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Intervertebral disc degeneration and pain are associated with the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome activation and the processing of interleukin-1 beta (IL-1β). Activation of thehm inflammasome is triggered by Toll-like receptor stimulation and requires the cofactor receptor cluster of differentiation 14 (CD14). Short Link N (sLN), a peptide derived from link protein, has been shown to modulate inflammation and pain in discs in vitro and in vivo; however, the underlying mechanisms remain elusive. This study aims to assess whether sLN modulates IL-1β and inflammasome activity through interaction with CD14. Disc cells treated with lipopolysaccharides (LPS) with or without sLN were used to assess changes in Caspase-1, IL-1β, and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Peptide docking of sLN to CD14 and immunoprecipitation were performed to determine their interaction. The results indicated that sLN inhibited LPS-induced NFκB and Caspase-1 activation, reducing IL-1β maturation and secretion in disc cells. A significant decrease in inflammasome markers was observed with sLN treatment. Immunoprecipitation studies revealed a direct interaction between sLN and the LPS-binding pocket of CD14. Our results suggest that sLN could be a potential therapeutic agent for discogenic pain by mitigating IL-1β and inflammasome activity within discs.

Background: Chronic graft-versus-host disease (GVHD) is a debilitating, and sometimes life threatening, complication of allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the activity, pharmacokinetics, and safety of ruxolitinib added to corticosteroids in paediatric patients (ie, <18 years) with moderate-to-severe chronic GVHD., Methods: In this single-arm, phase 2 study, patients were recruited at 21 hospitals or clinics across 14 countries in Asia, Europe, and Canada. Eligible patients were aged 28 days to younger than 18 years, had undergone allogenic HSCT, and had been diagnosed with treatment-naive or corticosteroid-refractory moderate-to-severe chronic GVHD, per 2014 National Institutes of Health consensus criteria. Patients received oral ruxolitinib dosing on the basis of their age at the start of treatment: those aged 12 years to younger than 18 years received 10 mg twice daily (age ≥12 to <18 years group), those aged 6 years to younger than 12 years (age ≥6 to <12 years group) received 5 mg twice daily, and those aged 2 years to younger than 6 years received 4 mg/m 2 twice daily (age ≥2 to <6 years group). Treatment was to be administered in 28-day cycles for approximately 36 months, alongside supportive treatment per institutional guidelines. The primary activity endpoint was overall response rate at cycle 7 day 1. Activity and safety analyses are reported in the full analysis set, which included all patients who received at least one dose of ruxolitinib. Here we report the prespecified interim analysis, scheduled to occur after all patients had completed 1 year of treatment or discontinued treatment, and the results for the primary endpoint evaluation reported here is to be considered final. This study is registered with ClinicalTrials.gov, NCT03774082, enrolment is complete, and the study is ongoing., Findings: Between May 20, 2020, and Sept 17, 2021, 48 patients were screened, of whom 45 were enrolled and received at least one dose of study drug (median age was 11·0 years [IQR 7·2-14·3], 16 [36%] were female, 29 [64%] were male, 21 [47%] were White, one [2%] was Black or African American, 23 [51%] were Asian, 17 [38%] were treatment-naive, 28 [62%] were corticosteroid-refractory). As of data cutoff (Oct 19, 2022), after a median ruxolitinib exposure of 55·1 weeks (IQR 13·1-75·3), the overall response rate at cycle 7 day 1 was 40·0% (18 of 45; 90% CI 27·7-53·3), with responses seen in seven (41%) of 17 treatment-naive patients and 11 (39%) of 28 corticosteroid-refractory patients. The most common treatment-related adverse events of grade 3 or worse were neutropenia (eight [18%] of 45) and thrombocytopenia (six [13%]). Seven (16%) patients had grade 3 or worse serious treatment-related adverse events; the most common was hyponatraemia (two [4%] of 45). Three (7%) patients died while on-treatment (within 30 days of treatment discontinuation), one due to Aspergillus infection, one due to septic shock, and one due to acute respiratory distress syndrome; none were considered to be related to study drug., Interpretation: Pending final analysis, this study suggests that ruxolitinib is active and well tolerated in both treatment-naive and corticosteroid-refractory patients aged 2 years to younger than 18 years with chronic GVHD, thereby supporting its use in this patient population. The safety profile of ruxolitinib in this patient population is consistent with that of adults. Final analysis of this study will provide further information on the long-term benefits of ruxolitinib in children with chronic GVHD., Funding: Novartis., Competing Interests: Declaration of interests FL has participated in speaker bureaus for Amgen, Bluebird Bio, BMS, Medac Pharma, Miltenyi Biotec, Neovii, Novartis, and SOBI. HJK has received consulting fees from Structure Therapeutics (GPCR) and is on Data Safety Monitoring Boards or advisory boards with Jazz Pharmaceuticals, Novartis, Sanofi, Recordati, and Takeda. CD-d-H has received royalties from Jazz Pharmaceuticals and Vertex; received honoraria from Novartis; received meeting and travel support from Jazz Pharmaceuticals and Novartis; and has participated on a data safety monitoring board for Novartis. TS, CR, ASP, KB, YS, and KS are employees of Novartis. TS, KB, ASP, YS, and KS hold shares in Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Histiocytic neoplasms are rare diseases involving macrophages, dendritic cells, and monocytes. They include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and histiocytic sarcoma. Histiocytic neoplasms are characterized by varied clinical courses and prognoses, necessitating a nuanced understanding of their classification, epidemiology, and clinical manifestations. Genetic studies have revealed somatic mutations, predominantly in the MAPK pathway, suggesting a clonal neoplastic nature. This review covers the current understanding of histiocytic neoplasms, molecular pathophysiology, with a particular focus on mutations in genes such as BRAF, MAP2K1, and the PI3K-AKT signaling pathways, and evolving treatment strategies, especially focusing on LCH, ECD, RDD, and JXG. The treatment landscape has evolved with advancements in targeted therapies. BRAF inhibitors, such as vemurafenib and dabrafenib, have shown efficacy, especially in high-risk LCH cases; however, challenges remain, including relapse post-treatment discontinuation, and adverse effects. MEK inhibitors have also demonstrated effectiveness, and cobimetinib has recently been approved for use in adults. Further research is required to determine the optimal treatment duration and strategies for managing therapy interruptions. Advancements in molecular genetics and targeted therapies have revolutionized the management of histiocytic neoplasms. However, ongoing research is crucial for optimizing patient outcomes., (© 2024. The Author(s).)

Photothermal therapy (PTT) is a promising cancer therapeutic approach due to its spatial selectivity and high potency. Indocyanine green (ICG) has been considered a biocompatible PTT agent. However, ICG has several challenges to hinder its clinical use including rapid blood clearance and instability to heat, light, and solvent, leading to a loss of photoactivation property and PTT efficacy. Herein, we leveraged stabilizing components, methyl-β-cyclodextrin and liposomes, in one nanoplatform (ICD lipo) to enhance ICG stability and the photothermal therapeutic effect against cancer. Compared to ICG, ICD lipo displayed a 4.8-fold reduction in degradation in PBS solvent after 30 days and a 3.4-fold reduction in photobleaching after near-infrared laser irradiation. Moreover, in tumor-bearing mice, ICD lipo presented a 2.7-fold increase in tumor targetability and inhibited tumor growth 9.6 times more effectively than did ICG without any serious toxicity. We believe that ICD lipo could be a potential PTT agent for cancer therapeutics.

Tomato yellow leaf curl virus (TYLCV) and tomato spotted wilt virus (TSWV) are well-known examples of the begomovirus and orthotospovirus genera, respectively. These viruses cause significant economic damage to tomato crops worldwide. Weeds play an important role in the ongoing presence and spread of several plant viruses, such as TYLCV and TSWV, and are recognized as reservoirs for these infections. This work applies a comprehensive approach, encompassing field surveys and molecular techniques, to acquire an in-depth understanding of the interactions between viruses and their weed hosts. A total of 60 tomato samples exhibiting typical symptoms of TYLCV and TSWV were collected from a tomato greenhouse farm in Nonsan, South Korea. In addition, 130 samples of 16 different weed species in the immediate surroundings of the greenhouse were collected for viral detection. PCR and reverse transcription-PCR methodologies and specific primers for TYLCV and TSWV were used, which showed that 15 tomato samples were coinfected by both viruses. Interestingly, both viruses were also detected in perennial weeds, such as Rumex crispus, which highlights their function as viral reservoirs. Our study provides significant insights into the co-occurrence of TYLCV and TSWV in weed reservoirs, and their subsequent transmission under tomato greenhouse conditions. This project builds long-term strategies for integrated pest management to prevent and manage simultaneous virus outbreaks, known as twindemics, in agricultural systems.

Purpose: As the survival rate from pediatric cancers has increased significantly with advances in treatment modalities, long-term endocrine complications have also risen. This study investigated the frequencies and risks of endocrine sequelae in childhood cancer survivors who received hematopoietic stem cell transplantation (HSCT)., Methods: This study included 200 pediatric patients who underwent HSCT. Clinical and endocrinological findings were collected retrospectively. The median follow-up duration after HSCT was 14 years., Results: Endocrine complications occurred in 135 patients (67.5%). Children who underwent HSCT at pubertal age (n=100) were at higher risk of endocrine complications than those who received it at prepubertal age (79% vs. 56%, P=0.001). The most common complication was hypogonadism (40%), followed by dyslipidemia (22%). Short stature and diabetes mellitus were more prevalent in the prepubertal group, whereas hypogonadism and osteoporosis were more common in the pubertal group. Being female, pubertal age at HSCT, and glucocorticoid use were predictors of an increased risk for any complication. Radiation exposure increased the risk of short stature and hypothyroidism. Hypogonadism was significantly associated with being female, pubertal age at HSCT, and high-dose radiation. Pubertal age at HSCT also increased the risks of osteoporosis and dyslipidemia., Conclusion: This study demonstrates that long-term endocrine complications are common after HSCT in children and adolescents. Age at HSCT is a critical factor for endocrine complications after HSCT. These findings suggest that surveillance strategies for endocrine complications in childhood cancer survivors should be specified according to age at HSCT.

The serotonin transporter (5-hydroxytryptamine transporter [5-HTT], Serotonin Transporter (SERT), SLC6A4) modulates the activity of serotonin via sodium-dependent reuptake. Given the established importance of serotonin in the control of pain, 5-HTT has received much interest in studies of pain states and as a pharmacological target for serotonin reuptake inhibitors (SRIs). Animal models expressing varying levels of 5-HTT activity show marked differences in pain behaviors and analgesic responses, as well as many serotonin-related physiological effects. In humans, functional nucleotide variations in the SLC6A4 gene, which encodes the serotonin transporter 5-HTT, are associated with certain pathologic pain conditions and differences in responses to pharmacological therapy. These findings collectively reflect the importance of 5-HTT in the intricate physiology and management of pain, as well as the scientific and clinical challenges that need to be considered for the optimization of 5-HTT-related analgesic therapies. PERSPECTIVE: The serotonin transporter 5-HTT/SCL6A4 is sensitive to pharmacological SRIs. Experimental studies on the physiological functions of serotonin, as well as genetic mouse models and clinical phenotype/genotype correlations of nucleotide variation in the human 5-HTT/SCL6A4 gene, provide new insights for the use of SRIs in chronic pain management., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Immune checkpoints are involved in mechanisms by which tumours escape from the host immune system. Our aim was to evaluate acute myeloid leukaemia (AML) patients to determine expression levels of checkpoint molecules according to diagnosis and treatments, and to identify optimal candidates for checkpoint blockade., Methods: Bone marrow (BM) samples were obtained from 279 AML patients at different disease status and from 23 controls. Flow cytometric analyses of PD-1 and PD-L1/PD-L2 expression were performed., Results: Programmed death-1 (PD-1) expression levels on CD8 + T-cells at AML diagnosis were increased compared to controls. PD-L1 and PD-L2 expression levels on leukaemic cells at diagnosis were significantly higher in secondary AML than in de novo AML. PD-1 levels on CD8 + and CD4 + T-cells after allo-SCT were significantly higher than those at diagnosis and after CTx. PD-1 expression on CD8 + T-cells increased in the acute GVHD group than in the non-GVHD group. The overall survival of patients with high PD-1 expression on CD8 + T-cells was significantly shorter than that of patients with low PD-1 expression., Conclusions: In conclusion, patients who underwent allo-SCT exhibited high PD-1 expression, suggesting that allo-SCT increases PD-1 expression on T-cells, and the patients with high PD-1 expression on CD8 + T-cells after allo-SCT showed the poor prognosis. For these patients, PD-1 blockade could be an immunotherapeutic strategy., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome ® and m-Clodrosome ® ) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes., Results: We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N 3 and radiolabeling. Functionalization with Man-N 3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome ® and m-Clodrosome ® ., Conclusion: The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent., (© 2024. The Author(s).)

Osteoarthritis (OA) is characterized by cartilage damage, inflammation, and pain. Vascular endothelial growth factor receptors (VEGFRs) have been associated with OA severity, suggesting that inhibitors targeting these receptors alleviate pain (via VEGFR1) or cartilage degeneration (via VEGFR2). We have developed a nanoparticle-based formulation of pazopanib (Votrient), an FDA-approved anticancer drug that targets both VEGFR1 and VEGFR2 (Nano-PAZII). We demonstrate that a single intraarticular injection of Nano-PAZII can effectively reduce joint pain for a prolonged time without substantial side effects in two different preclinical OA rodent models involving either surgical (upon partial medial meniscectomy) or nonsurgical induction (with monoiodoacetate). The injection of Nano-PAZII blocks VEGFR1 and relieves OA pain by suppressing sensory neuronal ingrowth into the knee synovium and neuronal plasticity in the dorsal root ganglia and spinal cord. Simultaneously, the inhibition of VEGFR2 reduces cartilage degeneration. These findings provide a mechanism-based disease-modifying drug strategy that addresses both pain symptoms and cartilage loss in OA.

Background : We aimed to analyze the correlation between in-hospital mortality and hemodynamic changes, using polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) initiation time in patients with cancer with refractory septic shock. Methods : Forty-six patients with cancer who received PMX-DHP for refractory septic shock were retrospectively analyzed and classified into early (≤3 h between refractory septic shock and PMX-DHP; n = 17) and late (>3 h; n = 29) initiation groups. The vasopressor inotropic score ( VIS ), sequential organ failure assessment (SOFA) score, and lactate clearance before and 24 h post-PMX-DHP were compared. Results : Overall, 52.17% died from multiple organ dysfunction, with a lower mortality rate in the early initiation group. The VIS and SOFA score decreased in both groups, but the magnitude of decrease was not significant. Lactate clearance improved in both groups, with greater improvement in the early initiation group. Univariable analysis identified associations of in-hospital mortality with early initiation, ΔC-reactive protein, lactate clearance, ΔSOFA score, and Δ VIS . Multivariable analysis demonstrated associations of in-hospital mortality risk with ΔSOFA score and early PMX-DHP initiation. Overall survival was higher in the early initiation group. Early initiation of PMX-DHP in patients with cancer with refractory septic shock reduced in-hospital mortality and improved lactate clearance.

Pain is the prime symptom of osteoarthritis (OA) that directly affects the quality of life. Protein kinase Cδ (PKCδ/Prkcd) plays a critical role in OA pathogenesis; however, its significance in OA-related pain is not entirely understood. The present study investigated the functional role of PKCδ in OA pain sensation. OA was surgically induced in control (Prkcd fl/fl ), global- (Prkcd fl/fl ; ROSA CreERT2 ), and sensory neuron-specific conditional knockout (cKO) mice (Prkcd fl/fl; NaV1.8/Scn10a CreERT2 ) followed by comprehensive analysis of longitudinal behavioral pain, histopathology and immunofluorescence studies. GlobalPrkcd cKO mice prevented cartilage deterioration by inhibiting matrix metalloproteinase-13 (MMP13) in joint tissues but significantly increased OA pain. Sensory neuron-specificdeletion of Prkcd in mice did not protect cartilage from degeneration but worsened OA-associated pain. Exacerbated pain sensitivity observed in global- and sensory neuron-specific cKO of Prkcd was corroborated with markedly increased specific pain mediators in knee synovium and dorsal root ganglia (DRG). These specific pain markers include nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), and their cognate receptors, including tropomyosin receptor kinase A (TrkA) and vascular endothelial growth factor receptor-1 (VEGFR1). The increased levels of NGF/TrkA and VEGF/VEGFR1 were comparable in both global- and sensory neuron-specific cKO groups. These data suggest that the absence of Prkcd gene expression in the sensory neurons is strongly associated with OA hyperalgesia independent of cartilage protection. Thus, inhibition of PKCδ may be beneficial for cartilage homeostasis but could aggravate OA-related pain symptoms., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Intensive multimodal treatment can improve survival in patients with high-risk neuroblastoma, and consolidative radiation therapy has contributed to local control. We examined the clinical outcomes of patients who underwent consolidative radiation therapy at our institution., Methods: We retrospectively reviewed the records of patients with high-risk neuroblastoma who underwent consolidative radiation therapy from March 2001 to March 2021 at Asan Medical Center. Patients underwent multimodal treatment including high-dose chemotherapy, surgery, stem cell transplantation, and maintenance therapy. Radiation (median, 21.0 Gy; range, 14-36) was administered to the primary site and surrounding lymph nodes., Results: This study included 37 patients, and the median age at diagnosis was 2.8 years (range, 1.3-10.0). Four patients exhibited local failure, and 5-year free-from locoregional failure rate was 88.7%, with a median followup period of 5.7 years. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 59.1% and 83.6%, respectively. Univariate analysis revealed that patients with neuron-specific enolase levels > 100 ng/mL had significantly worse DFS and OS (P = 0.036, 0.048), and patients with no residual disease before radiation therapy showed superior OS (P = 0.029). Furthermore, patients with 11q deletion or 17q gain exhibited poor DFS and OS, respectively (P = 0.021, 0.011). Six patients experienced grade 1 acute toxicity. Late toxicity was confirmed in children with long-term survival, predominantly hypothyroidism and hypogonadism, typically < grade 3, possibly attributed to combination treatment. Four patients experienced late toxicity ≥ grade 3 with chronic kidney disease, growth hormone abnormality, ileus, premature epiphyseal closure, and secondary tumor, and recovered by hospitalization or surgical treatment., Conclusions: In patients with high-risk neuroblastoma, consolidative radiotherapy to the primary tumor site resulted in excellent local control and a tolerable safety profile.

Purpose: We aimed to determine the current application and survival trends of hematopoietic stem cell transplantation (HSCT) among Korean children and adolescents with cancer., Materials and Methods: Data of patients aged < 20 years with KCD-10 (Korean Classifications of Diseases, 10th revision) C codes and specific designation codes were collected from the National Health Insurance Service database. Thirty claim codes for HSCT were included, and data from 2009 to 2019 were analyzed., Results: The operational definition of pediatric cancer yielded an annual average of 2,000, with annual cases decreasing. In 2019, 221 HSCTs were performed, a decrease from the ten-year average of 276. Allografts outnumbered autografts with a ratio of 1.5:1. The source of allograft was bone marrow in 15% of patients in 2009; however, it substantially decreased to 3.3% in 2019. Furthermore, 70.5% of allogeneic HSCT used peripheral blood stem cell (PBSC) grafts, which increased to 89.3% by 2015. Cord blood utilization markedly decreased to 2.7% in 2018. The 5-year overall survival (OS) rate of all patients was 85.1%. Overall mortality decreased among patients who underwent recent HSCT, and they exhibited a higher 5-year OS rate., Conclusion: In Korea, the number of pediatric patients with cancer is declining; however, the ratio of transplants to all patients remains constant. Patients who recently underwent transplantation showed better survival rates, possibly due to HSCT optimization. Korea showed a substantially greater PBSC utilization in pediatric HSCT. An in-depth examination encompassing donor relations and cause of death with a prospective registry is required in future studies.

Background and Objectives: To evaluate the prevalence of REM sleep behavior disorder (RBD) and its possible prodromal conditions, isolated dream enactment behavior (DEB) and isolated REM without atonia (RWA), in a general population sample, and the factors associated with diagnosis and symptom frequency., Methods: From a population-based prospective cohort in Korea, 1,075 participants (age 60.1 ± 7.0 years; range 50-80 years; men 53.7%) completed the RBD screening questionnaire (RBDSQ), a structured telephone interview for the presence and characteristics of repeated DEB, and home polysomnography (PSG). RWA was measured on submentalis EMG, including 30-second epoch-based tonic and phasic activity as well as 3-second mini-epoch-based phasic and any EMG activities. Based on the presence of repeated DEB and any EMG activity of ≥22.3%, we categorized the participants into no RBD, isolated RWA, isolated DEB, and RBD groups., Results: RBD was diagnosed in 20 participants, isolated RWA in 133 participants, and isolated DEB in 48 participants. Sex and DEB frequency-adjusted prevalence of RBD was 1.4% (95% CI 1.0%-1.8%), isolated RWA was 12.5% (95% CI 11.3%-13.6%), and isolated DEB was 3.4% (95% CI 2.7%-4.1%). Total RBDSQ score was higher in the RBD and isolated DEB groups than in the isolated RWA and no RBD group (median 5 [interquartile range (IQR) 4-6] for RBD, median 4 [IQR 3-6] for isolated DEB, median 2 [IQR 1-3] for isolated RWA, and median 2 [IQR 1-4] for no RBD groups, p < 0.001). RBDSQ score of ≥5 had good specificity but poor positive predictive value (PPV) for RBD (specificity 84.1% and PPV 7.7%) and its prodromal conditions (specificity 85.2% and PPV 29.1%). Among the RWA parameters, any EMG activity showed the best association with the RBD and its possible prodromes (area under the curve, 0.917). Three-second mini-epoch-based EMG activity and phasic EMG activity were correlated with the frequency of DEB (standardized Jonckheere-Terpstra statistic [std. J-T static] for trend = 0.488, p < 0.001, and std. J-T static = 3.265, p = 0.001, respectively)., Discussion: This study provides prevalence estimates of RBD and its possible prodromal conditions based on a structured telephone interview and RWA measurement on PSG from the general population., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: To investigate whether the association between SJLsc (sleep-corrected social jetlag) and depressive mood is significant and independent of sleep debt., Methods: Participants from the general adult population were interviewed using structured questionnaires on sleep duration, weekday/weekend sleep schedules, and depressive mood (Patient Health Questionnaire-9). Social jetlag (SJL) was measured by SJLsc and standard SJL (SJLs). SJLs was the absolute difference between mid-sleep time on free days (MSF) and workdays (MSW). For SJLsc, both MSF and MSW were adjusted for average sleep duration across the week according to the direction of sleep debt. Sleep debt was defined by sleep extension on free days. The association of SJL with depression was investigated, and covariates included age, sex, sociodemographic factors, insomnia symptoms, sleep duration, and sleep debt., Results: A total of 1982 individuals (1089 men; age 43.1 ± 14.4 years) were analyzed. SJL was present in 24.6% measured by SJLsc and 51.0% by SJLs. SJLsc and SJLs were significantly associated with depressive mood (r = 0.06, P = 0.02; r = 0.06, P = 0.01, respectively), independent of sleep debt. Sleep debt was also associated with depression (r = 0.07, P < 0.01)., Conclusions: By adopting sleep-corrected formula for SJL, this study found that misaligned and insufficient sleep, at levels occurring in routine social life, can negatively affect mood. Minimizing social jetlag and sleep deprivation may promote individual psychological well-being., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Limited by preparation time and ligand solubility, synthetic protocols for cyclodextrin-based metal-organic framework (CD-MOF), as well as subsequent derived materials with improved stability and properties, still remains a challenge. Herein, an ultrafast, environmentally friendly, and cost-effective microwave method is proposed, which is induced by graphene oxide (GO) to design CD-MOF/GOs. This applicable technique can control the crystal size of CD-MOFs from macro- to nanocrystals. CD-MOF/GOs are investigated as a new type of supramolecular adsorbent. It can selectively adsorb the dye molecule methylene green (MG) owing to the synergistic effect between the hydrophobic nanocavity of CDs, and the abundant O-containing functional groups of GO in the composites. Following high temperature calcination, the resulting N, S co-doped porous carbons derived from CD-MOF/GOs exhibit a high capacitance of 501 F g -1 at 0.5 A g -1 , as well as stable cycling stability with 90.1% capacity retention after 5000 cycles. The porous carbon exhibits good electrochemical performance due to its porous surface containing numerous electrochemically active sites after dye adsorption and carbonization. The design strategy by supramolecular incorporating a variety of active molecules into CD-MOFs optimizes the properties of their derived materials, furthering development toward the fabrication of zeitgeisty and high-performance energy storage devices., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Photothermal therapy (PTT) is a novel cancer treatment using a photoabsorber to cause hyperthermia to kill tumors by laser irradiation. Prussian blue nanoparticles (PB NPs) are considered as next-generation photothermal agents due to the facile synthesis and excellent absorption of near-infrared light. Although PB NPs demonstrate remarkable PTT capabilities, their clinical application is limited due to their systemic toxicity. Bacterial cellulose (BC) has been applied to various bio-applications based on its unique properties and biocompatibility. Herein, we design composites with PB NPs and BC as an injectable, highly biocompatible PTT agent (IBC-PB composites). Injectable bacterial cellulose (IBC) is produced through the trituration of BC, with PB NPs synthesized on the IBC surface to prepare IBC-PB composites. IBC-PB composites show in vitro and in vivo photothermal therapeutic effects similar to those of PB NPs but with significantly greater biocompatibility. Specifically, in vitro therapeutic index of IBC-PB composites is 26.5-fold higher than that of PB NPs. Furthermore, unlike PB NPs, IBC-PB composites exhibit no overt toxicity in mice as assessed by blood biochemical analysis and histological images. Hence, it is worth pursuing further research and development of IBC-PB composites as they hold promise as safe and efficacious PTT agents for clinical application., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To examine the association of subjective age (SA) with sleep quality in an adult population., Methods: In the Korean Sleep and Headache Study, 2,349 participants (49.2% men; 48.1 ± 16.4 years old) were interviewed face-to-face using structured questionnaires between September and December 2018. SA was assessed by asking participants their perceived age in years and then compared with their chronological age (CA). Participants were assigned to three groups: feeling younger, feeling their age, and feeling older. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Association between SA and sleep quality was analyzed with multiple linear regression controlling for demographics, psychosocial, and sleep characteristics., Results: The group feeling older (n = 404, 17.2%; men, 58.2%; age, 46.5 ± 16.2 years) had worse sleep quality than the groups feeling younger and feeling their age (PSQI score, 4.3 ± 2.7, 3.8 ± 2.4, 3.4 ± 2.1, respectively, p <.001; prevalence of poor sleep quality, 29.0%, 18.4%, 13.5% respectively, p <.001). The association between SA and the PSQI score remained significant after adjusting for confounders (β = 1.05, 95% confidence interval 0.26, 1.83; p <.001). Stratified analyses by sex and CA showed that the association between SA and the PSQI score was significant only in women and in middle-aged and older group (aged 50-79), suggesting that sex and CA modified the association., Conclusion: Age perception was associated with self-reported sleep quality, independent of CA. SA may be a useful marker that complements the conventional assessment of subjective sleep quality.

Background and Purpose: Excess or insufficient sleep, irregular sleep-wake patterns, and an extreme early or late chronotypes adversely impact physical and mental health. Changes in sleep characteristics should therefore be tracked, and factors that contribute to poor sleep should be identified. We investigated the changes in sleep patterns among South Korean adults during 2009-2018., Methods: Using data of a representative sample of South Korean adults from the 2009 ( n =2,658, 48.5% males; age=44.5±15.0 years old [mean±standard deviation], age range=19-86 years) and 2018 ( n =2,389, 49.1% males; age=47.9±16.3 years, age range=19-92 years) Korean Headache-Sleep Study, we explored changes in sleep timing, sleep duration, chronotype, and social jetlag (SJL). Logistic regression analysis was used to examine the association between average sleep duration and depression., Results: From 2009 to 2018, bedtimes were advanced by 10 and 25 min on workdays and free days, respectively. Meanwhile, wake-up times were advanced by 13 min and delayed by 12 min on workdays and free days, respectively. The average sleep duration significantly decreased from 7.45 h to 7.13 h. The prevalence of short sleep duration (<7 h) increased, whereas that of long sleep duration (≥8 h) decreased. A circadian preference toward eveningness and SJL increased. The prevalence of depression increased from 4.6% to 8.4%, and there were significant reverse J-shaped and U-shaped associations between average sleep duration and depression in 2009 and 2018, respectively., Conclusions: Changes in sleep patterns and the association between sleep duration and depressive mood were determined from a representative sample of the South Korean adult population. Interventions to modify sleep behaviors might improve public health., Competing Interests: Min Kyung Chu, a contributing editor of the Journal of Clinical Neurology, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Korean Neurological Association.)

Neck pain (NP) is a prevalent symptom among migraine patients, but its disability on headache impact and the contributing factors for comorbid NP are poorly understood. This study aimed to investigate NP disability on the impact of headaches among migraineurs and factors linked to comorbid NP, including sleep-related variables. This cross-sectional study was conducted at a university hospital headache center, for headache patients at their first visits. Included in the study were 295 patients with migraines (217 females; 39.0  ±  10.8 years; 101 chronic migraine). Information on NP, history of physician-diagnosed cervical spine or disc disorders, detailed parameters of headache, and sleep and mood variables were collected. Logistic analysis of the severe impact of headache and contributing factors for NP were performed. NP was present in 153 participants (51.9%) with migraine, with high NP disability observed in 28 patients, and 125 patients had low NP disability. In multivariable analysis, NP disability, medication days per month, severe disability of migraine, and excessive daytime sleepiness were significant predictors for severe impact of headache. Thirty-seven patients with physician-diagnosed cervical spine or disc disorders were excluded from the NP analysis. Higher monthly headache days, female gender, and a high likelihood of obstructive sleep apnea were positively correlated with the presence of NP among migraineurs in multivariable analysis. Overall, the study highlights the potential impact of sleep-related variables and monthly headache days on NP in these patients. The high disability of NP was also associated with severe impact of headache.

Chronic pain conditions create major financial and emotional burdens that can be devastating for individuals and society. One primary source of pain is arthritis, a common inflammatory disease of the joints that causes persistent pain in affected people. The main objective of pharmacological treatments for either rheumatoid arthritis (RA) or osteoarthritis (OA) is to reduce pain. Non-steroidal anti-inflammatory drugs, opioids, and opioid antagonists have each been considered in the management of chronic pain in arthritis patients. Naltrexone is an oral-activated opioid antagonist with biphasic dose-dependent pharmacodynamic effects. The molecule acts as a competitive inhibitor of opioid receptors at high doses. However, naltrexone at low doses has been shown to have hormetic effects and provides relief for chronic pain conditions such as fibromyalgia, multiple sclerosis (MS), and inflammatory bowel disorders. Current knowledge of naltrexone suggests that low-dose treatments may be effective in the treatment of pain perception in chronic inflammatory conditions observed in patients with either RA or OA. In this review, we evaluated the therapeutic benefits of low-dose naltrexone (LDN) on arthritis-related pain conditions.

Osteosarcoma is the most common type of primary malignant bone tumor. 18 F-FDG PET/CT is useful for staging, detecting recurrence, monitoring response to neoadjuvant chemotherapy, and predicting prognosis. Here, we review the clinical aspects of osteosarcoma management and assess the role of 18 F-FDG PET/CT, in particular with regard to pediatric and young adult patients., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Anti-CD19 chimeric antigen receptor (CAR)-T cells have improved the outcomes of patients with B cell leukemia and lymphoma. However, their applications and positive outcomes remain limited. CAR-T cells are currently restricted to autologous blood as their source and their use can lead to downregulation of CD19 expression along with complications such as graft-versus-host disease and cytokine release syndrome. The present study aimed to develop anti-CD19/CD22 bispecific CAR structures using an anti-CD22 monoclonal antibody clone from chickens and analyze them in natural killer (NK)-92 cells, a human NK cell line, in vitro and in vivo . Anti-CD19/CD22 CAR-NK-92 cell cytotoxicity was assessed by the survival of target cells and counted using flow cytometry. Anti-CD22/CD19 and loop-structured anti-CD19/CD22 bi-specific CAR-NK-92 cells showed improved efficacy against OCI-Ly7 cells, a human B cell lymphoma cell line, compared with other CAR structures. These results demonstrate the potential of anti-CD19/CD22 bispecific CAR-NK cells and suggested that optimizing CAR structures in NK cells can improve the efficacy of CAR therapy., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kim et al.)

Background: Patients with relapsed osteosarcoma have poor treatment outcomes. High-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT) has been used in several high-risk malignant solid tumors; however, few studies have evaluated their role in treating osteosarcoma. We evaluated the effectiveness of HDCT/ASCT in relapsed pediatric osteosarcoma cases., Procedure: We retrospectively reviewed the medical records of 40 patients diagnosed with and treated for relapsed osteosarcoma at Asan Medical Center and Samsung Medical Center from January 1996 to July 2019., Results: The median age of this cohort was 13.4 years (range: 6.1-18.2). The cohort's 5-year overall survival (OS) was 51.0% ± 0.1% during a median follow-up period of 67.5 months. Twenty-five patients (62.5%) achieved complete remission (CR) with salvage treatment, and the 5-year OS was 82.4% ± 0.1%, whereas none of the remaining 15 patients who did not achieve CR survived (p < .0001). Of the 25 CR cases, 15 underwent subsequent HDCT/ASCT. We compared the effect of HDCT/ASCT among patients who achieved CR. There were no significant differences in the 5-year OS outcomes between patients who did and did not receive HDCT/ASCT (83.9% ± 0.1%, 13/15 vs. 80.0% ± 0.1%, 8/10, respectively; p = .923)., Conclusion: To our knowledge, we report the first comparative cohort study that proved HDCT/ASCT does not significantly improve survival outcomes in relapsed osteosarcoma. Achievement of CR remains the most crucial factor for good survival outcomes., (© 2023 Wiley Periodicals LLC.)

Background: Childhood cancer has a high long-term morbidity and mortality rate. Five years after the initial cancer diagnosis, approximately two-thirds of childhood cancer survivors experience at least one late complication, with one-quarter experiencing severe, life-threatening complications. Chronic health conditions can impact survivors' life planning and daily activities, reducing their health-related quality of life. Comprehensive and longitudinal data are required for investigations of national claims data., Objective: This study aimed to address clinical and health policy interventions and improved survival rates. A comprehensive categorization of the long-term morbidities associated with childhood cancer survivorship is required. We analyzed the trajectory groups associated with long-term mortality among childhood cancer survivors., Methods: We collected data from a nationwide claims database of the entire Korean population. Between 2003 and 2007, patients diagnosed with and treated for cancer before the age of 20 years were included. With 8119 patients who survived >10 years, 3 trajectory groups were classified according to yearly changes in the number of diagnoses (the lowest in group 1 and the highest in group 3)., Results: The patterns of most comorbidities and survival rates differed significantly between the trajectory groups. Group 3 had a higher rate of mental and behavioral disorders, neoplasms, and blood organ diseases than the other two groups. Furthermore, there was a difference in the number of diagnoses by trajectory groups over the entire decade, and the disparity increased as the survival period increased. If a patient received more than four diagnoses, especially after the fourth year, the patient was likely to be assigned to group 3, which had the worst prognosis. Group 1 had the highest overall survival rate, and group 3 had the lowest (P<.001). Group 3 had the highest hazard ratio of 4.37 (95% CI 2.57-7.42; P<.001) in a multivariate analysis of late mortality., Conclusions: Our findings show that the pattern of comorbidities differed significantly among trajectory groups for late death, which could help physicians identify childhood cancer survivors at risk for late mortality. Patients with neoplasms, blood organ diseases, or mental and behavioral disorders should be identified as having an increased risk of late mortality. Furthermore, vigilance and prompt action are essential to mitigate the potential consequences of a child cancer survivor receiving four or more diagnoses within a year., (©Hyery Kim, Hae Reong Kim, Sung Han Kang, Kyung-Nam Koh, Ho Joon Im, Yu Rang Park. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 24.03.2023.)

Nanoparticles are primarily taken up by immune cells after systemic administration. Thus, they are considered an ideal drug delivery vehicle for immunomodulation. Because the spleen is the largest lymphatic organ and regulates the systemic immune system, there have been studies to develop spleen targeting nanoparticles for immunomodulation of cancer and immunological disorders. Inflammatory bowel disease (IBD) includes disorders involving chronic inflammation in the gastrointestinal tract and is considered incurable despite a variety of treatment options. Hydrogen sulfide (H 2 S) is one of the gasotransmitters that carries out anti-inflammatory functions and has shown promising immunomodulatory effects in various inflammatory diseases including IBD. Herein, we developed a delicately tuned H 2 S donor delivering liposome for spleen targeting (ST-H 2 S lipo) and studied its therapeutic effects in a dextran sulfate sodium (DSS) induced colitis model. We identified the ideal PEG type and ratio of liposome for a high stability, loading efficiency, and spleen targeting effect. In the treatment of the DSS-induced colitis model, we found that ST-H 2 S lipo and conventional long-circulating liposomes loaded with H 2 S donors (LC-H 2 S lipo) reduced the severity of colitis, whereas unloaded H 2 S donors did not. Furthermore, the therapeutic effect of ST-H 2 S lipo was superior to that of LC-H 2 S lipo due to its better systemic immunomodulatory effect than that of LC-H 2 S lipo. Our findings demonstrate that spleen targeting H 2 S lipo may have therapeutic potential for IBD.

Background: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (PD1) block tumor growth by reinvigorating the immune system; however, determining their efficacy only by the changes in tumor size may prove inaccurate. As the immune cells including macrophages in the tumor microenvironment (TME) are associated with the response to anti-PD1 therapy, tumor-associated macrophages (TAMs) imaging using nanoparticles can noninvasively provide the immune enrichment status of TME. Herein, the mannosylated-serum albumin (MSA) nanoparticle was labeled with radioactive isotope 68 Ga to target the mannose receptors on macrophages for noninvasive monitoring of the TME according to anti-PD1 therapy., Results: B16F10-Luc and MC38-Luc tumor-bearing mice were treated with anti-PD1, and the response to anti-PD1 was determined by the tumor volume. According to the flow cytometry, the responders to anti-PD1 showed an increased proportion of TAMs, as well as lymphocytes, and the most enriched immune cell population in the TME was also TAMs. For noninvasive imaging of TAMs as a surrogate of immune cell augmentation in the TME via anti-PD1, we acquired [ 68 Ga] Ga-MSA positron emission tomography. According to the imaging study, an increased number of TAMs in responders at the early phase of anti-PD1 treatment was observed in both B16F10-Luc and MC38-Luc tumor-bearing mice models., Conclusion: As representative immune cells in the TME, non-invasive imaging of TAMs using MSA nanoparticles can reflect the immune cell enrichment status in the TME closely associated with the response to anti-PD1. As non-invasive imaging using MSA nanoparticles, this approach shows a potential to monitor and evaluate anti-tumor response to immune checkpoint inhibitors., (© 2023. The Author(s).)

Currently, research on superparamagnetic iron oxide nanoparticles (SPIONs) for magnetic hyperthermia applications is steadily increasing. In this work, SPIONs were synthesized by the bromide-assisted polyol method and angle-shaped SPIONs were successfully generated with the optimized concentration of bromide. The influence of bromide concentration on the shape of the generated SPIONs as well as the heating characteristics under an alternating magnetic field (AMF) was thoroughly investigated. At a concentration of 20 mg mL -1 of the angle-shaped SPIONs, the highest temperature curve up to 23 °C was observed under AMF with 140 Oe and 100 kHz for 10 min. With the biotoxicity assay, no significant cytotoxicity was observed in the normal fibroblast of HFB-141103 as well as tumor cells of U87MG and FSall treated with the angle-shaped SPIONs at a concentration below 100 μg mL -1 . However, significantly decreased cellular viability was observed in tumor cells of U87MG and FSall treated with 100 μg mL -1 of the angle-shaped SPIONs under AMF with 140 Oe and 100 kHz. Based on these results, it is thought that the angle-shaped SPIONs synthesized by the bromide-assisted polyol method will provide highly efficient magnetic hyperthermia therapy for cancers under biologically safe AMF with 140 Oe and 100 kHz., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Pain is the major reason that patients suffering from osteoarthritis (OA) seek medical care. We found that vascular endothelial growth factors (VEGFs) mediate signaling in OA pain pathways. To determine the specific contributions of VEGFs and their receptors (VEGFRs) to joint pathology and pain transmission during OA progression, we studied intra-articular (IA) injections of VEGF ligands into murine knee joints. Only VEGF ligands specific for the activation of VEGFR1, but not VEGFR2, induced allodynia within 30 min. Interventions in OA by inhibitors of VEGFRs were done in vivo using a preclinical murine OA model by IA injections of selective inhibitors of VEGFR1/VEGFR2 kinase (pazopanib) or VEGFR2 kinase (vandetanib). OA phenotypes were evaluated using pain-associated murine behavioral tests and histopathologic analyses. Alterations in VEGF/VEGFR signaling by drugs were determined in knee joints, dorsal root ganglia, and spinal cord by immunofluorescence microscopy. Pazopanib immediately relieved OA pain by interfering with pain transmission pathways. Pain reduction by vandetanib was mainly due to the inhibition of cartilage degeneration by suppressing VEGFR2 expression. In conclusion, IA administration of pazopanib, which simultaneously inhibits VEGFR1 and VEGFR2, can be developed as an ideal OA disease-modifying drug that rapidly reduces joint pain and simultaneously inhibits cartilage degeneration., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Renal tumors account for approximately 7% of all childhood cancers. These include Wilms tumor (WT), clear cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor of the kidney (MRTK), renal cell carcinoma (RCC), congenital mesoblastic nephroma (CMN) and other rare tumors. We investigated the epidemiology of pediatric renal tumors in Korea., Materials and Methods: From January 2001 to December 2015, data of pediatric patients (0-18 years) newly-diagnosed with renal tumors at 26 hospitals were retrospectively analyzed., Results: Among 439 patients (male, 240), the most common tumor was WT (n=342, 77.9%), followed by RCC (n=36, 8.2%), CCSK (n=24, 5.5%), MRTK (n=16, 3.6%), CMN (n=12, 2.7%), and others (n=9, 2.1%). Median age at diagnosis was 27.1 months (range 0-225.5) and median follow-up duration was 88.5 months (range 0-211.6). Overall, 32 patients died, of whom 17, 11, 1, and 3 died of relapse, progressive disease, second malignant neoplasm, and treatment-related mortality. Five-year overall survival and event free survival were 97.2% and 84.8% in WT, 90.6% and 82.1% in RCC, 81.1% and 63.6% in CCSK, 60.3% and 56.2% in MRTK, and 100% and 91.7% in CMN, respectively (p < 0.001)., Conclusion: The pediatric renal tumor types in Korea are similar to those previously reported in other countries. WT accounted for a large proportion and survival was excellent. Non-Wilms renal tumors included a variety of tumors and showed inferior outcome, especially MRTK. Further efforts are necessary to optimize the treatment and analyze the genetic characteristics of pediatric renal tumors in Korea.

Background: X-ray fluorescence (XRF) imaging for metal nanoparticles (MNPs) is a promising molecular imaging modality that can determine dynamic biodistributions of MNPs. However, it has the limitation that it only provides functional information., Purpose: In this study, we aim to show the feasibility of acquiring functional and anatomic information on the same platform by demonstrating a dual imaging modality of pinhole XRF and computed tomography (CT) for gold nanoparticle (GNP)-injected living mice., Methods: By installing a transmission CT detector in an existing pinhole XRF imaging system using a two-dimensional (2D) cadmium zinc telluride (CZT) gamma camera, XRF and CT images were acquired on the same platform. Due to the optimal X-ray spectra for XRF and CT image acquisition being different, XRF and CT imaging were performed by 140 and 50 kV X-rays, respectively. An amount of 40 mg GNPs (1.9 nm in diameter) suspended in 0.20 ml of phosphate-buffered saline were injected into the three BALB/c mice via a tail vein. Then, the kidney and tumor slices of mice were scanned at specific time points within 60 min to acquire time-lapse in vivo biodistributions of GNPs. XRF images were directly acquired without image reconstruction using a pinhole collimator and a 2D CZT gamma camera. Subsequently, CT images were acquired by performing CT scans. In order to confirm the validity of the functional information provided by the XRF image, the CT image was fused with the XRF image. After the XRF and CT scan, the mice were euthanized, and major organs (kidneys, tumor, liver, and spleen) were extracted. The ex vivo GNP concentrations of the extracted organs were measured by inductively coupled plasma mass spectrometry (ICP-MS) and L-shell XRF detection system using a silicon drift detector, then compared with the in vivo GNP concentrations measured by the pinhole XRF imaging system., Results: Time-lapse XRF images were directly acquired without rotation and translation of imaging objects within an acquisition time of 2 min per slice. Due to the short image acquisition time, the time-lapse in vivo biodistribution of GNPs was acquired in the organs of the mice. CT images were fused with the XRF images and successfully confirmed the validity of the XRF images. The difference in ex vivo GNP concentrations measured by the L-shell XRF detection system and ICP-MS was 0.0005-0.02% by the weight of gold (wt%). Notably, the in vivo and ex vivo GNP concentrations in the kidneys of three mice were comparable with a difference of 0.01-0.08 wt%., Conclusions: A dual imaging modality of pinhole XRF and CT imaging system and L-shell XRF detection system were successfully developed. The developed systems are a promising modality for in vivo imaging and ex vivo quantification for preclinical studies using MNPs. In addition, we discussed further improvements for the routine preclinical applications of the systems., (© 2022 American Association of Physicists in Medicine.)

Objective: Wake-up stroke (WUS) is an ischemic stroke occurring during nocturnal sleep with neurological deficits observed upon awakening. Our study aimed to investigate the association between WUS, sleep curtailment, and sleep behavior according to the obstructive sleep apnea (OSA) risk in patients with acute ischemic stroke., Methods: This single-centered, retrospective study included hospitalized subjects with acute ischemic stroke occurring within 30 days. A total of 250 participants were classified as WUS or not and enquired about their sleep habits concerning sleep time on weekdays and weekends, demographic factors, and assessed comorbid medical conditions. Weekend catch-up sleep (CUS) was defined as the extension of sleep duration during weekends. The average weekly sleep duration and chronotype were assessed. The association between WUS and sleep factors was analyzed., Results: WUS was observed in 70 patients (28.0%) with acute ischemic stroke. There were no significant differences in the demographic and stroke-related variables between the WUS and non-WUS (NWUS) groups. Upon stratified analysis based on risk of OSA, average weekly sleep duration (odds ratio, [OR] = 0.60, 95% confidence interval, [CI] = 0.41-0.89; p = 0.011), the presence of weekend CUS (OR = 0.07, 95% CI = 0.01-0.97; p = 0.047), and chronotype (OR = 0.62, 95% CI = 0.39-0.98; p = 0.041) were independently associated with WUS in low-risk group with OSA, but not in the high-risk group., Conclusions: Short sleep duration and lack of compensation are significantly associated with WUS in low-risk OSA group. Insufficient sleep and sleep behaviors could play a different role in causing ischemic stroke during sleep when patients are stratified by their risk of sleep apnea., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest. The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: https://doi.org/10.1016/j.sleep.2020.09.030., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Seizures and delirium tremens (DTs) are recognized as severe alcohol-withdrawal symptoms. Prolonged admission and serious complications associated with alcohol withdrawal are responsible for increased costs and use of medical and social resources. This study investigated the predictive value of quantitative electroencephalography (QEEG) for developing alcohol-related DTs after alcohol-withdrawal seizure (AWS)., Methods: We compared differences in QEEG in patients after AWS (n = 13). QEEG was performed in the intensive care unit within 48 h of admission, including in age- and sex-matched healthy controls. We also investigated the prognostic value of QEEG for the development of alcohol DTs after AWS in a retrospective, case-control study. The spectral power of each band frequency and the ratio of the theta to alpha band (TAR) in the electroencephalogram were analyzed using iSyncBrain ® (iMediSync, Inc., Korea)., Results: The beta frequency and the alpha frequency band power were significantly higher and lower, respectively, in patients than in age- and sex-matched healthy controls. In AWS patients with DTs, the relative beta-3 power was lower, particularly in the left frontal area, and the TAR was significantly higher in the central channel than in those without DTs., Conclusion: Quantitative EEG showed neuronal excitability and decreased cognitive activities characteristic of AWS associated with alcohol-withdrawal state, and we demonstrated that quantitative EEG might be a helpful tool for detecting patients at a high risk of developing DTs during an alcohol-dependence period., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The intratumoral accumulation of nanomedicine has been considered a passive process, referred to as the enhanced permeability and retention effect. Recent studies have suggested that the tumor uptake of nanomedicines follows an energy-dependent pathway rather than being a passive process. Herein, to explore the factor candidates that are associated with nanomedicine tumor uptake, a molecular marker identification platform is developed by integrating microscopic fluorescence images of a nanomedicine distribution with spatial transcriptomics information. When this approach is applied to PEGylated liposomes, molecular markers related to hypoxia, glycolysis, and apoptosis can be identified as being related to the intratumoral distribution of the nanomedicine. It is expected that the method can be applied to explain the distribution of a wide range of nanomedicines and that the data obtained from this analysis can enhance the precise utilization of nanomedicines., (© 2022 Wiley-VCH GmbH.)

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) represents an effective treatment for severe Parkinson's disease (PD), but little is known about the long-term benefit., Objective: To investigate the survival rate and long-term outcome of DBS., Methods: We investigated all 81 patients including 37 males and 44 females who underwent bilateral STN DBS from March 2005 to March 2008 at a single institution. The current survival status of the patients was investigated. Preoperative and postoperative follow-up assessments were analyzed., Results: The mean age at the time of surgery was 62 (range 27-82) years, and the median clinical follow-up duration was 145 months. Thirty-five patients (43%) died during the follow-up period. The mean duration from DBS surgery to death was 110.46 ± 40.8 (range 0-155) months. The cumulative survival rate is as follows: 98.8 ± 1.2% (1 year), 95.1 ± 2.4% (5 years), and 79.0 ± 4.5% (10 years). Of the 81 patients, 33 (40%) were ambulatory up to more than 11 years. The Unified Parkinson's Disease Rating Scale (UPDRS) score was significantly improved until 5 years after surgery although it showed a tendency to increase again after 10 years. The patient group with both electrodes located within the STN showed a higher rate of survival and maintained ambulation., Conclusion: STN DBS is a safe and effective treatment for patients with advanced PD. This study based on the long-term follow-up of large patient populations can be used to elucidate the long-term fate of patients who underwent bilateral STN DBS for PD., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Lipid nanoparticles (LNPs) have been one of the most successful nano-delivery vehicles that enable efficient delivery of cytotoxic chemotherapy agents, antibiotics, and nucleic acid therapeutics. During the coronavirus disease (COVID-19) pandemic, LNP-based COVID-19 messenger RNA (mRNA) vaccines from Pfizer/BioNTech and Moderna have been successfully developed, resulting in global sales of $37 billion and $17.7 billion, respectively, in 2021. Based on this success, the development of multiple LNP-based RNA therapeutics is gaining momentum due to its potential in vaccines and therapeutics for various genetic diseases and cancers. Furthermore, imaging techniques can be utilized to evaluate the pharmacokinetics and pharmacodynamics (PK/PD) effects, which helps target discovery and accelerates the development of LNP-based mRNA therapies. A thorough introduction and explanation of the components of LNPs and its functions along with various production methods of formulating LNPs are provided in this review. Furthermore, recent advances in LNP-based RNA therapeutics in clinics and clinical trials are explored. Additionally, the evaluation of PK/PD of LNPs for RNA delivery and the current and potential roles in developing LNP-based mRNA pharmaceutics through imaging techniques will be discussed., Competing Interests: Competing Interests: Hyung-Jun Im is a consultant of Cellbion. Hyung-Jun Im is a co-founder and Chief Scientific Officer of Portrai. Hyewon Youn is a co-founder and Chief Scientific Officer of BIK-Therapeutics. There is no competing financial interest., (© The author(s).)

Tropomyosin receptor kinase A (TrkA/NTRK1) is a high-affinity receptor for nerve growth factor (NGF), a potent pain mediator. NGF/TrkA signaling elevates synovial sensory neuronal distributions in the joints and causes osteoarthritis (OA) pain. We investigated the mechanisms of pain transmission as to whether peripheral sensory neurons are linked to the cellular plasticity in the dorsal root ganglia (DRG) and are critical for OA hyperalgesia. Sensory neuron-specific deletion of TrkA was achieved by tamoxifen injection in 4-week-old TrkA fl/fl ;Na V 1.8 CreERT2 ( Ntrk1 fl/fl ;Scn10a CreERT2 ) mice. OA was induced by partial medial meniscectomy (PMM) in 12-week-old mice, and OA-pain-related behavior was analyzed for 12 weeks followed by comprehensive histopathological examinations. OA-associated joint pain was markedly improved without cartilage protection in sensory-neuron-specific conditional TrkA knock-out (cKO) mice. Alleviated hyperalgesia was associated with suppression of the NGF/TrkA pathway and reduced angiogenesis in fibroblast-like synovial cells. Elevated pain transmitters in the DRG of OA-induced mice were significantly diminished in sensory-neuron-specific TrkA cKO and global TrkA cKO mice. Spinal glial activity and brain-derived neurotropic factor (BDNF) were significantly increased in OA-induced mice but were substantially eliminated by sensory-neuron-specific deletion. Our results suggest that augmentation of NGF/TrkA signaling in the joint synovium and the peripheral sensory neurons facilitate pro-nociception and centralized pain sensitization.

Purpose: Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs., Methods: Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan)., Results: The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or > 25 ng/mL (Taiwan and Singapore), and/or β-human chorionic gonadotropin (β-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated β-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum β-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS., Conclusion: Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The utilization of an anionic redox reaction as an innovative strategy for overcoming the limitations of cathode capacity in lithium-ion batteries has recently been the focus of intensive research. Li 2 O-based materials using the anionic (oxygen) redox reaction have the potential to deliver a much higher capacity than commercial cathodes using cationic redox reactions based on transition-metal ions. However, parasitic reactions attributed to the superoxo species (such as LiO 2 ), derived from the Li 2 O active material of the cathode, deteriorate the stability of the interface between the cathode and electrolyte, which has limited the commercialization of Li 2 O-based cathodes. To address this issue, malonic-acid-functionalized fullerenes (MC 60 ) were applied in the electrolyte as an additive for scavenging the superoxo radicals (O 2 1- in LiO 2 ) that trigger parasitic reactions. MC 60 can efficiently capture superoxo radicals using the π-conjugated surface and the malonate functionality on the surface. As a result, MC 60 considerably enhanced the available capacity and cycling performance of the Li 2 O-based cathodes, decreased the interfacial layer formed on the cathode surface, and hindered the generation of byproducts, such as Li 2 CO 3 , CO 2 , and C-F 3 , derived from parasitic reactions. In addition, the loss of Li 2 O from the cathode surface during cycling was also suppressed, validating the ability of MC 60 to capture superoxo radicals. This result confirms that the introduction of MC 60 can effectively alleviate the parasitic reactions at the cathode/electrolyte interface and improve the electrochemical performance of Li 2 O-based cathodes by scavenging the superoxo species.

We developed hybrid nanospheres comprised of two of the most important biomolecules in nature, DNA and proteins, which have excellent biocompatibility, high drug payload capacity, in vivo imaging ability, and in vitro / in vivo cancer targeting capability. The synthesis can be done in a facile one-pot assembly system that includes three steps: step-growth polymerization of two DNA oligomers, addition of streptavidin to assemble spherical hybrid nanostructures, and functionalization of hybrid nanospheres with biotinylated aptamers. To test the feasibility of cancer targeting and drug-loading capacity of the hybrid nanospheres, MUC1-specific aptamers (MA3) were conjugated to nanosphere surfaces (apt-nanospheres), and doxorubicin (Dox) was loaded into nanospheres by DNA intercalation. The successful construction of nanospheres and apt-nanospheres was confirmed by agarose gel electrophoresis and dynamic light scattering (DLS). Their uniform spherical morphology was confirmed by transmission electron microscopy (TEM). Fluorescence spectra of nanospheres demonstrated high Dox-loading capability and slow-release characteristics. In vitro MUC1-specific binding of the apt-nanospheres was confirmed by flow cytometry and confocal microscopy. Dox-loaded apt-nanospheres significantly increased cytotoxicity of the MUC1-positive cancer cells due to aptamer-mediated selective internalization, as shown via cell viability assays. Apt-nanospheres could also be imaged in vivo through the synthesis of hybrid nanospheres using fluorescent dye-conjugated DNA strands. Finally, in vivo specific targeting ability of apt-nanospheres was confirmed in a MUC1-positive 4T1 tumor-bearing mouse model, whereas apt-nanospheres did not cause any sign of systemic toxicity in normal mice. Taken together, our self-assembled DNA-streptavidin hybrid nanospheres show promise as a biocompatible cancer targeting material for contemporary nanomedical technology.

The development of molecular imaging probes to identify key cellular changes within lung metastases may lead to noninvasive detection of metastatic lesions in the lung. In this study, we constructed a macrophage-targeted clickable albumin nanoplatform (CAN) decorated with mannose as the targeting ligand using a click reaction to maintain the intrinsic properties of albumin in vivo . We also modified the number of mannose molecules on the CAN and found that mannosylated serum albumin (MSA) harboring six molecules of mannose displayed favorable pharmacokinetics that allowed high-contrast imaging of the lung, rendering it suitable for in vivo visualization of lung metastases. Due to the optimized control of functionalization and surface modification, MSA enhanced blood circulation time and active/passive targeting abilities and was specifically incorporated by mannose receptor (CD206)-expressing macrophages in the metastatic lung. Moreover, extensive in vivo imaging studies using single-photon emission computed tomography (SPECT)/CT and positron emission tomography (PET) revealed that blood circulation of time-optimized MSA can be used to discern metastatic lesions, with a strong correlation between its signal and metastatic burden in the lung.

Background: This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes., Methods: A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken., Results: From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had β-human chorionic gonadotropin values <50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates were 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by the radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patients with bifocal tumors, an extended field RT was associated with better outcomes. In multivariable analysis, only RT fields were associated with RFS. In relapsed patients, salvage rates were high at 85.7%. Additionally, patients who received salvage RT had a better outcome (91.6% vs. 66.7%)., Conclusions: Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lung cancer is the prominent cause of cancer-associated death primarily because of distant metastatic disease. The metastatic potential of non-small cell lung cancer (NSCLC) is associated with tumor cell aggregation. However, the systemic mechanotransduction mechanism by which tumor cells dynamically aggregate and disseminate is poorly understood, especially in NSCLC. In this study, we examine whether the cell surface matrix plays an important role in metastasis. We used poly-2-hydroxyethyl methacrylate-based 3D spheroid formation methods to mimic in vivo metastatic lesions. Supra-structural analysis of human NSCLC A549 cells stained with ruthenium red for transmission electron microscopy (TEM) showed that glycocalyx surrounding the cell surface in 2D culture decreases in 3D culture. Comprehensive gene expression analysis revealed that the genes associated with cell adhesion were distinctly enriched in A549 cell spheroids. Of these, downregulation of the tumor metastatic microenvironment facilitator LOXL2, a copper-dependent enzyme catalyzing posttranslational oxidative deamination of peptidyl lysine, was of special interest. Knockdown of LOXL2 thickened the cell surface matrix in 2D culture and impaired compact aggregate formation in 3D culture. Moreover, A549 cell spheroids with endogenous overexpression of LOXL2 increased their dissemination on basement extracellular matrix Matrigel. Overall, these data imply that cell detachment-downregulated LOXL2 contributes to cell surface matrix remodeling, leading to collective dissemination of free-floating aggregates., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The incorporation of a reduced-intensity conditioning (RIC) regimen in hematopoietic cell transplantation (HCT) for patients with hemophagocytic lymphohistiocytosis (HLH) has decreased early mortality but is associated with a high rate of mixed chimerism and graft failure. Here, we present a successful single-center experience using busulfan and a fludarabine-based RIC regimen for the treatment of HLH., Methods: The medical records of pediatric patients with HLH who underwent HCT using a busulfan/ fludarabine-based RIC regimen between January 2008 and December 2017 were reviewed retrospectively., Results: Nine patients received HCT with a busulfan/fludarabine-based RIC regimen. Three patients had primary HLH, and the other six patients had secondary HLH with multiple reactivations. All three patients with primary HLH had UNC13D mutations. All patients achieved neutrophil and platelet engraftment at a median of 11 days (range, 10‒21) and 19 days (range, 13‒32), and all eight evaluable patients had sustained complete donor chimerism at the last follow-up. Two patients (22%) experienced grade 2 acute graft-versus- host disease (GVHD). Two patients (22%) developed chronic GVHD, and one died from chronic GVHD. One patient (11%) experienced reactivation 4 months after HCT from a syngeneic donor and died of the disease. The 8-year overall survival and event-free survival rates were 78%. No early treatment-related mortality within 100 days after HCT was observed., Conclusion: Our experience suggests that a busulfan/fludarabine-based RIC regimen is a viable option for pediatric patients with HLH who require HCT.