Role of the STING-IRF3 pathway in ambient GABA homeostasis and cognitive function.

Targeting altered expression and/or activity of GABA transporters (GATs) provide therapeutic benefit for age-related impairments, including cognitive dysfunction. However, the mechanisms underlying the transcriptional regulation of GATs are unknown. In the present study, we demonstrated that the stimulator of interferon genes (STING) upregulates GAT1 and GAT3 expression in the brain which resulted in cognitive dysfunction. Genetic and pharmacological intervention of STING suppressed the expression of both GAT1 and GAT3, increased the ambient GABA concentration, and therefore, enhanced tonic GABAA inhibition of principal hippocampal neurons, resulting in spatial learning and working memory deficits in mice in a type I interferon (IFN I)-independent manner. Stimulation of the STING-GAT pathway efficiently restored cognitive dysfunction in STING-deficient mice models. Our study uncovered for the first time that the STING signaling pathway regulates GATs expression in a cell autonomous manner and therefore could be a novel target for GABAergic cognitive deficits.Significance Statement GABA concentration in extracellular space is maintained by GABA release and clearance of GABA back to brain cells for degradation. GABA clearance from the synaptic cleft predominantly depends on level and activity of GABA transporters (GATs) in the brain. Insufficient GABA clearance resulted to an aberrant tonic GABAA inhibition in brain. In this study, we have identified an unusually high GABA content in brain of STING-deficient mice, resulting in cognitive impairment. Our results show that STING regulates GATs expression through STING-TBK1-IRF3 pathway and thus regulates GABAergic tone. This is the first study that indicates that the STING-TBK1-IRF3 signaling pathway maintains GABA homeostasis in brain, which may offer a novel therapeutic target for modulating GABAergic tone in cases of cognitive dysfunction.

Emotional responses of Korean and Chinese women to Hangul phonemes to the gender of an artificial intelligence voice.

Introduction: This study aimed to explore the arousal and valence that people experience in response to Hangul phonemes based on the gender of an AI speaker through comparison with Korean and Chinese cultures. Methods: To achieve this, 42 Hangul phonemes were used, in a combination of three Korean vowels and 14 Korean consonants, to explore cultural differences in arousal, valence, and the six foundational emotions based on the gender of an AI speaker. A total 136 Korean and Chinese women were recruited and randomly assigned to one of two conditions based on voice gender (man or woman). Results and discussion: This study revealed significant differences in arousal levels between Korean and Chinese women when exposed to male voices. Specifically, Chinese women exhibited clear differences in emotional perceptions of male and female voices in response to voiced consonants. These results confirm that arousal and valence may differ with articulation types and vowels due to cultural differences and that voice gender can affect perceived emotions. This principle can be used as evidence for sound symbolism and has practical implications for voice gender and branding in AI applications.

Adequate Dose of Levothyroxine for Thyroid-Stimulating Hormone Suppression after Total Thyroidectomy in Patients with Differentiated Thyroid Cancer.

BACKGRUOUND: The adequate dose of levothyroxine (LT4) for patients who have undergone total thyroidectomy (TT) for differentiated thyroid cancer (DTC) is uncertain. We evaluated the LT4 dose required to achieve mild thyroid-stimulating hormone (TSH) suppression in DTC patients after TT. METHODS: The electronic medical records of patients who underwent TT for DTC and received mild TSH suppression therapy were reviewed. Linear regression analysis was performed to evaluate the association between LT4 dose (µg/kg) and an ordinal group divided by body mass index (BMI). We also evaluated the trend in LT4 doses among groups divided by BMI and age. RESULTS: In total, 123 patients achieved mild TSH suppression (0.1 to 0.5 mIU/L). The BMI variable was divided into three categories: <23 kg/m2 (n=46), ≥23 and <25 kg/m2 (n=30), and ≥25 kg/m2 (n=47). In the linear regression analysis, BMI was negatively associated with the LT4 dose after adjusting for age and sex (P<0.001). The LT4 doses required to achieve mild TSH suppression based on the BMI categories were 1.86, 1.71, and 1.71 µg/kg, respectively (P for trend <0.001). Further analysis with groups divided by age and BMI revealed that a higher BMI was related to a lower LT4 dose, especially in younger patients aged 20 to 39 (P for trend=0.011). CONCLUSION: The study results suggest an appropriate LT4 dose for mild TSH suppression after TT based on body weight in patients with DTC. Considering body weight, BMI, and age in estimating LT4 doses might help to achieve the target TSH level promptly.

RIPK3 causes mitochondrial dysfunction and albuminuria in diabetic podocytopathy through PGAM5-Drp1 signaling.

BACKGROUND: Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD. METHODS: We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3. RESULTS: RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05-4.98]) and incident chronic kidney disease (HR 4.08 [1.10-15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1. CONCLUSIONS: The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.

Transcriptome Profiling of Gene Expression in Atlantic Salmon (Salmo salar) at Early Stage of Development.

For Atlantic salmon development, the most critical phase is the early development stage from egg to fry through alevin. However, the studies investigating the early development of Atlantic salmon based on RNA-seq are scarce and focus only on one stage of development. Therefore, using the RNA-seq technology, the assessment of different gene expressions of various early development stages (egg, alevin, and fry) was performed on a global scale. Over 22 GB of clean data was generated from 9 libraries with three replicates for each stage with over 90% mapping efficiency. A total of 5534 genes were differentially expressed, among which 19, 606, and 826 genes were specifically expressed in each stage, respectively. The transcriptome analysis showed that the number of differentially expressed genes (DEGs) increased as the Atlantic salmon progressed in development from egg to fry stage. In addition, gene ontology enrichment demonstrated that egg and alevin stages are characterized by upregulation of genes involved in spinal cord development, neuron projection morphogenesis, axonogenesis, and cytoplasmic translation. At the fry stage, upregulated genes were enriched in the muscle development process (muscle cell development, striated muscle cell differentiation, and muscle tissue development), immune system (defense response and canonical NF-kappaB signal transduction), as well as epidermis development. These results suggest that the early development of Atlantic salmon is characterized by a dynamic shift in gene expression and DEGs between different stages, which provided a solid foundation for the investigation of Atlantic salmon development.

Generation of rescued Japanese encephalitis virus genotype 1 from infectious full-size clone using reverse genetics.

Japanese encephalitis virus (JEV) is a pathogen responsible for high mortality and morbidity rates among children with encephalitis. Since JEV genotype 1 (GI) is the most prevalent strain in South Korea these days, corresponding research and vaccine development is urgently required. Molecular genetic studies on JEV vaccines can be boosted by obtaining genetically stable full-length infectious JEV complementary DNA (cDNA) clones. Furthermore, the significance of the reverse genetics system in facilitating molecular biological analyses of JEV properties has been demonstrated. This study constructed a recombinant JEV-GI strain using a reverse genetics system based on a Korean wild-type GI isolate (K05GS). RNA extracted from JEV-GI was used to synthesize cDNA, a recombinant full-length JEV clone, pTRE-JEVGI, was generated from the DNA fragment, and the virus was rescued. We performed in vitro and in vivo experiments to analyze the rescued JEV-GI virus. The rescued JEV-GI exhibited similar characteristics to wild-type JEV. These results suggest that our reverse genetics system can generate full-length infectious clones that can be used to analyze molecular biological factors that influence viral properties and immunogenicity. Additionally, it may be useful as a heterologous gene expression vector and help develop new strains for JEV vaccines.

Microbial upcycling of methane to phytoene using metabolically engineered Methylocystis sp. MJC1 strain.

Methane, a potent greenhouse gas, requires sustainable mitigation strategies. Here, the microbial upcycling of methane to phytoene, a valuable colorless carotenoid with applications in the cosmeceutical industry was demonstrated. To achieve this goal, a stepwise metabolic engineering approach was employed in Methylocystis sp. MJC1, a methane-oxidizing bacterium. The incorporation of crtE and crtB genes from Deinococcus radiodurans R1 established the phytoene biosynthetic pathway. This pathway was fine-tuned through promoter optimization, resulting in a phytoene production of 450 µg/L from 37 mmol/L methane. Disrupting the ackA gene reduced a by-product, acetate, by 50 % and increased phytoene production by 56 %. Furthermore, overexpressing the dxs gene boosted phytoene titer 3-fold. The optimized strain produced 15 mg/L phytoene from 2 mol/L methane in fed-batch fermentation, a 4-fold increase in phytoene titer and 4-fold in yield. This demonstrates Methylocystis sp. MJC1's potential for efficient phytoene production and presents a novel approach for greenhouse gas reduction.

Beyond Legal Boundaries: Public and Clinician Perspectives on Treatment Withdrawal in Infants With Poor Neurological Prognosis.

BACKGROUND: Despite medical advancements in neonatal survival rates, many children have poor neurological outcomes. Because the law in Korea restricts the withdrawal of life-sustaining treatment to only cases of imminent death, treatment discontinuation may not be an option, even in patients with poor neurological prognosis. This study investigated the opinions of the general population and clinicians regarding life-sustaining treatment withdrawal in such cases using hypothetical scenarios. METHODS: We conducted a cross-sectional study on the general population and clinicians using a web-based questionnaire. The sample of the general population from an online panel comprised 500 individuals aged 20-69 years selected by quota sampling. The clinician sample comprised 200 clinicians from a tertiary university hospital. We created hypothetical vignettes and questionnaire items to assess attitudes regarding mechanical ventilation withdrawal for an infant at risk of poor neurological prognosis due to birth asphyxia at 2 months and 3 years after the incidence. RESULTS: Overall, 73% of the general population and 74% of clinicians had positive attitudes toward mechanical ventilator withdrawal at 2 months after birth asphyxia. The proportion of positive attitudes toward mechanical ventilator withdrawal was increased in the general population (84%, P < 0.001) and clinicians (80.5%, P = 0.02) at 3 years after birth asphyxia. Religion, spirituality, the presence of a person with a disability in the household, and household income were associated with the attitudes of the general population. In the multivariable logistic regression analysis of the general population, respondents living with a person with a disability or having a disability were more likely to find the withdrawal of the ventilator at 2 months and 3 years after birth asphyxia not permissible. Regarding religion, respondents who identified as Christians were more likely to find the ventilator withdrawal at 2 months after birth asphyxia unacceptable. CONCLUSION: The general population and clinicians shared the perspective that the decision to withdraw life-sustaining treatment in infants with a poor neurological prognosis should be considered before the end of life. A societal discussion about making decisions centered around the best interest of pediatric patients is warranted.

Elucidation of the effects of 2,5-hexandione as a metabolite of n-hexane on cognitive impairment in leptin-knockout mice (C57BL/6-Lepem1Shwl/Korl).

Exposure to n-hexane and its metabolite 2,5-hexandione (HD) is a well-known cause of neurotoxicity, particularly in the peripheral nervous system. To date, few studies have focused on the neurotoxic effects of HD on cognitive impairment. Exposure to HD and diabetes mellitus can exacerbate neurotoxicity. There are links among HD, diabetes mellitus, and cognitive impairment; however, the specific mechanisms underlying them remain unclear. Therefore, we aimed to elucidate the neurotoxic effects of HD on cognitive impairment in ob/ob (C57BL/6-Lepem1Shwl/Korl) mice. We found that HD induced cognitive impairment by altering the expression of genes (FN1, AGT, ACTA2, MYH11, MKI67, MET, CTGF, and CD44), miRNAs (mmu-miR15a-5p, mmu-miR-17-5p, and mmu-miR-29a-3p), transcription factors (transcription factor AP-2 alpha [TFAP2A], serum response factor [Srf], and paired box gene 4 [PAX4]), and signaling pathways (ERK/CERB, PI3K/AKT, GSK-3ß/p-tau/amyloid-ß), as well as by causing neuroinflammation (TREM1/DAP12/NF-κB), oxidative stress, and apoptosis. The prevalent use of n-hexane in various industrial applications (for instance, shoe manufacturing, printing inks, paints, and varnishes) suggests that individuals with elevated body weight and glucose levels and those employed in high-risk workplaces have greater probability of cognitive impairment. Therefore, implementing screening strategies for HD-induced cognitive dysfunction is crucial. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00228-1.

Analysis of factors associated with patients' global impression of change scores in inpatients with peripheral facial palsy: A retrospective study at a Korean Medicine Hospital.

The incidence of peripheral facial palsy is on the rise, with psychological issues influencing quality of life due to visible symptoms. Consequently, patient-reported outcome measures are critical in assessing the disease burden and the treatment efficacy of peripheral facial palsy from patients' perspective. This study examines factors influencing patients' global impression of change (PGIC) scores, a type of patient-reported outcome measure, in hospitalized patients with peripheral facial palsy. This retrospective study analyzed the electronic medical records of 200 patients with peripheral facial palsy who were admitted to the Korean Medicine Hospital, Kyung Hee University Medical Center from May 1, 2022 to April 30, 2023. Impact of demographic, electrophysiological, intervention, and clinical factors on PGIC scores were evaluated. Descriptive statistics showed that the length of hospitalization (P = .020), time from disease onset to hospitalization (P = .022), lacrimal disorders (P = .002), House-Brackmann (HB) grade evaluated at admission (P = .016) and at discharge (P < .001), improvement in HB-grade from admission to discharge (P = .002), and total facial disability index (FDI) score at discharge (P < .001) were significantly associated with PGIC scores. In multivariate logistic regression analysis, HB-grade at admission (OR: 13.89, 95% CI: 2.18-113.60), length of stay (OR: 0.27, 95% CI: 0.07-0.92), time from disease onset to hospitalization (OR: 5.55, 95% CI: 1.36-24. 77), tear-related symptoms (OR: 0.41, 95% CI: 0.17-0.96), total FDI score (OR: 0.45, 95% CI: 0.20-0.98), and greater improvement in HB-grade at discharge compared to admission (OR: 0.08, 95% CI: 0.02-0.31) were significantly associated with PGIC scores. Patients with milder initial disease severity, hospitalization period exceeding 7 days, shorter time from disease onset to hospitalization, improvement of lacrimal symptoms, total FDI score, and HB-grade between admission and discharge experienced more significant subjective improvement in peripheral facial palsy.

Machine Learning-Based Models for Advanced Fibrosis and Cirrhosis Diagnosis in Chronic Hepatitis B Patients With Hepatic Steatosis.

BACKGROUND AND AIMS: The global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants noninvasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population. METHODS: Treatment-naive CHB patients with concurrent HS who underwent liver biopsy in 10 medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from SHAP (Shapley Additive exPlanations), were compared with Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index using the area under receiver-operating characteristic curve (AUROC) and decision curve analysis (DCA). RESULTS: Of 1,198 eligible patients, the random forest model achieved AUROCs of 0.778 (95% confidence interval [CI], 0.749-0.807) for diagnosing advanced fibrosis (random forest advanced fibrosis model) and 0.777 (95% CI, 0.748-0.806) for diagnosing cirrhosis (random forest cirrhosis model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the random forest advanced fibrosis model obtained an AUROC of 0.825 (95% CI, 0.787-0.862) in patients with hepatitis B virus DNA ≥105 IU/mL, and the random forest cirrhosis model had an AUROC of 0.828 (95% CI, 0.774-0.883) in female patients. The 2 models outperformed Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index in the training cohort, and also performed well in the validation cohort. CONCLUSIONS: The random forest models provide reliable, noninvasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the comanagement of the 2 diseases. CLINICALTRIALS: gov, Number: NCT05766449.

Acute myocardial infarction prognosis prediction with reliable and interpretable artificial intelligence system.

OBJECTIVE: Predicting mortality after acute myocardial infarction (AMI) is crucial for timely prescription and treatment of AMI patients, but there are no appropriate AI systems for clinicians. Our primary goal is to develop a reliable and interpretable AI system and provide some valuable insights regarding short, and long-term mortality. MATERIALS AND METHODS: We propose the RIAS framework, an end-to-end framework that is designed with reliability and interpretability at its core and automatically optimizes the given model. Using RIAS, clinicians get accurate and reliable predictions which can be used as likelihood, with global and local explanations, and "what if" scenarios to achieve desired outcomes as well. RESULTS: We apply RIAS to AMI prognosis prediction data which comes from the Korean Acute Myocardial Infarction Registry. We compared FT-Transformer with XGBoost and MLP and found that FT-Transformer has superiority in sensitivity and comparable performance in AUROC and F1 score to XGBoost. Furthermore, RIAS reveals the significance of statin-based medications, beta-blockers, and age on mortality regardless of time period. Lastly, we showcase reliable and interpretable results of RIAS with local explanations and counterfactual examples for several realistic scenarios. DISCUSSION: RIAS addresses the "black-box" issue in AI by providing both global and local explanations based on SHAP values and reliable predictions, interpretable as actual likelihoods. The system's "what if" counterfactual explanations enable clinicians to simulate patient-specific scenarios under various conditions, enhancing its practical utility. CONCLUSION: The proposed framework provides reliable and interpretable predictions along with counterfactual examples.

Burden and preparedness of care partners of people living with amyotrophic lateral sclerosis at home in Korea: A care partner survey.

INTRODUCTION/AIMS: The care burden of people living with amyotrophic lateral sclerosis (pALS) increases with disease progression. This study aimed to investigate the home care status and preparedness of care partners of pALS (cALS) in Korea. METHODS: An online survey was conducted with family care partners of patients diagnosed with ALS for over 1 year in 2022. The data collected included care time, depression evaluated using the patient health questionnaire-9 (PHQ-9), preparedness for caregiving scale (PCS), and caregiver competence scale (CCS). Results were compared based on whether the pALS underwent a tracheostomy or not. RESULTS: Ninety-eight cALS of 98 pALS participated in the study, of whom 59 pALS had undergone tracheostomy. Among the cALS, 60.2% were spouses, and 34.7% were children. The cALS took care of the patients for 13 (8-20) hours/day (median, interquartile range [IQR]) on weekdays and 15 (10-24) h/day on weekends. Among the cALS, 91.8% were depressed, and 28.6% had severe depression. The median (IQR) PCS and CCS scores were low (11/32 (8-15) and 8/20 (8-11), respectively), and both were lower in those caring for patients without than with tracheostomy (p < .001 and p < .02, respectively). Most cALS (77.6%) wished to continue caring for their pALS at home. DISCUSSION: Family care partners of pALS spend more than half of each day caring for patients and are often depressed. Most cALS preferred providing care at home, but felt ill-prepared. Designing home-based medical care is necessary for pALS to thrive at home.

Cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders harboring RMRP mutations in two Korean children: A case report.

RATIONALE: Cartilage-hair hypoplasia (CHH, OMIM # 250250) is a rare autosomal recessive disorder, which includes cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders. CHH-AD is caused by homozygous or compound heterozygous mutations in the RNA component of the mitochondrial RNA-processing Endoribonuclease (RMRP) gene. PATIENT CONCERNS: Here, we report 2 cases of Korean children with CHH-AD. DIAGNOSES: In the first case, the patient had metaphyseal dysplasia without hypotrichosis, diagnosed by whole exome sequencing (WES), and exhibited only skeletal dysplasia and lacked extraskeletal manifestations, such as hair hypoplasia and immunodeficiency. In the second case, the patient had skeletal dysplasia, hair hypoplasia, and immunodeficiency, which were identified by WES. INTERVENTIONS: The second case is the first CHH reported in Korea. The patients in both cases received regular immune and lung function checkups. OUTCOMES: Our cases suggest that children with extremely short stature from birth, with or without extraskeletal manifestations, should include CHH-AD as a differential diagnosis. LESSONS SUBSECTIONS: Clinical suspicion is the most important and RMRP sequencing should be considered for the diagnosis of CHH-AD.

MurSS: A Multi-Resolution Selective Segmentation Model for Breast Cancer.

Accurately segmenting cancer lesions is essential for effective personalized treatment and enhanced patient outcomes. We propose a multi-resolution selective segmentation (MurSS) model to accurately segment breast cancer lesions from hematoxylin and eosin (H&E) stained whole-slide images (WSIs). We used The Cancer Genome Atlas breast invasive carcinoma (BRCA) public dataset for training and validation. We used the Korea University Medical Center, Guro Hospital, BRCA dataset for the final test evaluation. MurSS utilizes both low- and high-resolution patches to leverage multi-resolution features using adaptive instance normalization. This enhances segmentation performance while employing a selective segmentation method to automatically reject ambiguous tissue regions, ensuring stable training. MurSS rejects 5% of WSI regions and achieves a pixel-level accuracy of 96.88% (95% confidence interval (CI): 95.97-97.62%) and mean Intersection over Union of 0.7283 (95% CI: 0.6865-0.7640). In our study, MurSS exhibits superior performance over other deep learning models, showcasing its ability to reject ambiguous areas identified by expert annotations while using multi-resolution inputs.

SupporTive Care At Home Research (STAHR) for patients with advanced cancer: Protocol for a cluster non-randomized controlled trial.

Advancements in the treatment and management of patients with cancer have extended their survival period. To honor such patients' desire to live in their own homes, home-based supportive care programs have become an important medical practice. This study aims to investigate the effects of a multidimensional and integrated home-based supportive care program on patients with advanced cancer. SupporTive Care At Home Research is a cluster non-randomized controlled trial for patients with advanced cancer. This study tests the effects of the home-based supportive care program we developed versus standard oncology care. The home-based supportive care program is based on a specialized home-based medical team approach that includes (1) initial assessment and education for patients and their family caregivers, (2) home visits by nurses, (3) biweekly regular check-ups/evaluation and management, (4) telephone communication via a daytime access line, and (5) monthly multidisciplinary team meetings. The primary outcome measure is unplanned hospitalization within 6 months following enrollment. Healthcare service use; quality of life; pain and symptom control; emotional status; satisfaction with services; end-of-life care; advance planning; family caregivers' quality of life, care burden, and preparedness for caregiving; and medical expenses will be surveyed. We plan to recruit a total of 396 patients with advanced cancer from six institutions. Patients recruited from three institutions will constitute the intervention group, whereas those recruited from the other three institutions will comprise the control group.

The impact of specialized pediatric palliative care on advance care planning and healthcare utilization in children and young adults: a retrospective analysis of medical records of in-hospital deaths.

BACKGROUND: Pediatric palliative care supports children and young adults with life-limiting conditions and their families, seeking to minimize suffering and enhance quality of life. This study evaluates the impact of specialized palliative care (SPC) on advance care planning (ACP) and patterns of end-of-life care for patients who died in the hospital. METHODS: This is a retrospective cohort study of medical records extracted from a clinical data warehouse, covering patients who died aged 0-24 in an academic tertiary children's hospital in South Korea. Participants were categorized into before (2011-2013; pre-period) and after (2017-2019; post-period) the introduction of an SPC service. Within the post-period, patients were further categorized into SPC recipients and non-recipients. RESULTS: We identified 274 and 205 patients in the pre-period and post-period, respectively. ACP was conducted more and earlier in the post-period than in the pre-period, and in patients who received palliative care than in those who did not. Patients who received SPC were likely to receive less mechanical ventilation or cardiopulmonary resuscitation and more opioids. A multivariable regression model showed that earlier ACP was associated with not being an infant, receiving SPC, and having a neurological or neuromuscular disease. CONCLUSIONS: SPC involvement was associated with more and earlier ACP and less intense end-of-life care for children and young adults who died in the hospital. Integrating palliative care into routine care can improve the quality of end-of-life care by reflecting patients' and their families' values and preferences.

Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1α-SOD-mediated mitochondrial protection.

BACKGROUND: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity. PURPOSE: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT). METHODS: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death. RESULTS: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs. CONCLUSION: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.