MB2033, an anti-PD-L1 × IL-2 variant fusion protein, demonstrates robust anti-tumor efficacy with minimal peripheral toxicity.

Interleukin-2 (IL-2), a cytokine with pleiotropic immune effects, was the first approved cancer immunotherapy agent. However, IL-2 is associated with systemic toxicity due to binding with its ligand IL-2Rα, such as vascular leakage syndrome, limiting its clinical applications. Despite efforts to extend the half-life of IL-2 and abolish IL-2Rα interactions, the risk of toxicity remains unresolved. In this study, we developed the bispecific fusion protein MB2033, comprising a novel IL-2 variant (IL-2v) connected to anti-programmed death ligand 1 (PD-L1) via a silenced Fc domain. The IL-2v of MB2033 exhibits attenuated affinity for IL-2Rßγ without binding to IL-2Rα. The binding affinity of MB2033 for PD-L1 is greater than that for IL-2Rßγ, indicating its preferential targeting of PD-L1+ tumor cells to induce tumor-specific immune activation. Accordingly, MB2033 exhibited significantly reduced regulatory T cell activation, while inducing comparable CD8+ T cell activation to recombinant human IL-2 (rhIL-2). MB2033 induced lower immune cell expansion and reduced cytokine levels compared with rhIL-2 in human peripheral blood mononuclear cells, indicating a decreased risk of peripheral toxicity. MB2033 exhibited superior anti-tumor efficacy, including tumor growth inhibition and complete responses, compared with avelumab monotherapy in an MC38 syngeneic mouse model. In normal mice, MB2033 was safer than non-α IL-2v and tolerable up to 30 mg/kg. These preclinical results provide evidence of the dual advantages of MB2033 with an enhanced safety and potent clinical efficacy for cancer treatment.

Safety and effectiveness of integrative Korean medicine for the management of patients sustaining injuries in traffic accidents during pregnancy: A retrospective chart review and questionnaire survey.

The number of traffic accidents (TAs) is rising each year, and the severity of injuries can vary. Many people experience limitations in activities of daily living following TAs, affecting their quality of life. In pregnant women, even simple injuries caused by a TA could lead to unfavorable obstetric outcomes. Thus, we conducted a retrospective chart review and follow-up questionnaire survey to assess the safety and effectiveness of integrative Korean medicine (KM) treatment for pregnant women injured in TAs. To assess integrative KM effectiveness, the numeric rating scale (NRS) for TA-related symptoms, neck disability index (NDI) score, Oswestry disability index (ODI) score, shoulder pain and disability index score, Western Ontario and McMaster Universities Arthritis Index score, EuroQol 5-dimension 5-level (EQ-5D-5L) score, and patient global impression of change score were investigated for pregnant women injured in TAs. Additionally, for safety evaluation, obstetric and neonatal outcomes, as well as symptoms related to pregnancy, were assessed. At the end of treatment and follow-up, there were significant reductions in NDI and ODI scores, as well as NRS for neck pain, lower back pain, and headache, compared to scores at baseline. EQ-5D-5L scores significantly increased. A follow-up of 50 patients showed no major differences in obstetric and neonatal outcomes compared to the typical outcomes that occur in pregnant women and neonates. Major improvements were observed in the symptoms of patients who underwent integrative KM treatment after being injured in TAs. The symptoms occurred at a rate similar to those in typical pregnant women, while causality with integrative KM treatment was assessed to be unlikely or unclear. Therefore, integrative KM treatment may be considered an alternative treatment option for pregnant women who currently have limited treatment options.

Correlation between aggression at the veterinary clinic and problem behaviors at home for cats in the USA.

OBJECTIVES: The aim of the study was to determine whether cats that exhibit aggression during veterinary visits are more likely to have behavior problems at home. METHODS: An online, anonymous, cross-sectional survey was developed and distributed to residents in the USA who were aged over 18 years and who were the primary owners of at least one cat. The survey collected information about cat and household factors, and utilized a validated questionnaire instrument for obtaining behavioral information of pet cats. RESULTS: Aggression at the veterinary clinic was reported in 42.6% of the cats. The frequency of aggression exhibited at the veterinary clinic was lower in cats that lived in multi-cat households. Most cats did not receive medications intended to reduce fear, anxiety and/or pain before veterinary visits. Aggression at the veterinary clinic was positively associated with behavior problems at home, including stranger-directed aggression, owner-directed aggression, resistance to restraint, familiar cat aggression, dog-directed aggression, house-soiling, separation-related behaviors and scratching claws on inappropriate surfaces indoors. CONCLUSIONS AND RELEVANCE: Cats that exhibit aggression at the veterinary clinic are more likely to exhibit aggression and anxiety-related behaviors at home. Veterinarians should screen cats that exhibit aggression at the veterinary clinic for behavior problems at home to institute prompt diagnosis and treatment.

Attitudes and practices toward feral cats of male and female dog or cat owners and non-owners in Seoul, South Korea.

The number of pet cats in South Korea has sharply increased since 2010. Problems have arisen with feral or stray cats, creating conflict among residents, to such an extent that the government provides some sites for people to offer feeding stations for the stray cats. This study investigated hypotheses on people's attitudes toward feral cats in Seoul, South Korea: (i) dog and cat owners would show more positive attitudes than non-owners toward feral cats; (ii) females would have more positive attitudes toward feral cats than males; (iii) the number of Seoul-provided feeding stations by district would be correlated with people's positive attitudes toward feral cats. Responses from 7,394 participants were used for the final analyses with 3,179 males, 3,607 females, and 599 others (includes "decline to state"). Cat owners reported more extremely positive attitudes toward feral cats than people who had no cats. Females more often had cats than males, and they were more extremely positive toward pet and feral cats than males, and strongly opposed to culling as a management strategy. The attitudes toward feral cats of people with only dogs were intermediate between people with cats and people without pets, more resembling those of people without pets. There was a correlation between the number of city-provided feeding stations and people's attitudes toward feral cats, but only in the areas with at least 40 feeder stations; having many city-provided feeding stations was associated with very negative attitudes to feral cats. Whether the very large number of feeding stations were provided in the two neighborhoods due to a previously excessive number of feral cats in those neighborhoods, vs. those feeding stations attracting or provisioning an ever-growing number of feral cats, is unknown. These results show sharp differences in attitudes between cat owners and non-owners, and between males and females. Results resemble findings in other studies, perhaps with more extreme differences between sub-groups. The study revealed that attitudes toward pet and feral cats in Seoul were complex and varied with pet ownership, with sex, and with neighborhood context.

Long-term follow-up of inpatients with traumatic fractures who received integrative Korean Medicine treatment: A retrospective analysis and questionnaire survey study.

Previous studies have reported pain reduction after Korean medicine (KM) treatment in patients with fractures. However, these studies were limited by small sample sizes and short observation periods. To address these limitations, we aimed to analyze the outcomes of patients with traumatic fractures who received integrative KM treatment and investigate their long-term progress through follow-up observations. This study was a retrospective analysis and questionnaire survey conducted at a multi-center inpatient care setting in Korea. A total of 1150 patients who had traumatic fractures and received at least 5-day inpatient care at one of 5 KM hospitals. Finally, 339 patients completed the follow-up survey. The questionnaire survey was administered 3 months post discharge. The primary outcome was the difference in numeric rating scale (NRS) scores at admission and discharge for fracture-related pain. The secondary outcomes were EuroQol 5-Dimension 5-Level (EQ-5D-5L) score, Oswestry Disability Index, Neck Disability Index, Western Ontario and McMaster Universities Arthritis Index, Shoulder Pain and Disability Index, and Patient Global Impression of Change (PGIC) score. The follow-up questionnaire survey included questions on surgery and imaging before admission and after discharge and treatment within the past 3 months. The mean NRS score at follow-up showed a significant decrease of 4.41 points compared with that at admission (P < .001). The mean EQ-5D-5L score at follow-up showed a significant increase of 0.18 points compared with that at admission (P < .05). In the follow-up survey on PGIC, 307 participants (90.56%) were "minimally improved" or better. Integrative KM treatment can help improve pain, functional impairment, and long-term quality of life in patients with traumatic fractures.

Platelet-Derived Growth Factor-BB Priming Enhances Vasculogenic Capacity of Bone Marrow-Derived Endothelial Precursor Like Cells.

BACKGROUND: Human endothelial progenitor cells (EPCs) were first identified in the peripheral blood and later in the cord blood and bone marrow (BM) with different vascularization capacity and different surface marker profiles. However, their identity and functional roles in neovascularization have not been clearly demonstrated in vivo and in vitro. METHODS: Characterization of BM-EPC like cells were performed by fluorescence-activated cell sorting, immunofluorescence staining, enzyme-linked immunosorbent assay, Matrigel tube formation assay, and western blot analysis. RESULTS: BM-EPC like cells were identified by selective adhesion to fibronectin and collagen from BM mononuclear cells, which generate fast-growing colonies with spindle morphology, express surface markers of CD105, vWF, UEA-I lectin binding, secrete HGF, VEGF, TGF-beta1 but can be distinguished from circulating EPC and endothelial cells by no expression of surface markers such as CD31, CD309, CD45, and CD34. These BM-EPC like cells shared many cell surface markers of BM-mesenchymal stem cells (MSC) but also can be distinguished by their vasculogenic property and other unique surface markers. Furthermore, the vasculogenic capacity of BM-EPC like cells were enhanced by co-culture of BM-MSC or PDGF-BB priming. PDGF-BB stimulated cell migration, proliferation, and secretion of laminin ß-1, which was proposed as one of the mechanisms involved in the better vascularization of BM-EPC like cells. CONCLUSION: PDGF-BB priming may be applied to improve the potency and function of BM-EPC like cells as vasculogenic cell therapy for the ischemic vascular repair.

Predictors of suicide ideation among South Korean adolescents: A machine learning approach.

BACKGROUND: The current study developed a predictive model for suicide ideation among South Korean (Korean) adolescents using a comprehensive set of factors across demographic, physical and mental health, academic, social, and behavioral domains. The aim of this study was to address the pressing public health concerns of adolescent suicide in Korea and the methodological limitations of suicidal research. METHODS: This study used machine learning methods (decision tree, logistic regression, naive Bayes classifier) to improve the accuracy of predicting suicidal ideation and related factors among a nationally representative sample of Korean middle school students (N = 6666). RESULTS: Factors within all domains, including demographic characteristics, physical and mental health, and academic, social, and behavioral, were important in predicting suicidal thoughts among Korean adolescents, with mental health being the most important factor. LIMITATIONS: The predictive model of the current research does not infer causality, and there may have been some loss of information due to measurement issues. CONCLUSIONS: Study results provide insights for taking a multidimensional approach when identifying adolescents at risk of suicide, which may be used to further address their needs through intervention programs within the school setting. Considering the cultural stigma attached to disclosing suicidal ideation and behavior, the current study proposes the need for a preventive screening process based on the observation and assessment of adolescents' general characteristics and experiences in everyday life.

The Effectiveness of Pharmacopuncture in Patients with Lumbar Spinal Stenosis: A Protocol for a Multi-Centered, Pragmatic, Randomized, Controlled, Parallel Group Study.

Purpose: Lumbar spinal stenosis (LSS) is a chronic degenerative disease. Non-surgical intervention is recommended, considering the risks and benefits for the affected age group, as well as the characteristics of the disease. However, to date, no studies have compared various non-surgical interventions to ascertain the appropriate first-line non-surgical treatment for LSS. Therefore, the objective of this study will be to assess the efficacy of pharmacopuncture as a non-surgical, conservative treatment for LSS. Patients and Methods: A multi-centered, pragmatic, parallel-group study will be conducted. In total, 98 patients will be recruited at seven institutes; recruitment began in May 2022. After two treatment sessions per week over a period of 12 weeks, follow-up assessments will be held at weeks 13, 25, and 53. Results: The efficacy of pharmacopuncture and conservative care will be pragmatically compared in patients radiologically diagnosed with LSS. Pain severity will be measured using the numeric rating scale and visual analog scale. Walking distance will also be evaluated. Patient-centered evaluations will include the Zurich Claudication Questionnaire, Short-Form 12 for Health-Related Quality of Life, EuroQoL 5 Dimension 5 Levels, and Patient Global Impression of Change. Conclusion: The results of this study will confirm the efficacy of pharmacopuncture in comparison to conventional non-surgical treatment and will thus facilitate the prioritization of patient-centered interventions for LSS. Trial registration: This study was registered at Clinicaltrials.gov (registration identifier: NCT05242497) and CRiS (registration identifier: KCT0007145).

Effectiveness and Safety of Pharmacopuncture Therapy for Chronic Low Back Pain: A Protocol for a Pragmatic Randomized Controlled Trial.

Purpose: Chronic low back pain (LBP) is a common musculoskeletal disorder that affects everyday life; moreover, it occasionally causes disability and increases medical expenditure. This pragmatic randomized clinical trial aims to investigate the effects of pharmacopuncture on chronic LBP by comparing the effectiveness of pharmacopuncture and physiotherapy strategies. Patients and Methods: In this two-armed, parallel, multi-center randomized controlled study, the participants will randomly undergo 10 sessions of pharmacopuncture therapy or physiotherapy over five weeks based on the randomization outcomes. The primary outcome will be the numeric rating scale (NRS) score of LBP. The secondary outcomes will include the NRS score of radiating leg pain, visual analog scale (VAS) score of LBP and radiating leg pain, Oswestry disability index, the Korean version of the Roland-Morris disability questionnaire, patient global impression of change (PGIC), short Form-12 health survey version 2, and 5-level EuroQol-5 dimension (EQ-5D-5L). Conclusion: This protocol aims to examine the comparative effectiveness of pharmacopuncture, which is a widely used therapy in Korean medicine, with respect to the standard therapy through a pragmatic randomized controlled trial to present useful data to facilitate clinical or policy decision making. Trial Registration: Clinicaltrials.gov (NCT04833309); Clinical Research Information Service (KCT0006088).

Defining Terms Used for Animals Working in Support Roles for People with Support Needs.

The nomenclature used to describe animals working in roles supporting people can be confusing. The same term may be used to describe different roles, or two terms may mean the same thing. This confusion is evident among researchers, practitioners, and end users. Because certain animal roles are provided with legal protections and/or government-funding support in some jurisdictions, it is necessary to clearly define the existing terms to avoid confusion. The aim of this paper is to provide operationalized definitions for nine terms, which would be useful in many world regions: "assistance animal", "companion animal", "educational/school support animal", "emotional support animal", "facility animal", "service animal", "skilled companion animal", "therapy animal", and "visiting/visitation animal". At the International Society for Anthrozoology (ISAZ) conferences in 2018 and 2020, over 100 delegates participated in workshops to define these terms, many of whom co-authored this paper. Through an iterative process, we have defined the nine terms and explained how they differ from each other. We recommend phasing out two terms (i.e., "skilled companion animal" and "service animal") due to overlap with other terms that could potentially exacerbate confusion. The implications for several regions of the world are discussed.

Structural Priming and Inverse Preference Effects in L2 Grammaticality Judgment and Production of English Relative Clauses.

This study investigated inverse preference effects in L2 structural priming of English relative clauses and their potential influences on subsequent learning of target structures. One hundred fourteen Chinese learners of English at a low-to-intermediate proficiency level participated in a structural priming experiment with a pretest-posttest design. The experimental group underwent a priming task in which they orally produced syntactic structures immediately after viewing English object or passive relative clauses as primes, whereas the control group only read sentences unrelated to English relative clauses. A grammaticality judgment task and a sentence completion task were used to measure the inverse preference effect and its subsequent effects on L2 learning. The results showed the presence of structural priming and inverse preference effects in immediate production, which extended to subsequent learning of L2. In subsequent grammaticality judgments and production, L2 learners performed better with English object relative clauses than with English passive relative clauses in comparison with the pretest. The results are discussed in terms of the structural frequency in both L1 and L2 as well as the implicit learning mechanisms of structural priming.

Optimization of accelerated solvent extraction of ellagitannins in black raspberry seeds using artificial neural network coupled with genetic algorithm.

This study aimed to identify ellagitannins in black raspberry seeds (BRS) and to optimize accelerated solvent extraction of ellagitannins using an artificial neural network (ANN) coupled with genetic algorithm. Fifteen monomeric and dimeric ellagitannins were identified in BRS. For ANN modeling, extraction time, extraction temperature, and solvent concentration were set as input variables, and total ellagitannin content was set as output variable. The trained ANN had a mean squared error value of 0.0102 and a regression correlation coefficient of 0.9988. The predicted optimal extraction conditions for maximum total ellagitannin content were 63.7% acetone, 4.21 min, and 43.9 °C. The actual total ellagitannin content under the optimal extraction conditions was 13.4 ± 0.0 mg/g dry weight, and the prediction error was 0.75 ± 0.27%. This study is the first attempt to analyze the composition of ellagitannins in BRS and to determine optimal extraction conditions for maximum total ellagitannin content from BRS.

The efficacy and safety of non-resistance manual therapy in inpatients with acute neck pain caused by traffic accidents: A randomized controlled trial.

BACKGROUND: Neck pain and functional impairment are common complications of traffic accidents (TAs); however, the effects of manual therapy on these symptoms have rarely been studied in the literature. Thus, this randomized controlled trial aims to assess the effectiveness and safety of non-resistance manual therapy (NRT)-a treatment combining mobilization and pressure release techniques-on acute neck pain caused by TA. METHOD: This study will use a two-armed, parallel, assessor-blinded randomized controlled trial design and will be conducted in the Daejeon Jaseng Hospital of Korean Medicine in South Korea. One hundred twenty patients will be recruited and randomized into an integrative Korean medicine treatment (IMKT) + NRT group and IMKT group in a 1:1 ratio. The primary outcome is a change in the numeric rating scale for neck pain immediately after treatment on hospital day 5 compared to those at baseline. The secondary outcomes are numeric rating scale for radiating arm pain, visual analogue scale for neck pain and radiating arm pain, cervical active range of motion, neck disability index, Patient Global Impression of Change, Short Form-12 Health Survey, and Posttraumatic Stress Disorder Checklist for DSM-5. DISCUSSION: The findings of this study on the effectiveness and safety of NRT will be helpful for patients with TA-induced neck pain in clinical practice and will provide evidence for developing relevant healthcare-related policies. TRIAL REGISTRATION: This protocol has been registered at Clinicaltrials.gov (NCT04660175).

Animal Welfare Assessment in 16 Zoos in South Korea Using the Modified Animal Welfare Assessment Grid.

Various assessment tools that have been proposed thus far have disadvantages in that they are complex, time-consuming, non-objective, and not convenient for assessing multiple zoos. This study aimed to develop a simple, objective, and reliable welfare assessment tool, the modified Animal Welfare Assessment Grid (AWAG), that can be applied in South Korea, where there is no licensing system for zoos. The AWAG has four main sections: physical, psychological, environmental, and procedural. These four sections include 23 welfare factors like general conditions, behaviors, housing, and restraints, for which each individual or group of animals is given a score. The modified AWAG system was applied by converting the 10-point rating scale of the original AWAG to a 6-point Likert scale. Sixteen zoos in Korea were selected based on the zoos with the most animals. Three inspectors assessed the scores of each animal and then averaged the results. The total data surveyed included 16,065 items. Zoos were largely classified into four grades based on the size of the zoo, animal species, and operating organization. In a relatively short period of 14 days, all the zoos were successfully assessed. Despite the shortened and modified assessment tool, the inter-rater reliability among inspectors was 0.942 with high objectivity. The modified AWAG could identify welfare differences between grades of Korean zoos. There were large differences between zoos in most environmental sections and some zoos were evaluated as having inadequate welfare levels. The modified AWAG showed high usability and objectivity. In addition, it was possible to determine which environmental or procedural sections could potentially help improve physical and psychological scores. The modified AWAG is an objective method that could set the direction for the improvement of zoo welfare in the future.

A Comparative Study of Three Measurement Methods of Chinese Character Recognition for L2 Chinese Learners.

Measuring Chinese character recognition ability is essential in research on character learning among learners of Chinese as a second language (CSL). Three methods are typically used to evaluate character recognition competence by investigating the following properties of a given character: (a) pronunciation (phonological method), (b) meaning (semantic method), and (c) pronunciation and meaning (phonological and semantic or PS method). However, no study has explored the similar or dissimilar outcomes that these three measurements might yield. The current study examined this issue by testing 162 CSL learners with various L1 backgrounds and Chinese proficiency levels. Participants' performance in character recognition measured using a phonological method, a semantic method, and a PS method was compared, which led to two major findings. In terms of similarity, participants' performance in character recognition and the influence of L1 background and Chinese proficiency level on character recognition was similar across the three methods. As for differences, the semantic method could yield a character recognition test with better quality than the other two methods, and the three methods yielded different best fitting models and showed different predictions for Chinese proficiency across different L1 groups. Theoretical and practical implications of these findings are proposed.

Effects of trazodone on behavioral and physiological signs of stress in dogs during veterinary visits: a randomized double-blind placebo-controlled crossover clinical trial.

OBJECTIVE: To determine whether a single dose of trazodone administered to dogs before a veterinary visit reduced their behavioral and physiologic signs of stress and owners' stress during veterinary visits. SAMPLE: 20 dogs and their owners. PROCEDURES: In this randomized double-blinded placebo-controlled crossover clinical trial, dogs with a history of anxiety during veterinary visits were scheduled for 2 veterinary visits 1 week apart and randomly assigned to receive a single oral dose of either trazodone (9 to 12 mg/kg) or a placebo 90 minutes before transport to the veterinary clinic for alternate visits between September 21 and November 3, 2019. For each visit, we collected and assessed owner-completed surveys of dog stress score (DSS) and owner stress score; various investigator-reported scores, including from video-recorded behavior analyses; and patient-related physiologic data. RESULTS: Dogs treated with trazodone versus placebo had lower mean DSSs, assessed by owners for physical examination and assessed by video analysis for time spent in the examination room; lower mean SD of normal-to-normal intervals, root mean square of successive heartbeat interval difference, and respiratory rate; and higher mean heart rate. No meaningful differences were observed in other behavioral or physiologic outcomes, including serum cortisol concentrations. CLINICAL RELEVANCE: A single dose of trazodone before transport reduced signs of stress during veterinary visits for dogs in the present study and may be useful as an anti-anxiety medication for similarly affected dogs, potentially resulting in higher-quality clinical examinations and improved patient welfare.

Safety of Chuna Manipulation Therapy in 289,953 Patients with Musculoskeletal Disorders: A Retrospective Study.

Studies have reported that mild adverse events (AEs) are common after manual therapy and that there is a risk of serious injury. We aimed to assess the safety of Chuna manipulation therapy (CMT), a traditional manual Korean therapy, by analysing AEs in patients who underwent this treatment. Patients who received at least one session of CMT between December 2009 and March 2019 at 14 Korean medicine hospitals were included. Electronic patient charts and internal audit data obtained from situation report logs were retrospectively analysed. All data were reviewed by two researchers. The inter-rater agreement was assessed using the Cohen's kappa coefficient, and reliability analysis among hospitals was assessed using Cronbach's Alpha coefficient. In total, 2,682,258 CMT procedures were performed in 289,953 patients during the study period. There were 50 AEs, including worsened pain (n = 29), rib fracture (n = 11), falls during treatment (n = 6), chest pain (n = 2), dizziness (n = 1), and unpleasant feeling (n = 1). The incidence of mild to moderate AEs was 1.83 (95% confidence interval [CI] 1.36-2.39) per 100,000 treatment sessions, and that of severe AEs was 0.04 (95% CI 0.00-0.16) per 100,000 treatment sessions. Thus, AEs of any level of severity were very rare after CMT. Moreover, there were no instances of carotid artery dissection or spinal cord injury, which are the most severe AEs associated with manual therapy in other countries.