attitudes toward IDUs.

The daily eating window significantly impacts weight and metabolic health, yet its ideal duration remains uncertain. Thirty-four healthy middle-aged women were randomly assigned to two intervention groups: 8-h time-restricted eating (TRE) and 14-h time-extended eating (EXE). Each intervention lasted 4 wk, with a 16-d washout period before switching to the other intervention. Clinical biomarkers were collected before and after each intervention, and sleep quality was assessed using the Korean Version of the Pittsburgh Sleep Quality Index (PSQI-K). Additionally, a daily visual analogue scale (VAS) was used to evaluate psychological changes. The TRE group experienced significant weight reduction, lower fasting plasma glucose and total serum cholesterol levels compared to the EXE group, but with an increase in systolic blood pressure. The EXE group showed improved blood pressure. The TRE group reported higher stress levels on the VAS, but the PSQI-K indicated improved sleep quality during the second intervention. An 8-h TRE, without calorie restriction or diet composition changes, proves more beneficial for weight management and plasma glucose control compared to the 14-h EXE among Korean women. Implementation of this approach is recommended to be gradual to mitigate psychological fluctuations and adverse blood pressure changes. The trial was registered with ClinicalTrials.gov (ID: NCT05964179) and Clinical Research Information Service (CRIS, Korea) (ID: KCT0008640)., Competing Interests: Declaration of competing interests The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Currently, optimal treatment strategy for resectable primary small cell carcinoma of the esophagus (PSmCCE) remains controversial. To address this, we conducted a multicenter study to evaluate treatment patterns and long-term survival of PSmCCE patients who underwent radical resection., Methods: This retrospective multicenter study included resected PSmCCE patients who received radical resection at seven high-volume cancer centers. Overall survival (OS) and median survival time (MST) were calculated by using a Kaplan-Meier method and the log-rank test was utilized to assess differences. Multivariable Cox analysis was performed to identify independent prognostic factors., Results: A total of 352 patients with resected PSmCCE were included. For PSmCCE with stage cT1-2N0M0, patients who received surgery plus adjuvant therapy showed better survival than those who received surgery alone (5-year OS rate: 32.8% vs. 19.2%, MST: 44.0 vs. 33.0 months, P = 0.035). Multivariable Cox survival analysis revealed an independent correlation between receiving surgery plus adjuvant therapy and improved OS (hazard ratio [HR] 0.529; 95% confidence interval [CI] 0.280-0.997; P = 0.049). For stage cT3N0M0/T1-3N1M0 PSmCCE, patients who received neoadjuvant therapy followed by surgery had superior long-term survival compared with those who received surgery combined with adjuvant therapy and those who received surgery alone (5-year OS rate: 27.2% vs. 9.5% vs. 0%, MST: 36.0 vs. 24.0 vs. 20.0 months, P = 0.014). Multivariable Cox survival analysis showed that neoadjuvant therapy was independently associated with improved OS (HR 0.384, 95% CI 0.203-0.728; HR 0.550, 95% CI 0.312-0.968; P = 0.013)., Conclusions: Adjuvant therapy was associated with improved survival in stage cT1-2N0M0 PSmCCE, but this should be confirmed in prospective studies. For stage cT3N0M0/T1-3N1M0 cases, neoadjuvant therapy followed by surgery should be considered., Competing Interests: Disclosure All authors have no conflicts of interest to declare., (© 2024. Society of Surgical Oncology.)

Ferroptosis, characterized by iron‑mediated non‑apoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantio‑obtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has anti‑hyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit‑8, EdU staining and migration assays were employed to assess the anti‑liver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoyl‑CoA desaturase 1 (SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo . Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory element‑binding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.

Objectives: The obesity prevalence in South Korea in 2021 stood at 38.4%. South Korea faces unique challenges in providing essential and emergency guidelines for weight management because of stepping into an aging society. We aimed to determine the daily diet patterns among the general Korean population and to investigate the association between such patterns and different obesity., Study Design: Longitudinal prospective cohort study., Methods: A total of 6539 adult participants (mean age 50.8 years, 52.9% male) with normal-weight adults were included from the Ansan-Ansung cohort of 10,030 Korean adults aged 40 or older and followed for an average of 11 years. Obesity was defined according to the criteria from the Korean Society for The Study of Obesity. Baseline dietary intake was assessed using a validated 103-item food frequency questionnaire. Dietary patterns were derived from k-means cluster analysis., Results: In the multivariate analysis, referring to white rice + baechu kimchi, participants from multigrain rice + baechu kimchi showed lower HR for obesity development (waist circumference defined-obesity; HR: 0.87, 95% CI: 0.79, 0.95; body fat percentage defined-obesity; HR: 0.89, 95% CI: 0.80, 0.98). Further analysis documented that except for body fat percentage defined-obesity, consuming milk or dairy products was linked to a reduced incidence of the other three obesity (body mass index defined-obesity; HR: 0.84, 95% CI: 0.72, 0.99; waist circumference defined-obesity; HR: 0.82, 95% CI: 0.71, 0.94; waist-to-hip ratio defined-obesity; HR: 0.75, 95% CI: 0.61, 0.91)., Conclusions: Following a diet that includes multigrain rice, fermented baechu kimchi, and dairy products is linked to a decreased risk of obesity in Korean adults. Public health programs and policies could incorporate these dietary recommendations, targeting specific population groups such as schoolchildren, adults, and the elderly. Additionally, further research is needed to explore the synergistic effects of various foods and their interactions within dietary patterns on obesity outcomes., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aβ-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aβ toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aβ deposition in Aβ 1-42 -injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aim: Chronic kidney disease (CKD) is a heterogeneous disorder that affects the kidney structure and function. This study investigated the effect of the interaction between genetic factors and dietary pattern on kidney dysfunction in Korean adults., Methods: Baseline data were obtained from the Ansan and Ansung Study of the Korean Genome and Epidemiology Study involving 8230 participants aged 40-69 years. Kidney dysfunction was defined as an estimated glomerular filtration rate < 90 mL/minute/1.73 m 2 . Genomic DNAs genotyped on the Affymetrix® Genome-Wide Human SNP array 5.0 were isolated from peripheral blood. A genome-wide association study using a generalized linear model was performed on 1,590,162 single-nucleotide polymorphisms (SNPs). To select significant SNPs, the threshold criterion was set at P-value < 5 × 10 - 8 . Linkage disequilibrium clumping was performed based on the R 2 value, and 94 SNPs had a significant effect. Participants were divided into two groups based on their generic risk score (GRS): the low-GR group had GRS > 0, while the high-GR group had GRS ≤ 0., Results: Three distinct dietary patterns were extracted, namely, the "prudent pattern," "flour-based and animal food pattern," and "white rice pattern," to analyze the effect of dietary pattern on kidney function. In the "flour-based and animal food pattern," higher pattern scores were associated with a higher prevalence of kidney dysfunction in both the low and high GR groups (P for trend < 0.0001 in the low-, high-GR groups of model 1; 0.0050 and 0.0065 in the low-, high-GR groups of model 2, respectively)., Conclusions: The results highlight a significant association between the 'flour-based and animal food pattern' and higher kidney dysfunction prevalence in individuals with both low and high GR. These findings suggest that personalized nutritional interventions based on GR profiles may become the basis for presenting GR-based individual dietary patterns for kidney dysfunction., (© 2024. The Author(s).)

Environmental concentrations of antimicrobials can inhibit Cyanobacteria, but little is known about their effects on Cyanobacteria-blooming freshwater ecosystem. Here, a 21 days' outdoor freshwater mesocosm experiment was established to study effects of single and combined tetracycline, triclocarban and zinc at environmental concentrations on microbial community, microbial function and antimicrobial resistance using amplicon- and metagenomic-based methods. Results showed that three chemicals reshaped the microbial community with magnified effects by chemical combinations. Relative abundance of Cyanobacteria was decreased in all chemical groups, especially from 74.5 to 0.9% in combination of three chemicals. Microbial community networks were more simplified after exposure. Proteobacteria and Bacteroidetes predominated in Cyanobacteria-degraded ecosystems, and their relative abundances were significantly correlated with antibiotic resistome, suggesting that they might host antibiotic resistance genes. Notably, relative abundance (copy per 16 S rRNA gene) of total antibiotic resistome reached five to nine folds higher than the initial abundance in chemical-combined groups. The affected antibiotic resistance genes referred to a wide range of antibiotic classes. However, weak effects were detected on biocide/metal resistance and microbial virulence. Three chemicals posed complicated effects on microbial function, some of which had consistent variations across the groups, while some varied greatly in chemical groups. The findings highlight sensitivity of Cyanobacteria-blooming ecosystem to antimicrobials., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The traditional treatment modalities for esophageal cancer include surgery, chemotherapy, and radiotherapy, each presenting its own limitations. With advancements in endoscopic techniques and the integration of immunotherapy, the feasibility and safety of organ preservation have significantly improved, offering patients improved survival and quality of life. The selection of patients suitable for organ preservation treatment demands ongoing exploration. Those selected for this approach require rigorous monitoring, with surgical intervention as a salvation for tumor progression or metastasis, though the timing of surgery remains a topic of debate. Organ preservation and watch-and-wait strategy may provide a more conservative treatment option, aiming to maximize quality of life.

Background: The immune microenvironment assumes a significant role in the pathogenesis of osteoarthritis (OA). However, the current biomarkers for the diagnosis and treatment of OA are not satisfactory. Our study aims to identify new OA immune-related biomarkers to direct the prevention and treatment of OA using multi-omics data., Methods: The discovery dataset integrated the GSE89408 and GSE143514 datasets to identify biomarkers that were significantly associated with the OA immune microenvironment through multiple machine learning methods and weighted gene co-expression network analysis (WGCNA). The identified signature genes were confirmed using two independent validation datasets. We also performed a two-sample mendelian randomization (MR) study to generate causal relationships between biomarkers and OA using OA genome-wide association study (GWAS) summary data (cases n = 24,955, controls n = 378,169). Inverse-variance weighting (IVW) method was used as the main method of causal estimates. Sensitivity analyses were performed to assess the robustness and reliability of the IVW results., Results: Three signature genes (FCER1G, HLA-DMB, and HHLA-DPA1) associated with the OA immune microenvironment were identified as having good diagnostic performances, which can be used as biomarkers. MR results showed increased levels of FCER1G (OR = 1.118, 95% CI 1.031-1.212, P = 0.041), HLA-DMB (OR = 1.057, 95% CI 1.045 -1.069, P = 1.11E-21) and HLA-DPA1 (OR = 1.030, 95% CI 1.005-1.056, P = 0.017) were causally and positively associated with the risk of developing OA., Conclusion: The present study identified the 3 potential immune-related biomarkers for OA, providing new perspectives for the prevention and treatment of OA. The MR study provides genetic support for the causal effects of the 3 biomarkers with OA and may provide new insights into the molecular mechanisms leading to the development of OA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pang, Cai, Cao, Zhang, Zeng, Liu, Wang, Qu, Chen, Deng and Tan.)

Background: Delayed disclosure is a prevalent and serious issue among victims of child sexual abuse (CSA). Identifying the factors associated with delayed disclosure can identify the profile of children who are at risk of delaying disclosures and inform measures to facilitate timely disclosure., Objective: The current study represented a pioneering effort to investigate factors that are related to disclosure of CSA in Singapore. It examined the influence of various victim and abuse characteristics on the time taken for a victim to disclose CSA., Participants and Setting: A total of 252 CSA cases that were referred to the psychology department of Singapore's Ministry of Social and Family Development (MSF) from 2017 to 2021 were analyzed., Methods: Cases were coded for the study variables and multivariate Cox regression was conducted to analyze the impact of each variable of interest on the time taken to disclose the abuse., Results: It was found that the following sub-populations of CSA victims were associated with delayed disclosure: younger victims, female victims (as compared to male victims), victims with higher severity of sexual abuse (e.g., forced intercourse), and victims who were abused by in-home caregivers (as compared to acquaintances)., Conclusions: The findings from the study generated practical implications to help reduce the time victims take to disclose CSA in the Singaporean context., Competing Interests: Declaration of competing interest We have no known conflict of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflicts of interest The authors hereby declare that they have no conflict of interest.

Background and Objective: Disclosure of CSA is key to victims having access to support and protection, but the current understanding of what factors play a key role is still limited. The present review aims to understand a range of socio-ecological factors that can either facilitate or obstruct the disclosure of CSA., Methods and Results: Through a systematic review of 27 quantitative studies published from 2000 to 2022, the current review identified 17 significant predictors of CSA disclosure. Facilitators of disclosure included older age, being female, higher IQ, recent abuse, resistance during abuse, clergy perpetrator, non-offending caregiver support, and acculturation. Barriers to disclosure included intellectual disability, avoidant coping, romantic relationships with the perpetrator, family criminality, domestic violence, adherence to traditional Asian values, and ethnic minority identity. The findings also suggested that the relationship between predictors and disclosure tends to be mixed, contradictory, or indirect/interactional, emphasizing the importance of situating the findings in specific social-ecological contexts., Conclusions: The findings can inform future research and practice by providing a comprehensive understanding of the predictors of CSA disclosure and highlighting the importance of considering the socio-ecological context when interpreting findings. Moreover, the review provides a valuable resource for professionals who work with victims of CSA, helping them better identify factors that may facilitate or hinder disclosure and allowing for tailored interventions., Competing Interests: Declaration of competing interest There is no conflict of interest among authors to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The food system accounts for ∼ 40 % of human-generated greenhouse gas (GHG) emissions. Meanwhile, daily diet selection also impacts human nutrition status and health., Objectives: This study aimed to use the alternate Mediterranean Diet (aMED) score to evaluate the quality of a low-GHG emission diet and the association with risk of developing metabolic syndrome (MetS)., Methods: A total of 41,659 healthy participants without MetS 40 y of age or older were selected from the Health Examinees Study, an ongoing cohort study in South Korea from 2004. A dietary GHG emissions database was compiled following a national project and literature review. MetS was defined according to the Adult Treatment Panel III criteria of the National Cholesterol Education Program. The participants were grouped into quintiles based on 2,000  kcal -standardized daily diet-GHG emissions (Q1: the lowest energy-adjusted diet-GHG emissions). A multivariable logistic regression model was used to analyze the risk for MetS at follow-up. The aMED score was used to assess the diet quality of the different diet-related GHG emission groups., Results: Females with lower energy-adjusted diet-related GHG emissions had significantly lower risks of developing MetS ( p = 0.0043 ) than those with the highest energy-adjusted diet-related GHG emissions. In addition, the Q1 group, in comparison with the other groups, had a higher aMED score (3.02 for males and 3.00 for females), which indicated that the participants in this group had a diet that more closely matched the Mediterranean diet., Discussion: These findings provide a reference for dietary guidance and other policies aimed toward improving dietary intake and reducing diet-related GHG emissions in South Korea and worldwide. https://doi.org/10.1289/EHP12727.

Scope: Ultra-processing food (UPF) has been a nutrition and health interest. This study is aimed to investigate the association between UPF consumption and the risk of obesity or dyslipidemia., Methods and Results: This study is performed using an ongoing cohort study including 17 310 individuals aged ≥40 years in South Korea. UPF is categorized by the NOVA system and FCS, respectively. After an average 5-year follow-up, there is a positive association between NOVA-defined UPF and dyslipidemia. The risk of the Q4 group is almost 20% higher than that of the Q1 group (men, adjusted HR = 1.209 [95% CI 1.039-1.407], women, adjusted HR = 1.195 [95% CI 1.096-1.303]). Consuming high-FCS foods (less processed and healthier foods) show a lower risk for dyslipidemia in both sexes and lower obesity risk in women compared to low-FCS consumption (men, dyslipidemia, adjusted HR = 0.857 [95% CI 0.744-0.988]; women, dyslipidemia, adjusted HR = 0.919 [95% CI 0.850-0.993], obesity, adjusted HR = 0.759 [95% CI 0.628-0.916])., Conclusion: Higher UPF intakes assessed by the NOVA system and FCS are associated with increased incidences of dyslipidemia and obesity. Furthermore, NOVA-defined UPF shows a statistically significant negative association with AMED score, indicating poor diet quality., (© 2023 Wiley-VCH GmbH.)

Background: Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that are potentially hazardous to human health. Dietary exposure is recognized as one of the major pathways of exposure to PAHs among humans. While some PAH exposures have been associated with metabolic syndrome (MetS) in the general population, most epidemiological studies are based on urinary metabolites of a few noncarcinogenic PAHs., Objective: To investigate the association between estimates of dietary exposure to major carcinogenic PAHs and MetS in Korean adults., Methods: Multi-cycle Korean National Health and Nutrition Examination Survey (KNHANES) database (n = 16,015) and PAH measurement data from the total diet survey were employed to estimate daily PAH intake for each participating adult. After adjusting for potential confounders, multinomial logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) between PAHs and MetS of the participating adults., Results: Benzo(a)pyrene exposure was associated with an increased risk of MetS in men (OR = 1.30; 95% Cl: 1.03-1.63; P-trend = 0.03). In women, however, only chrysene and low high-density lipoprotein (HDL-c) were positively associated with an increased risk of MetS (OR = 1.24; 95% CI: 1.03-1.48; P-trend = 0.0172). Among men, smokers were at an increased risk for MetS, regardless of whether they were exposed to low or high total PAHs and benzo(a)pyrene levels., Significance: Our findings suggested that PAHs are associated with the risk of MetS and MetS components in Korean adults. In particular, it was confirmed that smoking may influence the relationship between PAH exposure and MetS.Further prospective cohort studies are required to confirm the causal relationship between PAHs and MetS., Impact Statement: Epidemiological studies on PAH exposure are often hampered by a lack of reliable exposure estimates, as biomonitoring of urine does not capture exposure to more toxic PAHs. Using multi-cycle KNHANES data and the measurement data from a total diet survey of Korea, we could develop a personalized PAH intake estimate for each participating adult and assessed the association with MetS., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background and Objectives: Osteoblasts are derived from bone marrow mesenchymal stem cells (BMMSCs) and play important role in bone remodeling. While our previous studies have investigated the cell subtypes and heterogeneity in osteoblasts and BMMSCs separately, cell-to-cell communications between osteoblasts and BMMSCs in vivo in humans have not been characterized. The aim of this study was to investigate the cellular communication between human primary osteoblasts and bone marrow mesenchymal stem cells., Methods and Results: To investigate the cell-to-cell communications between osteoblasts and BMMSCs and identify new cell subtypes, we performed a systematic integration analysis with our single-cell RNA sequencing (scRNA-seq) transcriptomes data from BMMSCs and osteoblasts. We successfully identified a novel preosteoblasts subtype which highly expressed ATF3, CCL2, CXCL2 and IRF1. Biological functional annotations of the transcriptomes suggested that the novel preosteoblasts subtype may inhibit osteoblasts differentiation, maintain cells to a less differentiated status and recruit osteoclasts. Ligand-receptor interaction analysis showed strong interaction between mature osteoblasts and BMMSCs. Meanwhile, we found FZD1 was highly expressed in BMMSCs of osteogenic differentiation direction. WIF1 and SFRP4 , which were highly expressed in mature osteoblasts were reported to inhibit osteogenic differentiation. We speculated that WIF1 and sFRP4 expressed in mature osteoblasts inhibited the binding of FZD1 to Wnt ligand in BMMSCs, thereby further inhibiting osteogenic differentiation of BMMSCs., Conclusions: Our study provided a more systematic and comprehensive understanding of the heterogeneity of osteogenic cells. At the single cell level, this study provided insights into the cell-to-cell communications between BMMSCs and osteoblasts and mature osteoblasts may mediate negative feedback regulation of osteogenesis process.

Background: Lipid pathways have been implicated in the pathogenesis of osteoporosis (OP). Lipid-lowering drugs may be used to prevent and treat OP. However, the causal interpretation of results from traditional observational designs is controversial by confounding. We aimed to investigate the causal association between genetically proxied lipid-lowering drugs and OP risk. Methods: We conducted two-step Mendelian randomization (MR) analyses to investigate the causal association of genetically proxied lipid-lowering drugs on the risk of OP. The first step MR was used to estimate the associations of drug target genes expression with low-density lipoprotein cholesterol (LDL-C) levels. The significant SNPs in the first step MR were used as instrumental variables in the second step MR to estimate the associations of LDL-C levels with forearm bone mineral density (FA-BMD), femoral neck BMD (FN-BMD), lumbar spine BMD (LS-BMD) and fracture. The significant lipid-lowering drugs after MR analyses were further evaluated for their effects on bone mineralization using a dexamethasone-induced OP zebrafish model. Results: The first step MR analysis found that the higher expression of four genes ( HMGCR , NPC1L1 , PCSK9 and PPARG ) was significantly associated with a lower LDL-C level. The genetically decreased LDL-C level mediated by the PPARG was significantly associated with increased FN-BMD (BETA = -1.38, p = 0.001) and LS-BMD (BETA = -2.07, p = 3.35 × 10 -5 ) and was marginally significantly associated with FA-BMD (BETA = -2.36, p = 0.008) and reduced fracture risk (OR = 3.47, p = 0.008). Bezafibrate (BZF) and Fenofibric acid (FBA) act as PPARG agonists. Therefore genetically proxied BZF and FBA had significant protective effects on OP. The dexamethasone-induced OP zebrafish treated with BZF and FBA showed increased bone mineralization area and integrated optical density (IOD) with alizarin red staining. Conclusion: The present study provided evidence that BZF and FBA can increase BMD, suggesting their potential effects in preventing and treating OP. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of OP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Pang, Zhang, Liu, Yi, Wang, Zhang, Deng, Chen, Greenbaum, Xiao, Deng and Tan.)

Background: MiRNAs can affect the radiosensitization of head and neck squamous cell carcinoma (HNSCC). We aimed to analyze the function of miR-125 family members in HNSCC using The Cancer Genome Atlas (TCGA) and determine their effect on radiation in laryngeal squamous cell cancer (LSCC)., Methods: First, we systematically analyzed the role of the miR-125 family in HNSCC using the TCGA database and found that miR-125a-5p is associated with radiotherapy. We then performed comprehensive enrichment analysis of miR-125a-5p and predicted target genes. Then, we performed transfection, cell proliferation assays, reverse transcription polymerase chain reaction, apoptosis assays, micronucleus tests, and western blotting on hep-2 cells selected with puromycin., Results: MiR-125 family members exhibited significantly different expression in HNSCC. They were significantly associated with tumor-node-metastasis staging, clinical stages, and histological grades. Radiation therapy had a statistically effect on miR-125 family members, except miR-125a-3p. Moreover, miR-125a-5p was related to overall survival in LSCC. Thus, we predicted 110 target genes and seven hub genes of miR-125a-5p. The proliferation rate of cells transfected with lentivirus vector expressing miR-125a-5p was significantly reduced compared to the other groups. The radiation effect was enhanced in cells transfected with miR-125a-5p. The ratio of apoptotic cells transfected and exposed to X-rays (10 Gy) was distinctly higher than that of the Ad-control group. Western blotting analysis revealed that miR-125a-5p upregulated the apoptotic regulators P53 and rH2AX. Thus, miR-125a-5p may increase radiosensitivity in LSCC via upregulation of pro-apoptotic genes., Conclusions: MiR-125 family members could be prognostic biomarkers of HNSCC and improve HNSCC sensitivity to radiotherapy by activating P53. Upregulating miR-125a-5p via lentivirus vectors may be a novel strategy to strengthen the effect of radiotherapy on LSCC., (© 2023. The Author(s).)

Background: Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas., Patients and Methods: A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world., Results: MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance., Conclusion: In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers., Competing Interests: Disclosure BL, GW, YX, SC, SC, and ZZ declare employment in Burning Rock Biotech. All other authors have declared no conflicts of interest. Data sharing The authors declare that relevant data supporting the findings of this study are available within the paper and its Supplementary files. Due to ethical and privacy concerns, we are unable to publish the patient-level data in our study, of which readers may contact the corresponding authors for the access for non-commercial purposes., (Copyright © 2023. Published by Elsevier Ltd.)

Surgery is the primary treatment for esophageal cancer, but the postoperative complication rate remains high. Therefore, it is important to prevent and manage postoperative complications to improve prognosis. Common perioperative complications of esophageal cancer include anastomotic leakage, gastrointestinal tracheal fistula, chylothorax, and recurrent laryngeal nerve injury. Respiratory and circulatory system complications, such as pulmonary infection, are also quite common. These surgery-related complications are independent risk factors for cardiopulmonary complications. Complications, such as long-term anastomotic stenosis, gastroesophageal reflux, and malnutrition are also common after esophageal cancer surgery. By effectively reducing postoperative complications, the morbidity and mortality of patients can be reduced, and their quality of life can be improved.

The impact of kimchi intake on weight management has been a topic of interest. We aimed to conduct an epidemiological study to investigate the association between kimchi intake and weight loss. Participants were selected from the Health Examinees cohort study. Kimchi intake was assessed by a 106-item semi-quantitative food frequency questionnaire, including four types of kimchi. Obesity was defined according to the Korean Society for the Study of Obesity guidelines. We performed a correlation analysis among all participants ( N = 58 290) and conducted a prospective risk assessment analysis among participants with a baseline BMI value ≥25 kg m -2 ( N = 20 066). In the correlation analysis, higher kimchi consumption was found to be associated with a lower increment in BMI change (men, β 0.169, 95% CI (0.025, 0.313); women, β 0.140, 95% CI (0.046, 0.236)) compared with the lower group. The risk assessment analysis indicated that moderate kimchi consumption is associated with normal weight development in men (Q3, hazard ratio, 1.28, 95% CI (1.06, 1.54)). Baechu [cabbage] kimchi intake also showed a significant association among men participants (all p for trend <0.05). In conclusion, moderate kimchi intake was associated with weight loss among middle-aged and older Koreans, especially in men.

Background: Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC)., Patients and Methods: Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596)., Results: A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28], with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802)., Conclusions: NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC., Competing Interests: Disclosure The authors have declared no conflicts of interest. Data sharing Deidentified individual participant data (including a data dictionary) that underlie the results reported in this article will be shared beginning 9 months and ending 36 months following publication. Investigators who wish to use the data for individual patient data meta-analysis can direct their proposal to the corresponding author (tan.lijie@zs-hospital.sh.cn). Data will be made available via an appropriate data archive., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreER T2 transgenic (Tg) mouse employing previously identified hematopoietic stem cell (HSC) enhancer for Runx1, eR1 (+24 m). Kinetic analysis of labeled cells after tamoxifen injection and transplantation assays revealed that eR1-driven CreER T2 activity marks dormant adult HSCs which slowly but steadily contribute to unperturbed hematopoiesis. Fetal and child HSCs that are uniformly or intermediately active were also efficiently targeted. Notably, a gene ablation at distinct developmental stages, enabled by this system, resulted in different phenotypes. Similarly, an oncogenic Kras induction at distinct ages caused different spectrums of malignant diseases. These results demonstrate that the eR1-CreER T2 Tg mouse serves as a powerful resource for the analyses of both normal and malignant HSCs at all developmental stages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Understanding the principle of regulated cell death (RCD) such as ferroptosis and apoptosis provides opportunities to overcome sorafenib resistance of HCC. Complexin II (CPLX2) is involved in calcium-dependent fusion of vesicles and plasma membrane, and recent studies showed CPLX2 is involved in cancer progression. However, the expression and function of CPLX2 are unclear in hepatocellular carcinoma (HCC). qPCR and western blotting assays were used to detect the levels of CPLX2. MTT and colony formation assays were used to detect cell viability. The contents of iron, ROS, MDA, and GSH were used to evaluate the function of CPLX2 on ferroptosis, while the flow cytometry and TUNEL assays were used to evaluate the role of CPLX2 on apoptosis. Our analysis showed CPLX2 is significantly upregulated in HCC, which predicts poor overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), and disease-specific survival (DSS) for patients with HCC. Further function enrichment analysis of genes related to CPLX2 showed CPLX2 is involved in the NRF2 pathway. Downregulation of CPLX2 can inhibit NRF2 expression and the transcription of its downstream genes, which confirms that CPLX2 is involved in NRF2 pathway. Cell viability assay showed that ferroptosis and apoptosis inhibitors can reverse the inhibition effect of CPLX2-knockdown on cell survival, respectively. And downregulation of CPLX2 significantly promotes the contents of iron, ROS, and MDA, while inhibiting the GSH level of HCC cell lysate, suggesting CPLX2 involved in ferroptosis. Moreover, downregulation of CPLX2 promotes the apoptosis of HCC cells by flow cytometry and TUNEL assay. And upregulation of NRF2 can partly reverse the inhibitory effect of CPLX2-downregulation on ferroptosis and apoptosis. Finally, we found downregulation of CPLX2 aggravates cell death induced by sorafenib. CPXL2 regulates ferroptosis and apoptosis through NRF2 pathway, and CPLX2 knockdown promotes cell death induced by sorafenib. CPLX2 might be an effective target for therapy patients with HCC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The objective of this study was to compare the characteristics of Dental Pulp Stem Cells (DPSCs) derived from healthy human permanent teeth with those that were orthodontically-intruded to serve as potential Mesenchymal Stem Cells (MSC). Recruited subjects were treated with orthodontic intrusion on one side of the maxillary first premolar while the opposite side served as the control for a period of six weeks before the dental pulp was extracted. Isolated DPSCs from both the control and intruded samples were analyzed, looking at the morphology, growth kinetics, cell surface marker profile, and multilineage differentiation for MSC characterisation. Our study showed that cells isolated from both groups were able to attach to the cell culture flask, exhibited fibroblast-like morphology under light microscopy, able to differentiate into osteogenic, adipogenic and chondrogenic lineages as well as tested positive for MSCs cell surface markers CD90 and CD105 but negative for haematopoietic cell surface markers CD34 and HLA-DR. Both groups displayed a trend of gradually increasing population doubling time from passage 1 to passage 5. Viable DPSCs from both groups were successfully recovered from their cryopreserved state. In conclusion, DPSCs in the dental pulp of upper premolar not only remained viable after 6 weeks of orthodontic intrusion using fixed appliances but also able to develop into MSCs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Lau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

During the COVID-19 pandemic, immunization programs for other respiratory infections, notably influenza continued worldwide but attracted less public or political attention than COVID-19 vaccinations. Due to non-pharmaceutical intervention measures the global influenza burden decreased substantially; but with lifting of restrictions a rebound in other respiratory virus pathogens is both plausible and likely. This article discusses lessons identified from the UK and USA, and provides recommendations for future influenza vaccination programs in light of emerging data from the southern hemisphere and the need for harmonization with COVID-19 vaccination, focusing on operational delivery and messaging to practitioners and the public.

BACKGROUNDCytochrome P450 family 8 subfamily B member 1 (CYP8B1) generates 12α-hydroxylated bile acids (BAs) that are associated with insulin resistance in humans.METHODSTo determine whether reduced CYP8B1 activity improves insulin sensitivity, we sequenced CYP8B1 in individuals without diabetes and identified carriers of complete loss-of-function (CLOF) mutations utilizing functional assays.RESULTSMutation carriers had lower plasma 12α-hydroxylated/non-12α-hydroxylated BA and cholic acid (CA)/chenodeoxycholic acid (CDCA) ratios compared with age-, sex-, and BMI-matched controls. During insulin clamps, hepatic glucose production was suppressed to a similar magnitude by insulin, but glucose infusion rates to maintain euglycemia were higher in mutation carriers, indicating increased peripheral insulin sensitivity. Consistently, a polymorphic CLOF CYP8B1 mutation associated with lower fasting insulin in the AMP-T2D-GENES study. Exposure of primary human muscle cells to mutation-carrier CA/CDCA ratios demonstrated increased FOXO1 activity, and upregulation of both insulin signaling and glucose uptake, which were mediated by increased CDCA. Inhibition of FOXO1 attenuated the CDCA-mediated increase in muscle insulin signaling and glucose uptake. We found that reduced CYP8B1 activity associates with increased insulin sensitivity in humans.CONCLUSIONOur findings suggest that increased circulatory CDCA due to reduced CYP8B1 activity increases skeletal muscle insulin sensitivity, contributing to increased whole-body insulin sensitization.FUNDINGBiomedical Research Council/National Medical Research Council of Singapore.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in December 2019. An immediate prevention approach for the outbreak is the development of a vaccination program. Despite a growing number of publications showing the effectiveness of vaccination in preventing SARS-CoV-2 outbreak and reducing the mortality rate, substantial fatal adverse effects were reported after vaccination. Confirmation of the causal relationship of death is required to reimburse under the national vaccination program and could provide a reference for the selection of vaccination. However, a lack of guidelines in the laboratory study and autopsy approach hampered the investigation of post-vaccination death. In this paper, we performed a systematic electronic search on scientific articles related to severe Covid-19 vaccination adverse effects and approaches in identifying the severe side effects using PubMed and Cochrane libraries. A summary on the onset, biochemistry changes and histopathological analyzes of major lethally side effects post-vaccination were discussed. Ultimately, a checklist is suggested to improve the quality of investigation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Recently, single-cell RNA sequencing (scRNA-seq) technology was increasingly used to study transcriptomics at a single-cell resolution, scRNA-seq analysis was complicated by the "dropout", where the data only captures a small fraction of the transcriptome. This phenomenon can lead to the fact that the actual expressed transcript may not be detected. We previously performed osteoblast subtypes classification and dissection on freshly isolated human osteoblasts., Materials and Methods: Here, we used the scImpute method to impute the missing values of dropout genes from a scRNA-seq dataset generated on freshly isolated human osteoblasts., Results: Based on the imputed gene expression patterns, we discovered three new osteoblast subtypes. Specifically, these newfound osteoblast subtypes are osteoblast progenitors, and two undetermined osteoblasts. Osteoblast progenitors showed significantly high expression of proliferation related genes ( FOS, JUN, JUNB and JUND ). Analysis of each subtype showed that in addition to bone formation, these undetermined osteoblasts may involve osteoclast and adipocyte differentiation and have the potential function of regulate immune activation., Conclusions: Our findings provided a new perspective for studying the osteoblast heterogeneity and potential biological functions of these freshly isolated human osteoblasts at the single-cell level, which provides further insight into osteoblasts subtypes under various (pathological) physiological conditions., Competing Interests: The authors declare no conflict of interest. Liang Cheng is serving as Guest Editor of this journal. We declare that Liang Cheng had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Elisa Belluzzi., (© 2022 The Author(s). Published by IMR Press.)

Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near-exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling "inside-out" model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies., (© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background: The benefits of fish fatty acid intake for non-alcoholic fatty liver disease (NAFLD) are rarely reported, although a previous study assessed the relationship between oily fish consumption and the prevalence of NAFLD., Aims: We investigated whether oily fish and fish-based monounsaturated fatty acids, polyunsaturated fatty acids, and omega-3 fatty acids affect the development of NAFLD in South Korean adults., Methods: In this large-scale cohort study, 44,139 participants of the Health Examinees study were selected for analysis after 5 years of follow-up. NAFLD is diagnosed with a non-invasive index, the fatty liver index. Using multivariable Cox proportional hazards models, adjusted for age, body mass index, total energy intake, education, physical activity, smoking status, and drinking (alcohol) status, we calculated the hazard ratios and 95% confidence intervals., Results: For men, NAFLD had no statistically significant associations with quartiles of total oily fish or its fatty acid intake. However, among women, an inverse association was observed (all p for trend <0.05). Regarding the standard deviation (SD) increment of total oily fish or its fatty acid intake by one, all fatty acids from oily fish showed inverse associations for NAFLD in both men and women. After stratified analyses, we found that drinking status and menopause status were independent risk factors for NAFLD. Oily fish or its fatty acid intake has the same benefit pattern on metabolic dysfunction-associated fatty liver disease as NAFLD., Conclusion: Oily fish and its fatty acid intake showed a preventative benefit for NAFLD and metabolic dysfunction-associated fatty liver disease, especially in South Korean women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tan and Shin.)

Objectives: Antioxidants are common dietary compounds with multiple health benefits. This study aimed to identify the association between dietary antioxidant consumption and the incidence of type 2 diabetes (T2D) mellitus (defined using the Korean Diabetes Association criteria) in South Korean adults., Design: Baseline and follow-up data from the Health Examinees (HEXA) study, a large-scale community-based genomic cohort study conducted in South Korea SETTING: A South Korean community., Participants: A total of 20 594 participants, aged 40-79 years, who participated in the baseline and follow-up surveys of the HEXA study were included. After an average of 5 years of follow-up, there were 332 men and 360 women with T2D., Results: Participants with the highest total flavonoid consumption (Q5) had a lower risk of T2D (men: HR 0.63; 95% CI 0.42 to 0.93; p value for trend=0.0169; and women: HR 0.54; 95% CI 0.438 to 0.78; p value for trend=0.0001) than those with the lowest consumption (Q1). Dietary total antioxidant capacity was significantly inversely associated with the development of T2D mellitus in women participants alone (HR 0.58; 95% CI 0.40 to 0.83; p value for trend=0.0004). Stratified analyses according to age and body mass index (BMI) showed that dietary total flavonoid consumption and total antioxidant capacity had a negative association with the development of T2D in women aged >52 years and women with BMI >25 kg/m 2 ., Conclusions: Dietary flavonoid consumption and total antioxidant capacity were associated with a lower risk of T2D in South Korean adults, especially in women aged >52 years and overweight. The findings of this study may provide reference data for the modification of dietary guidelines for South Koreans., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC 50 value of 0.5 μM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by -NO 2 significantly enhanced the anticancer activity. Mechanism studies indicated that 4 and 4B induced cell cycle arrest at G2/M phase; in contrast, 4V induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca 2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds 4, 4B and 4V, suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Adenocarcinoma of the esophaogastric junction (AEG) has anatomical characteristics of spanning two organs and anatomical sites. Thoracic surgery and gastrointestinal surgery aim at the safe resection margin of esophagus, the scope of lower mediastinal lymph node dissection and whether transthoracic surgery will increase complications. However, there are great differences and controversies in the surgical approach, surgical method, lymph node dissection and extent of resection of AEG. For Siewert II AEG via abdominal mediastinal approach, due to the limitation of exposure and the difficulty of operation, it is difficult to acquire a satisfactory proximal resection margin, and very difficult to dissect the inferior mediastinal lymph nodes. The transthoracic approach can provide adequate exposure, reduce the difficulty of operation, obtain satisfactory resection margin of esophagus and allow lower mediastinal lymph node dissection, which may bring better prognosis. Although transthoracic approach may increase the incidence of pulmonary infection, the standard development of thoracoscopic technology will overcome the disadvantage of transthoracic approach for Siewert II AEG.

Objectives: Metabolic syndrome (MetS) is closely associated with dietary intake; however, few studies have investigated whether the consumption of fruits and vegetables and multivitamin use affect MetS in the Korean population. This study aimed to examine these effects in Korean adults., Methods: This was a cross-sectional study of 89,548 participants aged between 40 years and 69 years selected from the baseline data of the Health Examinees study conducted in Korea. Fresh vegetable and fruit consumption was assessed using a validated 106-item food frequency questionnaire. MetS and its components were defined using the National Cholesterol Education Program, Adult Treatment Panel III criteria. Multivariate logistic regression analyses were conducted to identify associations of fresh vegetable, fruit, and fresh vegetable+fruit consumption and multivitamin use with the prevalence of MetS., Results: Female in the highest quartile of fresh vegetable, fruit, and fresh vegetable + fruit consumption exhibited a lower prevalence of MetS than those in the lowest quartile. An inverse association with the prevalence of MetS was observed among male with only fresh vegetable consumption. The interaction between the 3 categories and multivitamin intake on the prevalence of MetS was not significant (all pinteraction>0.05), regardless of sex., Conclusions: Multivitamin use and consumption of fresh vegetables and fruits had no significant synergistic effects. Although fresh vegetable and fruit consumption showed an inverse association with the prevalence of MetS, this relationship was not altered by multivitamin use.

Maintaining genomic integrity and stability is crucial for life; yet, no tissue-driven mechanism that robustly safeguards the epithelial genome has been discovered. Epidermal stem cells (EpiSCs) continuously replenish the stratified layers of keratinocytes that protect organisms against various environmental stresses. To study the dynamics of DNA-damaged cells in tissues, we devised an in vivo fate tracing system for EpiSCs with DNA double-strand breaks (DSBs) and demonstrated that those cells exit from their niches. The clearance of EpiSCs with DSBs is caused by selective differentiation and delamination through the DNA damage response (DDR)-p53-Notch/p21 axis, with the downregulation of ITGB1. Moreover, concomitant enhancement of symmetric cell divisions of surrounding stem cells indicates that the selective elimination of cells with DSBs is coupled with the augmented clonal expansion of intact stem cells. These data collectively demonstrate that tissue autonomy through the dynamic coupling of cell-autonomous and non-cell-autonomous mechanisms coordinately maintains the genomic quality of the epidermis., Competing Interests: Declaration of interests E.K.N. is a founder and shareholder of EADERM and a member of its scientific advisory board. D.A.S. is a founder, equity owner, advisor to, director of, board member of, consultant to, investor in and/or inventor on patents licensed to Revere Biosensors, UpRNA, GlaxoSmithKline, Wellomics, DaVinci Logic, InsideTracker (Segterra), Caudalie, Animal Biosciences, Longwood Fund, Catalio Capital Management, Frontier Acquisition Corporation, AFAR (American Federation for Aging Research), Life Extension Advocacy Foundation (LEAF), Cohbar, Galilei, EMD Millipore, Zymo Research, Immetas, Bayer Crop Science, EdenRoc Sciences (and affiliates Arc-Bio, Dovetail Genomics, Claret Bioscience, MetroBiotech, Astrea, Liberty Biosecurity and Delavie), Life Biosciences, Alterity, ATAI Life Sciences, Levels Health, Tally (aka Longevity Sciences) and Bold Capital. D.A.S. is an inventor on a patent application filed by Mayo Clinic and Harvard Medical School that has been licensed to Elysium Health. More information at https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. The other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Bone mineral density (BMD) and whole-body lean mass (WBLM) are two important phenotypes of osteoporosis and sarcopenia. Previous studies have shown that BMD and lean mass were phenotypically and genetically correlated. To identify the novel common genetic factors shared between BMD and WBLM, we performed the conditional false discovery rate (cFDR) analysis using summary data of the genome-wide association study of femoral neck BMD (n = 53,236) and WBLM (n = 38,292) from the Genetic Factors for Osteoporosis Consortium (GEFOS). We identified eight pleiotropic Single Nucleotide Polymorphism (SNPs) (PLCL1 rs11684176 and rs2880389, JAZF1 rs198, ADAMTSL3 rs10906982, RFTN2/MARS2 rs7340470, SH3GL3 rs1896797, ST7L rs10776755, ANKRD44/SF3B1 rs11888760) significantly associated with femoral neck BMD and WBLM (ccFDR < 0.05). Bayesian fine-mapping analysis showed that rs11888760, rs198, and rs1896797 were the possible functional variants in the ANKRD44/SF3B1, JAZF1i, and SH3GL3 loci, respectively. Functional annotation suggested that rs11888760 was likely to comprise a DNA regulatory element and linked to the expression of RFTN2 and PLCL1. PLCL1 showed differential expression in laryngeal posterior cricoarytenoid muscle between rats of 6 months and 30 months of age. Our findings, together with PLCL1's potential functional relevance to bone and skeletal muscle function, suggested that rs11888760 was the possible pleiotropic functional variants appearing to coregulate both bone and muscle metabolism through regulating the expression of PLCL1. The findings enhanced our knowledge of genetic associations between BMD and lean mass and provide a rationale for subsequent functional studies of the implicated genes in the pathophysiology of diseases, such as osteoporosis and sarcopenia., (© 2021 John Wiley & Sons Ltd/University College London.)

Background: There is a dearth of information regarding the association between coffee consumption and its health effects with respect to mortality among Korean people., Objective: The aim of this study was to examine the association between coffee consumption and all-cause mortality and cause-specific mortality risks in the Korean population., Design: This prospective cohort study had a median follow-up period of 9.1 years., Participants/setting: In total, 173,209 participants aged 40 years and older from the Health Examinees study were enrolled between 2004 and 2013. The analytic sample included 110,920 participants without diabetes, cardiovascular disease (CVD), or cancer at baseline who could be linked with their death information., Main Outcome Measures: Deaths of participants until December 31, 2018 were ascertained using the death certificate database of the National Statistical Office. Cause of death was classified according to the International Classification of Diseases, 10th Revision., Statistical Analyses Performed: Participants were categorized according to the amount and type of coffee consumed. Cox proportional hazards regression analysis was performed to estimate the hazard ratio (HR) and 95%CI of all-cause mortality and cause-specific mortality, such as CVD and cancer mortality., Results: Compared with nonconsumers of coffee, participants who consumed > 3 cups/day had a reduced risk of all-cause mortality (HR 0.79, 95% CI 0.66 to 0.95). Participants who consumed ≤1 cup/day and 1 to 3 cups/day had a reduced risk of CVD mortality (≤1 cup/day: HR 0.58, 95% CI 0.69 to 0.94; 1 to 3 cups/day: HR 0.62, 95% CI 0.41 to 0.96)., Conclusions: This study provides evidence that greater coffee consumption is associated with a decreased risk of all-cause mortality and moderate coffee consumption (approximately 3 cups/day) is associated with a decreased risk of CVD mortality, regardless of the type of coffee, in a Korean population., (Copyright © 2021 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: We explored the feasibility and safety of modified subxiphoid thoracoscopic thymectomy for patients with locally invasive thymomas., Methods: Subxiphoid thoracoscopic thymectomy was performed on select patients with locally invasive thymomas (Masaoka stage III) using an auxiliary sternal retractor to create a larger operative field., Results: From June 2015 to March 2019, we performed modified subxiphoid thoracoscopic thymectomy on 48 patients with locally invasive thymomas: 39 patients had pericardium or lung infiltration and received a combination of a partial pericardium or lung wedge resection, and 9 patients had left innominate vein infiltration and underwent combined resection of the left innominate vein. Thoracoscopic thymectomy was performed from the subxiphoid pathway with an auxiliary sternal retractor in all 48 patients, and there were no conversions to median sternotomy. The median tumor size was 5 cm, and the maximal tumor size was 12 cm. The median blood loss was 50 mL. The median duration of chest tube placement was 3 days, and the median hospital stay was 4.5 days after surgery. All patients achieved a good recovery after surgery, and none had serious complications during the perioperative period. All patients underwent postoperative adjuvant radiotherapy and presented no local recurrence or distant metastasis until now., Conclusions: Modified subxiphoid thoracoscopic thymectomy with an auxiliary sternal retractor makes minimally invasive thymectomy easier and safer to perform and is an alternative approach for some patients with locally invasive thymomas., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-634). Dr. IJO has grant from Roche; he also has received consulting fee from Roche, Ono, MSD, Pfizer, Boehringer-Ingelheim, AstraZeneca and Takeda. Dr. YT reports grants from JSPS KAKENHI grant number JP18K15928 and grants from Takeda Science Foundation outside the submitted work. Dr. SW reports grant and personal fee from AstraZeneca and Boehringer Ingelheim, personal fee from Chugai Pharma, Ono Pharmaceutical, Bristol-Myers, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Novartis, Daiichi Sankyo. Dr. RC has received consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, MSD, BMS, Roche, TAKEDA, Pfizer, janssen, Bayer, Novartis; Dr. RC has Participation on a Data Safety Monitoring Board or Advisory Board with AZ, MSD, BMS, Roche, TAKEDA, Pfizer, janssen, Bayer, Novartis; Dr. RC has received Support for attending meetings and/or travel from Roche, MSD, Takeda; Dr. RC declares stock ownership with The christie private care. Dr. KM reports medical education grant, Africa from Varian and Pfizer, Clinical trial grant from AstraZeneca and Novartis; travel and accommodations to a clinical trial meeting, 2019 from AstraZeneca; Dr. KM is an unpaid Board of Directors of Global Access to Cancer Care Foundation. Dr. JCS has grant support from National Institute of Health and the Noah’s Hope Foundation; she also has a family member that owns stock options and receives financial compensation from Vida Diagnostics. Dr. MF participated in advisory board for Astrazeneca, AbbVie and Beigene LLC. Dr. DDR reports grants from Bristol-Myers Squibb, grants from AstraZeneca, grants from Boehringer Ingelheim, from Philips, from Olink, from Celgene, from Seattle Genetics, from Roche/Genentech, from Merck/Pfizer, outside the submitted work. Dr. FC reports fees for membership of an advisory board from Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Pharmamar, Novocure and MSD. Dr NS obtained commercial research grants from Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Japan, Ono Pharmaceutical, and Nippon Boehringer Ingelheim, and has received speaking honoraria from Eli Lilly, AstraZeneca, MSD Oncology, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Japan, Ono Pharmaceutical, Nippon Boehringer Ingelheim, and Bristol-Myers Squibb Japan. TH serves as an unpaid editorial board member of Translational Lung Cancer Research from Jan 2020 to Dec 2021. FC serves as an unpaid editorial board member of Translational Lung Cancer Research from Aug 2021 to Jul 2023. MF serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2019 to Sep 2021. SY serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2019 to Sep 2021. GM serves as an unpaid editorial board member of Translational Lung Cancer Research from Aug 2021 to Jul 2023. PH serves as an unpaid editorial board member of Translational Lung Cancer Research from Mar 2021 to Feb 2023. The other authors have no conflicts of interest to declare.

Scope: To identify the cross-sectional and prospective association between coffee consumption and nonalcoholic fatty liver disease (NAFLD) among South Korean adults., Methods and Results: Participants are selected from the Health Examinees study. NAFLD is defined using three non-invasive indexes: fatty liver index (FLI), hepatic steatosis index, and fibrosis-4 calculator (FIB-4). In the cross-sectional analysis, higher habitual coffee consumption is associated with a lower risk for NAFLD, define using the FLI, (men, odds ratio [OR] 0.702; women, OR 0.810) compared with non-consumers. Participants who consumed coffee with sugar and creamer also have a lower risk for NAFLD, defined using the FIB-4, compared with non-coffee-consumers (men, OR 0.739; women, OR 0.807). A prospective analysis indicated that higher coffee consumption is associated with a lower incidence of NAFLD, defined using the FLI, in men (hazard ratio, 0.706). In both men and women, a lower FIB-4 index score is associated with higher coffee consumption regardless of coffee type (all p-value <0.05)., Conclusions: Coffee consumption of >3 cups per day has a protective effect against the development of NAFLD to a certain extent, and a negative association is found between coffee consumed with sugar and creamer and the FIB-4 index score in South Korean adults., (© 2021 Wiley-VCH GmbH.)