The Role of Receptor Activator of Nuclear Factor-κB Ligand/Osteoprotegerin Ratio in Synovial Fluid as a Potential Marker for Periprosthetic Osteolysis Following Total Ankle Arthroplasty.

Background: Periprosthetic osteolysis is a prevalent complication following total ankle arthroplasty (TAA), implicating various cytokines in osteoclastogenesis as pivotal in this process. This study aimed to evaluate the relationship between osteolysis and the concentrations of osteoclastogenesis-related cytokines in synovial fluid and investigate its clinical value following TAA. Methods: Synovial fluid samples from 23 ankles that underwent revision surgery for osteolysis following TAA were analyzed as the osteolysis group. As a control group, we included synovial fluid samples obtained from 23 ankles during primary TAA for osteoarthritis. The receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio in these samples was quantified using sandwich enzyme-linked immunosorbent assay techniques, and a bead-based multiplex immunoassay facilitated the detection of specific osteoclastogenesis-related cytokines. Results: RANKL levels averaged 487.9 pg/mL in 14 of 23 patients in the osteolysis group, with no detection in the control group's synovial fluid. Conversely, a significant reduction in OPG levels was observed in the osteolysis group (p = 0.002), resulting in a markedly higher mean RANKL/OPG ratio (0.23) relative to controls (p = 0.020). Moreover, the osteolysis group had increased concentrations of various osteoclastogenesis-related cytokines (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, IL-8, IP-10, and monocyte chemotactic protein-1) in the synovial fluid relative to the control group. Conclusions: Our results demonstrated that periprosthetic osteolysis was associated with osteoclastogenesis activation through an elevated RANKL/OPG ratio following TAA. We assume that RANKL and other osteoclastogenesis-related cytokines in the synovial fluid have clinical value as a potential marker for the development and progression of osteolysis following TAA.

Transcriptomic profiling of intermediate cell carcinoma of the liver.

BACKGROUND: Intermediate cell carcinoma (Int-CA) is a rare and enigmatic primary liver cancer characterized by uniform tumor cells exhibiting mixed features of both HCC and intrahepatic cholangiocarcinoma. Despite the unique pathological features of int-CA, its molecular characteristics remain unclear yet. METHODS: RNA sequencing and whole genome sequencing profiling were performed on int-CA tumors and compared with those of HCC and intrahepatic cholangiocarcinoma. RESULTS: Int-CAs unveiled a distinct and intermediate transcriptomic feature that is strikingly different from both HCC and intrahepatic cholangiocarcinoma. The marked abundance of splicing events leading to intron retention emerged as a signature feature of int-CA, along with a prominent expression of Notch signaling. Further exploration revealed that METTL16 was suppressed within int-CA, showing a DNA copy number-dependent transcriptional deregulation. Notably, experimental investigations confirmed that METTL16 suppression facilitated invasive tumor characteristics through the activation of the Notch signaling cascade. CONCLUSIONS: Our results provide a molecular landscape of int-CA featured by METTL16 suppression and frequent intron retention events, which may play pivotal roles in the acquisition of the aggressive phenotype of Int-CA.

Early Integrated Palliative Care in Patients With Advanced Cancer: A Randomized Clinical Trial.

Importance: Limited data suggest that early palliative care (EPC) improves quality of life (QOL) and survival in patients with advanced cancer. Objective: To evaluate whether comprehensive EPC improves QOL; relieves mental, social, and existential burdens; increases survival rates; and helps patients develop coping skills. Design, Setting, and Participants: This nonblinded randomized clinical trial (RCT) recruited patients from 12 hospitals in South Korea from September 2017 to October 2018. Patients aged 20 years or older with advanced cancer who were not terminally ill but for whom standard chemotherapy has not been effective were eligible. Participants were randomized 1:1 to the control (receiving usual supportive oncological care) or intervention (receiving EPC with usual oncological care) group. Intention-to-treat data analysis was conducted between September and December 2022. Interventions: The intervention group received EPC through a structured program of self-study education materials, telephone coaching, and regular assessments by an integrated palliative care team. Main Outcomes and Measures: The primary outcome was the change in overall QOL score (assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care) from baseline to 24 weeks after enrollment, with evaluations also conducted at 12 and 18 weeks. Secondary outcomes were social and existential burdens (assessed with the McGill Quality of Life Questionnaire) as well as crisis-overcoming capacity and 2-year survival. Results: A total of 144 patients (83 males [57.6%]; mean [SD] age, 60.7 (7.2) years) were enrolled, of whom 73 were randomized to the intervention group and 71 to the control group. The intervention group demonstrated significantly greater changes in scores in overall health status or QOL from baseline, especially at 18 weeks (11.00 [95% CI, 0.78-21.22] points; P = .04; effect size = 0.42). However, at 12 and 24 weeks, there were no significant differences observed. Compared with the control group, the intervention group also showed significant improvement in self-management or coping skills over 24 weeks (20.51 [95% CI, 12.41-28.61] points; P < .001; effect size = 0.93). While the overall survival rate was higher in the intervention vs control group, the difference was not significant. In the intervention group, however, those who received 10 or more EPC interventions (eg, telephone coaching sessions and care team meetings) showed a significantly increased probability of 2-year survival (53.6%; P < .001). Conclusions and Relevance: This RCT demonstrated that EPC enhanced QOL at 18 weeks; however, no significant improvements were observed at 12 and 24 weeks. An increased number of interventions sessions was associated with increased 2-year survival rates in the intervention group. Trial Registration: ClinicalTrials.gov Identifier: NCT03181854.

Multiplex fluorescence loop-mediated isothermal amplification with lateral flow assay for rapid simultaneous detection of mecA and nuc genes in methicillin-resistant Staphylococcus aureus.

BACKGROUND: Antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), pose a significant threat to public health. Existing detection methods, like cultivation-based techniques, demand significant time and labor, while molecular diagnostic techniques, such as PCR, necessitate sophisticated instrumentation and skilled personnel. Although previous multiplex loop-mediated isothermal amplification assays based on fluorescent dyes (mfLAMP) offer simplicity and cost-effectiveness, they are prone to false-positive results. Therefore, developing a rapid and efficient multiplex assay for high-sensitivity MRSA is imperative to create a practical diagnostic tool for point-of-care testing. RESULTS: Here, we developed a mfLAMP combined with a lateral flow assay (mfLAMP-LFA) for the visual and simultaneous detection of the mecA (PBP2a-specific marker) and nuc (S. aureus-specific marker) genes in MRSA. We optimized mfLAMP-LFA using graphene oxide (GO)-based purification and specific DNA probes and evaluated its sensitivity, specificity, and stability. Utilizing GO to mitigate false-positive results by acting as a trap for free DNA probes, the mfLAMP-LFA method successfully identified mecAf and nucf-probes, exhibiting distinct red, green, and yellow fluorescence signals. The detection sensitivity of the developed mfLAMP-LFA method (1 CFU mL-1 in phosphate-buffered saline (PBS)) was comparable to other highly sensitive MRSA detection methods (1 CFU mL-1 in PBS). Furthermore, the method demonstrated specificity for MRSA, detecting it in irrigation water samples within the desired range and achieving reliable recovery rates from spiked samples. SIGNIFICANCE: This novel strategy is the first to incorporate GO into mfLAMP-LFA, enabling specific and sensitive MRSA detection and advancing rapid bacterial detection. This assay facilitates MRSA diagnostics, contributing to improved public health and food safety by delivering rapid, cost-effective point-of-care results. It enables the simultaneous detection of multiple bacteria, even in irrigation water samples artificially inoculated with MRSA, which contain aerobic bacteria at 2.7 × 102 CFU mL-1.

Factors Associated with Postoperative Recurrence in Stage I to IIIA Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation: Analysis of Korean National Population Data.

Purpose: Recent development in perioperative treatment of resectable non-small cell lung cancer (NSCLC) have changed the landscape of early lung cancer management. The ADAURA trial has demonstrated the efficacy of adjuvant osimertinib treatment in resectable NSCLC patients; however, studies are required to show which subgroup of patients are at a high risk of relapse and require adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. This study evaluated risk factors for postoperative relapse among patients who underwent complete resection. Materials and Methods: Data were obtained from the Korean Association for Lung Cancer Registry (KALC-R), a database created using a retrospective sampling survey by the Korean Central Cancer Registry (KCCR) and the Lung Cancer Registration Committee. Results: A total of 3,176 patients who underwent curative resection was evaluated. The mean observation time was approximately 35.4 months. Among stage I to IIIA NSCLC patients, the EGFR-mutant subgroup included 867 patients, and 75.2%, 11.2%, and 11.8% were classified as stage I, stage II, and stage III, respectively. Within the EGFR-mutant subgroup, 44 (5.1%) and 121 (14.0%) patients showed early and late recurrence, respectively. Multivariate analysis on association with postoperative relapse among the EGFR-mutant subgroup showed that age, pathologic N and TNM stages, pleural invasion status, and surgery type were independent significant factors. Conclusion: Among the population that underwent complete resection for early NSCLC with EGFR mutation, patients with advanced stage, pleural invasion, or limited resection are more likely to show postoperative relapse.

Imatinib in c-KIT-mutated metastatic solid tumors: A multicenter trial of Korean Cancer Study Group (UN18-05 Trial).

INTRODUCTION: We conducted an open-label, single-arm, multi-center phase II trial to evaluate the efficacy and safety of imatinib chemotherapy-refractory or metastatic solid tumor patients with c-KIT mutations and/or amplification. METHODS: c-KIT mutations and amplification were detected using NGS. Imatinib (400 mg daily) was administered continuously in 28-day cycles until disease progression, unacceptable adverse events, or death by any cause. The primary endpoint was the objective response rate (ORR). RESULT: In total, 18 patients were enrolled on this trial. The most common tumor type was melanoma (n = 15, 83.3%), followed by ovarian cancer, breast cancer, and metastasis of unknown origin (MUO) (each n = 1, 5.5%). The total number of evaluable patients was 17, of which one patient had a complete response, six patients had partial response, and two patients had stable disease. The overall response rate (ORR) of 41.2% (95% CI 17.80-64.60) and a disease control rate of 52.9% (95% CI 29.17-76.63). The median progression-free survival was 2.2 months (95% CI 1.29-3.20), and median overall survival was 9.1 months (95% CI 2.10-16.11). The most common adverse events were edema (31.3%), anorexia (25.0%), nausea (18.8%), and skin rash (18.8%). CONCLUSION: Imatinib demonstrated modest anti-tumor activity and a manageable safety profile in chemotherapy-refractory solid tumors with c-KIT mutation, especially in melanoma patients.

Real-world evidence of brigatinib as second-line treatment after crizotinib for ALK+ non-small cell lung cancer using South Korean claims data (K-AREAL).

PURPOSE: There is a lack of real-world data in Asian populations for brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor for patients with non-small cell lung cancer (NSCLC). This study analysed real-world outcomes and dosing patterns for brigatinib in patients with crizotinib-refractory ALK+ NSCLC in South Korea. METHODS: This retrospective, non-interventional, cohort study used South Korean Health Insurance and Review Assessment claims data for adults with ALK+ NSCLC who initiated brigatinib between 19 April 2019 and 31 March 2021 after receiving prior crizotinib. Patients' characteristics, time to discontinuation (TTD), time to dose reduction, overall survival (OS) and treatment adherence were assessed. RESULTS: The study included 174 patients (56.9% male; 27.0% with a history of brain metastases). Median duration of prior crizotinib was 17 (range 0.3-48) months. Median follow-up after brigatinib initiation was 18 (range 0-34) months. Overall, 88.5% of patients received full-dose brigatinib (180 mg/day) and 93.1% of patients were adherent (proportion of days covered ≥0.8). The median TTD was 24.9 months (95% CI 15.2-not reached). The probability of continuing treatment was 63.2% at 1 year and 51.5% at 2 years. The probability of continuing at full or peak dose was 79.7% at 1 year and 75.6% at 2 years. Median OS was not reached. The 2-year OS rate was 68.7%. CONCLUSIONS: In this first nationwide retrospective study using national insurance claim data, brigatinib demonstrated real-world clinical benefit as second-line treatment after prior crizotinib in ALK+ NSCLC patients in South Korea.

A High Immediate Postoperative Systemic Immune-inflammation Index Is Associated With Postoperative Symptomatic Cerebral Infarction in Moyamoya Patients Undergoing Combined Revascularization Surgery.

BACKGROUND: Inflammation plays a role in the pathogenesis of cerebral infarction. Postoperative symptomatic cerebral infarction (SCI) is a complication after revascularization surgery in patients with moyamoya disease (MMD). We investigated the association between the systemic-immune-inflammation index (SII) and postoperative SCI during hospital stay in such patients. METHODS: Perioperative data were retrospectively obtained from 681 MMD patients who underwent revascularization surgery. SII cutoff values were identified as those where the sum of sensitivity and specificity associated with SCI were highest. Patients were divided into 4 subgroups according to the preoperative and immediate postoperative cutoff SII: HH (preoperative and postoperative SII high, n=22), LH (low preoperative and high postoperative SII, n=68), HL (high preoperative and low postoperative SII, n=125), and LL (preoperative and postoperative SII low, n=466). RESULTS: Postoperative SCI occurred in 54 (7.6%) patients. The cutoff values for preoperative and immediate postoperative SII were 641.3 and 1925.4, respectively. Postoperative SCI during hospital stay was more frequent in the high postoperative SII group than in the low postoperative SII group (25.6% vs. 4.9%; P<0.001). Multivariate analysis revealed that a high immediate postoperative SII was a predictor of postoperative SCI (odds ratio, 11.61; 95% CI: 5.20-26.00; P<0.001). Postoperative SCI was lower in group LL than in group LH (3.6% vs. 23.5%, P<0.008) and was lower in group HL than in groups HH and LH (9.6% vs. 31.8% and 23.5%, both P<0.05). CONCLUSIONS: A high immediate postoperative SII was associated with postoperative SCI during hospital stay in MMD patients who underwent revascularization surgery.

Caregiving Appraisals and Emotional Valence: Moderating Effects of Activity Participation.

The present study examines the extent to which a two-factor model of affect explains how caregiving appraisals experienced by caregivers influence their own well-being. We used data from three waves of Nation Study of Caregiving (NSOC) to conduct latent growth curve models with the time-varying predictors to investigate the effect of between-person (BP) and within-person (WP) caregiving appraisals on positive and negative affect. Furthermore, we simultaneously modeled WP differences in activity participation and affective experience with multilevel modeling. Then, we tested the moderating effect of activity participation in the association between WP caregiving appraisals and emotional valence. We found that BP and WP caregiving negative appraisal also contribute to caregiver positive affect similar to that of negative affect. Time-varying effects of negative appraisals and emotional valence are consistent with the two-factor model. Future longitudinal investigations could target WP and BP activity participation to alleviate caregiving cognitive appraisal among caregivers.

Reproductive toxicity and molecular responses induced by telmisartan in Daphnia magna at environmentally relevant concentrations.

With aging population increasing globally, the use of pharmaceutically active compounds is rising. The cardiovascular drug telmisartan has been widely detected in various environmental compartments, including biota, surface waters, and sewage treatment plant effluents at concentrations ranging from ng/L to µg/L levels. This study evaluated the effects of telmisartan on the microcrustacean Daphnia magna at a wide range of concentrations (0.35, 0.70, 1.40, 500, and 1000 µg/L) and revealed significant ecotoxicological implications of this drug, even at environmentally relevant concentration. Acute exposure to telmisartan (1.40, 500, and 1000 µg/L) resulted in a notable decrease in heart rate, while chronic exposure accelerated the time to the first brood by 3 days and reduced neonate body size. Molecular investigations revealed marked downregulation of vitellogenin genes (Vtg1 and Vtg2). Non-monotonic dose responses were observed for gene expression, early-stage body length, and the total number of offspring produced, while the heart rate and time to the first brood showed clear concentration-dependent responses. These findings highlight the potential risks, notably to reproductive capacity, associated with exposure to telmisartan in environmentally relevant concentration, suggesting the need for further studies on the potential long-term ecological consequences.

Nationwide monitoring of legacy and emerging persistent organic pollutants and polycyclic aromatic hydrocarbons along the Korean coast.

Comprehensive studies simultaneously investigating the occurrence of chemicals of concern are limited. In this study, sediments and bivalves were collected from 24 locations along the Korean coast to evaluate the relative distribution, contamination characteristics, and ecological risks of legacy/emerging persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons (PAHs). Our findings reveal that the concentrations of these contaminants were comparable to or lower than historical levels in the same Korean coast and other Asian countries. Notably, PAHs exhibited the highest distribution in sediments (84 %), whereas short-chain chlorinated paraffins (SCCPs) were dominant in bivalves (91 %). This study highlighted significant correlations in the sediment levels of each legacy pollutants, suggesting similar sources and geochemical behaviors. However, SCCPs displayed unique contamination patterns. Ecologically, PAHs and SCCPs presented low risks in sediments compared to Canadian Sediment Quality Guidelines, however 100 % and 33 % of bivalves, respectively, exceeded US EPA/Canadian Fish Tissue Guidelines.

NRF2 is a spatiotemporal metabolic hub essential for the polyfunctionality of Th2 cells.

Upon encountering allergens, CD4+ T cells differentiate into IL-4-producing Th2 cells in lymph nodes, which later transform into polyfunctional Th2 cells producing IL-5 and IL-13 in inflamed tissues. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of NRF2 in polyfunctional Th2 cells in murine models of allergic asthma and in human Th2 cells. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma and polyfunctional Th2 cells in vivo. Deletion of the ROS sensor NRF2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, NRF2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality independently of IL-33, partially by inducing PPARγ. Treatment with an NRF2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.

The Effects of ML385 on Head and Neck Squamous Cell Carcinoma: Implications for NRF2 Inhibition as a Therapeutic Strategy.

Head and neck squamous cell carcinoma (HNSCC) affects squamous cells in the head and neck region and is currently ranked as the sixth most common cancer worldwide. NF-E2-related factor 2 (NRF2) plays a crucial role in cellular protection and defence mechanisms and NRF2 over-expression has been linked to various cancers; however, its role in the response of HNSCC cells remains elusive. We investigated the effects of ML385, a selective NRF2 inhibitor, on HNSCC to understand the underlying molecular mechanisms, and to assess the potential of ML385 as a therapeutic agent. We treated HNSCC cell lines with ML385 and observed a significant reduction in the expression of NRF2 and its downstream target, heme oxygenase-1 (HO-1), using Western blotting. We evaluated its effects on various cellular processes, including cell proliferation, cloning, migration, and wound healing, in HNSCC cell lines. ML385 treatment substantially reduced NRF2 expression, promoting a decrease in the investigated cellular activities. Additionally, we examined changes in the expression of cell-cycle-related proteins and found that ML385 induced cell cycle arrest at the G1/S phase in HNSCC cell lines. Our findings suggest that ML385 can regulate cell cycle progression, inhibit HNSCC growth, and have potential as a therapeutic agent for HNSCC.

Nationwide assessment of illicit drug consumption patterns in South Korea using wastewater-based epidemiology during the COVID-19 pandemic (2020-2022).

Illicit drugs have become a crucial global social issue, with South Korea experiencing a continuous increase in the number of offenders and drug smuggling. This study employed wastewater-based epidemiology to investigate consumption patterns of 8 illicit drugs and their 7 metabolites during the COVID-19 pandemic (2020-2022) in South Korea. Ten compouds were detected in the wastewater influent. Methamphetamine (METH) was prevalent in samples, followed by amphetamine and ecstasy (MDMA). Interestingly, MDMA and ketamine (KET), which were not detected in previous Korean studies conducted before COVID-19 pandemic, were detected in this study. METH exhibited the highest consumption rates, decreasing from 16.6 to 12.4 mg/day/1000 people between 2020 and 2022, while MDMA increased over the three years (mean: 1.16, 1.24, and 1.62 mg/day/1000 people in 2020, 2021, and 2022, respectively) (p < 0.05). Significant correlations were identified between regional income levels and the consumption rates of METH (p < 0.01), MDMA (p < 0.01), and KET (p < 0.05). Furthermore, METH and MDMA consumption rates in cities were positively correlated with the number of drug offenders arrested and local clubs in those cities. The findings of this study provide valuable insights into shaping regulatory policies related to illicit drugs and future studies.

Efficacy of Mobile App-Based Cognitive Behavioral Therapy for Insomnia: Multicenter, Single-Blind Randomized Clinical Trial.

BACKGROUND: Cognitive behavioral therapy for insomnia (CBTi) is the first-line therapy for chronic insomnia. Mobile app-based CBTi (MCBTi) can enhance the accessibility of CBTi treatment; however, few studies have evaluated the effectiveness of MCBTi using a multicenter, randomized controlled trial design. OBJECTIVE: We aimed to assess the efficacy of Somzz, an MCBTi that provides real-time and tailored feedback to users, through comparison with an active comparator app. METHODS: In our multicenter, single-blind randomized controlled trial study, participants were recruited from 3 university hospitals and randomized into a Somzz group and a sleep hygiene education (SHE) group at a 1:1 ratio. The intervention included 6 sessions for 6 weeks, with follow-up visits over a 4-month period. The Somzz group received audiovisual sleep education, guidance on relaxation therapy, and real-time feedback on sleep behavior. The primary outcome was the Insomnia Severity Index score, and secondary outcomes included sleep diary measures and mental health self-reports. We analyzed the outcomes based on the intention-to-treat principle. RESULTS: A total of 98 participants were randomized into the Somzz (n=49, 50%) and SHE (n=49, 50%) groups. Insomnia Severity Index scores for the Somzz group were significantly lower at the postintervention time point (9.0 vs 12.8; t95=3.85; F2,95=22.76; ηp2=0.13; P<.001) and at the 3-month follow-up visit (11.3 vs 14.7; t68=2.61; F2,68=5.85; ηp2=0.03; P=.01) compared to those of the SHE group. The Somzz group maintained their treatment effect at the postintervention time point and follow-ups, with a moderate to large effect size (Cohen d=-0.62 to -1.35; P<.01 in all cases). Furthermore, the Somzz group showed better sleep efficiency (t95=-3.32; F2,91=69.87; ηp2=0.41; P=.001), wake after sleep onset (t95=2.55; F2,91=51.81; ηp2=0.36; P=.01), satisfaction (t95=-2.05; F2,91=26.63; ηp2=0.20; P=.04) related to sleep, and mental health outcomes, including depression (t95=2.11; F2,94=29.64; ηp2=0.21; P=.04) and quality of life (t95=-3.13; F2,94=54.20; ηp2=0.33; P=.002), compared to the SHE group after the intervention. The attrition rate in the Somzz group was 12% (6/49). CONCLUSIONS: Somzz outperformed SHE in improving insomnia, mental health, and quality of life. The MCBTi can be a highly accessible, time-efficient, and effective treatment option for chronic insomnia, with high compliance. TRIAL REGISTRATION: Clinical Research Information Service (CRiS) KCT0007292; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=22214&search_page=L.

In vivo neural regeneration via AAV-NeuroD1 gene delivery to astrocytes in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Neonatal hypoxic-ischemic brain injury (HIBI) is a significant contributor to neonatal mortality and long-term neurodevelopmental disability, characterized by massive neuronal loss and reactive astrogliosis. Current therapeutic approaches for neonatal HIBI have been limited to general supportive therapy because of the lack of methods to compensate for irreversible neuronal loss. This study aimed to establish a feasible regenerative therapy for neonatal HIBI utilizing in vivo direct neuronal reprogramming technology. METHODS: Neonatal HIBI was induced in ICR mice at postnatal day 7 by permanent right common carotid artery occlusion and exposure to hypoxia with 8% oxygen and 92% nitrogen for 90 min. Three days after the injury, NeuroD1 was delivered to reactive astrocytes of the injury site using the astrocyte-tropic adeno-associated viral (AAV) vector AAVShH19. AAVShH19 was engineered with the Cre-FLEX system for long-term tracking of infected cells. RESULTS: AAVShH19-mediated ectopic NeuroD1 expression effectively converted astrocytes into GABAergic neurons, and the converted cells exhibited electrophysiological properties and synaptic transmitters. Additionally, we found that NeuroD1-mediated in vivo direct neuronal reprogramming protected injured host neurons and altered the host environment, i.e., decreased the numbers of activated microglia, reactive astrocytes, and toxic A1-type astrocytes, and decreased the expression of pro-inflammatory factors. Furthermore, NeuroD1-treated mice exhibited significantly improved motor functions. CONCLUSIONS: This study demonstrates that NeuroD1-mediated in vivo direct neuronal reprogramming technology through AAV gene delivery can be a novel regenerative therapy for neonatal HIBI.

Factors Affecting Life-Sustaining Treatment Decisions and Changes in Clinical Practice after Enforcement of the Life-Sustaining Treatment Decision (LST) Act: A Tertiary Hospital Experience in Korea.

Purpose: In Korea, the act on hospice and palliative care and decisions on life-sustaining treatment (LST) was implemented on February 4, 2018. We aimed to investigate relevant factors and clinical changes associated with LST decisions after law enforcement. Materials and Methods: This single-center retrospective study included patients who completed LST documents using legal forms at Asan Medical Center from February 5, 2018, to June 30, 2020. Results: 5896 patients completed LST documents, of which 2704 (45.8%) signed the documents in person, while family members of 3,192 (54%) wrote the documents on behalf of the patients. Comparing first year and following year of implementation of the act, the self-documentation rate increased (43.9% to 47.2%, p=0.014). Moreover, the number of LST decisions made during or after ICU admission decreased (37.8% vs. 35.2%, p=0.045), and the completion rate of LST documents during chemotherapy increased (6.6% vs. 8.9%, p=0.001). In multivariate analysis, age < 65 (OR, 1.724; 95% CI, 1.538-1.933; p<0.001), unmarried status (OR, 1.309; 95% CI, 1.097-1.561; p=0.003), palliative care consultation (OR, 1.538; 95% CI, 1.340-1.765; p<0.001), malignancy (OR, 1.864; 95% CI, 1.628-2.133; p<0.001), and changes in timing on the first year versus following year (OR, 1.124, 95% CI, 1.003-1.260, p=0.045) were related to a higher self-documentation rate. Conclusion: Age < 65, unmarried status, malignancy, and referral to a palliative care team were associated with patients making LST decisions themselves. Furthermore, the subject and timing of LST decisions have changed with the LST act.

Coil embolization of the middle cerebral artery bifurcation aneurysms: Feasibility and durability.

OBJECTIVE: To evaluate the feasibility and durability of coil embolization for MCAB aneurysms by analyzing clinical and radiological results. METHODS: From January of 2008 to June of 2018, we treated a total of 1785 aneurysms using coil embolization. The aneurysms were treated by both coiling and stent-assisted coiling. Among these cases, 223 MCAB aneurysms were analyzed retrospectively. Clinical and radiological assessments were conducted at admission, after treatment, at discharge, and at last clinical follow-up. RESULTS: Coil embolization was performed on 223 MCAB aneurysms in 217 patients. Peri-procedural ischemic, hemorrhagic, and other complications within 30 days after coil embolization occurred at rates of 8.0 %, 8.0 %, and 2.0 %, respectively, in the ruptured group and at 2.9 %, 1.2 %, and 0 %, respectively, in the unruptured group. The overall morbidity and mortality rates associated with complications were 2.3 % and 2.0 %. The cumulative major recurrence rates were 5.1 % at 12 months, 7.1 % at 18 months, and 11.9 % at three years after coil embolization. The mean follow-up period was 33.27 ± 25.48 months. Independent risk factors for major recurrence after coil embolization for MCAB aneurysms were a ruptured aneurysm, initial incomplete occlusion, the aneurysm size, and the neck size. CONCLUSION: Coil embolization is a good alternative treatment option for MCAB aneurysms compared to surgical clipping. Considering the risk factors for major recurrence, the follow-up angiography should continue up to three years after coil embolization.

Radiofrequency ablation versus intra-articular mesenchymal stem cell injection for knee osteoarthritis: a systematic review and network meta-analysis.

BACKGROUND: Knee osteoarthritis (OA) is a prevalent degenerative disease and causes disability, pain and imposes a substantial burden on patients. Conventional treatments for knee OA show limited effectiveness. Consequently, innovative treatments, such as radiofrequency ablation (RFA) and intra-articular mesenchymal stem cells (IA MSC), have gained attention for addressing these limitations. OBJECTIVE: We compared the efficacy of RFA and IA MSC for knee OA through a network meta-analysis (NMA). EVIDENCE REVIEW: A literature search was conducted using PubMed, MEDLINE, Embase, Cochrane Library, Web of Science and handsearching. Randomized controlled trials (RCTs) comparing RFA or IA MSC to conventional treatments for knee OA were included. The primary outcomes comprised the pain score and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The clinical outcomes were compared using a frequentist approach, and the treatments were ranked using the surface under the cumulative ranking curve (SUCRA) values. FINDINGS: We included 34 RCTs (n=2371). Our NMA revealed that RFA and IA MSC were significantly more effective than conventional treatments in managing pain at both 3 and 6 months with moderate certainty. Specifically, RFA demonstrated the highest SUCRA values, indicating its superior efficacy. For WOMAC scores, both RFA and MSC showed significant improvements at 3 months, with RFA maintaining its lead at 6 months, although MSC did not display significant superiority at this stage. CONCLUSIONS: This analysis suggests that RFA and MSC are resilient treatment options in knee OA. Despite some study heterogeneity, these treatments consistently outperformed conventional treatments, particularly in the short to mid-term, although with varying levels of certainty in their efficacy. PROSPERO REGISTRATION NUMBER: CRD42023492299.

Development and Effectiveness of a Standardized Hand-Off Program Using the SWITCH Tool for OR Nurses: A Randomized Controlled Trial.

The purpose of this study was to develop a standardized hand-off program based on the SWITCH tool (surgical procedure, wet, instruments, tissue, counts, have you any questions?) and to examine its effectiveness in terms of self-reported perceptions of hand-off satisfaction, self-efficacy, surgical nursing performance, and communication competence among OR staff members. This randomized controlled trial used a nonsynchronized control group with a pretest and posttest design. The nurses in the experimental group received one educational session and used the standardized hand-off tool for four weeks. The control group performed hand offs using the usual method rather than a tool. After the intervention, self-reported hand-off satisfaction (P = .001), self-efficacy (P = .005), and surgical nursing performance (P < .001) scores were significantly higher in the experimental group than in the control group. A standardized hand-off tool can improve nurse perceptions of satisfaction, self-efficacy, and surgical nursing performance.