Major cardiovascular events in long-term multiple myeloma survivors: a Korean case-control study (the CAREMM-2105 study).

PURPOSE: Despite improvements in multiple myeloma (MM) survival rates, data on cardiovascular outcomes in long-term survivors remain lacking. METHODS: This retrospective case-control study utilized the Korean National Health Insurance Service database (2009-2020) to compare the incidence of cardiovascular disease (CVD) between patients with MM and a matched control group, focusing on long-term (> 5 years) survivors. A preliminary case cohort (n = 15,402 patients with MM) and a matched control cohort (n = 123,216 patients without MM) were established based on birth year and sex. Following 1:1 propensity score matching, the final matched cohorts each comprised 15,402 participants. RESULTS: The case and control cohorts were comparable in mean age (66.2 ± 11.5 years vs. 66.1 ± 11.3 years), sex, age distribution, and comorbidities. By the 8-year follow-up, the cumulative incidence of CV events (12.5% vs. 22.1%) and CVD risk were significantly lower in the case cohort. The 5-year landmark analysis revealed significant differences in CVD incidence between the cohorts (7.8% [case cohort] vs. 9.8% [control cohort]), with variations across age groups and sex, highlighting a significantly higher CVD risk among patients aged < 50 years in the case cohort (P < 0.001). CONCLUSIONS: These findings underscore the need for vigilant CVD monitoring in MM long-term survivors, particularly those aged < 50 years at first diagnosis. IMPLICATION FOR CANCER SURVIVORS: This study highlights the importance of integrating cardiovascular monitoring and risk management into long-term care for MM survivors, with a focus on younger patients and personalized interventions.

Social context modulates multibrain broadband dynamics and functional brain-to-brain coupling in the group of mice.

Although mice are social, multiple animals' neural activities are rarely explored. To characterise the neural activities during multi-brain interaction, we simultaneously recorded local field potentials (LFP) in the prefrontal cortex of four mice. The social context and locomotive states predominately modulated the entire LFP structure. The power of lower frequency bands-delta to alpha-were correlated with each other and anti-correlated with gamma power. The high-to-low-power ratio (HLR) provided a useful measure to understand LFP changes along the change of behavioural and locomotive states. The HLR during huddled conditions was lower than that during non-huddled conditions, dividing the social context into two. Multi-brain analyses of HLR indicated that the mice in the group displayed high cross-correlation. The mice in the group often showed unilateral precedence of HLR by Granger causality analysis, possibly comprising a hierarchical social structure. Overall, this study shows the importance of the social environment in brain dynamics and emphasises the simultaneous multi-brain recordings in social neuroscience.

Cutting Balloon Angioplasty for Severe In-Stent Restenosis after Carotid Artery Stenting: Long-Term Outcomes and Review of Literature.

PURPOSE: Cutting balloon-percutaneous transluminal angioplasty (CB-PTA) is a feasible treatment option for in-stent restenosis (ISR) after carotid artery stenting (CAS). However, the longterm durability and safety of CB-PTA for ISR after CAS have not been well established. MATERIALS AND METHODS: We retrospectively reviewed medical records of patients with ISR after CAS who had been treated with CB-PTA from 2012 to 2021 in our center. Detailed information of baseline characteristics, periprocedural and long-term outcomes, and follow-up imaging was collected. RESULTS: During 2012-2021, a total of 301 patients underwent CAS. Of which, CB-PTA was performed on 20 lesions exhibiting severe ISR in 18 patients following CAS. No patient had any history of receiving carotid endarterectomy or radiation therapy. These lesions were located at the cervical segment of the internal carotid artery (n=16), proximal external carotid artery (n=1), and distal common carotid artery (n=1). The median time interval between initial CAS and detection of ISR was 390 days (interquartile range 324-666 days). The follow-up period ranged from 9 months to 9 years with a median value of 21 months. Four patients (22.2%) were symptomatic. The average of stenotic degree before and after the procedure was 79.2% and 34.7%, respectively. Out of the 18 patients receiving CB-PTA, 16 (88.9%) did not require additional stenting, and 16 (88.9%) did not experience recurrent ISR during the follow-up period. Two patients who experienced recurrent ISR were successfully treated with CB-PTA and additional stenting. No periprocedural complication was observed in any case. CONCLUSION: Regarding favorable periprocedural and long-term outcomes in our single-center experience, CB-PTA was a feasible and safe option for the treatment of severe ISR after CAS.

One-year antibody durability induced by EuCorVac-19, a liposome-displayed COVID-19 receptor binding domain subunit vaccine, in healthy Korean subjects.

OBJECTIVE: EuCorVac-19 (ECV-19), an adjuvanted liposome-displayed receptor binding domain (RBD) COVID-19 vaccine, previously reported interim Phase 2 trial results showing induction of neutralizing antibodies 3 weeks after prime-boost immunization. The objective of this study was to determine the longer-term antibody response of the vaccine. METHODS: To assess immunogenicity 6 and 12 months after vaccination, participants in the Phase 2 trial (NCT04783311) were excluded if they: 1) withdrew, 2) reported COVID-19 infection or additional vaccination, or 3) exhibited increasing Spike (S) antibodies (representing possible non-reported infection). Following exclusions, of the 197 initial subjects, anti-S IgG antibodies and neutralizing antibodies were further assessed in 124 subjects at the 6-month timepoint, and 36 subjects at the 12-month timepoint. RESULTS: Median anti-S antibody half-life was 52 days (interquartile range [IQR]:42-70), in the "early" period from 3 weeks to 6 months, and 130 days (IQR:97-169) in the "late" period from 6 to 12 months. There was a negative correlation between initial antibody titer and half-life. Anti-S and neutralizing antibody responses were correlated. Neutralizing antibody responses showed longer half-lives; the early period had a median half-life of 120 days (IQR:81-207), and the late period had a median half-life of 214 days (IQR:140-550). CONCLUSION: These data establish antibody durability of ECV-19, using a framework to analyze COVID-19 vaccine-induced antibodies during periods of high infection.

Improvement in Delivery of Ischemic Stroke Treatments but Stagnation of Clinical Outcomes in Young Adults in South Korea.

BACKGROUND: There is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke. This study investigated whether advances in these treatments improved outcomes in this population. METHODS: Using a prospective multicenter stroke registry in Korea, young adults (aged 18-50 years) with acute ischemic stroke hospitalized between 2008 and 2019 were identified. The observation period was divided into 4 epochs: 2008 to 2010, 2011 to 2013, 2014 to 2016, and 2017 to 2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed. RESULTS: A total of 7050 eligible patients (mean age, 43.1; men, 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (Ptrend=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008 to 2010 to 2017 to 2019 (9.5%-13.8% and 3.2%-9.2%, respectively; Ptrend<0.01). Door-to-needle time improved (Ptrend <.001), but onset-to-door and door-to-puncture times remained constant. Secondary prevention, including dual antiplatelets for noncardioembolic minor stroke (26.7%-47.0%), direct oral anticoagulants for atrial fibrillation (0.0%-56.2%), and statins for large artery atherosclerosis (76.1%-95.3%) increased (Ptrend<0.01). Outcome data were available from 2011. One-year mortality (2.5% in 2011-2013 and 2.3% in 2017-2019) and 3-month modified Rankin Scale scores 0 to 1 (68.3%-69.1%) and 0 to 2 (87.6%-86.2%) remained unchanged. The 1-year stroke recurrence rate increased (4.1%-5.5%; Ptrend=0.04), although the difference was not significant after adjusting for sex and age. CONCLUSIONS: Improvements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with acute ischemic stroke over the past decade, indicating a need for further progress.

Longitudinal Associations Between Food Insecurity and Suicidal Ideation Among Adults Aged ≥65 in the Korean Welfare Panel Study.

Objectives : This study aimed to explore longitudinal associations between food insecurity and suicidal ideation, and the moderating roles of intervention programs. Methods: Data were derived from the 2012-2019 waves of the Korean Welfare Panel Study. Participants aged ≥65 at baseline (n = 4,425) and their annual follow-up measurements for a mean of 6.58 years were included. Conditional fixed effects logistic regressions were used to test 1) associations between food insecurity and the onset of suicidal ideation; 2); whether associations were attenuated by food assistance and income support programs. Results: Food insecurity was associated with higher odds of suicidal ideation in the full sample (OR, 1.77; 95% CI, 1.37-2.29), among women (OR, 1.67; 95% CI, 1.24-2.26) and men (OR, 2.06; 95% CI, 1.25-3.40). The association between food insecurity and suicidal ideation was attenuated by participation in home-delivered meal services (OR, 0.43; 95% CI, 0.21-0.88). Conclusion: Food insecure older adults were more likely to consider committing suicide than their food secure counterparts. Food assistance through home-delivered meal services, but not other intervention programs, could weaken this link.

A Nonrandomized Phase 2 Trial of EG-Mirotin, a Novel, First-in-Class, Subcutaneously Deliverable Peptide Drug for Nonproliferative Diabetic Retinopathy.

Background and objectives: EG-Mirotin (active ingredient EGT022) targets nonproliferative diabetic retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin reverses capillary damage before NPDR progresses to an irreversible stage. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR. Methods: In this open-label, single-arm, single-center, exploratory phase II study, 10 patients (20 eyes) received EG-Mirotin once a day (3 mg/1.5 mL sterile saline) for 5 days and were evaluated for ischemic index changes and safety. End of study was approximately 8 ± 1 weeks (57 ± 7 days) after the first drug administration. Results: EG-Mirotin injections were well tolerated, with no dose-limiting adverse events, serious adverse events, or deaths. Four treatment-emergent adverse events (TEAEs) unrelated to the investigational drug were observed in 2 out of 10 participants (20%) who had received the investigational drug. The overall average percent change in ischemic index at each evaluation point compared with baseline was statistically significant (Greenhouse-Geisser F = 9.456, p = 0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse-Geisser F = 10.946, p = 0.002 for time × group interaction). Conclusions: The EG-Mirotin regimen established in this study was shown to be feasible and safe and was associated with a trend toward potential improvement in diabetes-induced ischemia and retinal capillary leakage.

Interim analysis from a phase 2 randomized trial of EuCorVac-19: a recombinant protein SARS-CoV-2 RBD nanoliposome vaccine.

BACKGROUND: Numerous vaccine strategies are being advanced to control SARS-CoV-2, the cause of the COVID-19 pandemic. EuCorVac-19 (ECV19) is a recombinant protein nanoparticle vaccine that displays the SARS-CoV-2 receptor-binding domain (RBD) on immunogenic nanoliposomes. METHODS: Initial study of a phase 2 randomized, observer-blind, placebo-controlled trial to assess the immunogenicity, safety, and tolerance of ECV19 was carried out between July and October 2021. Two hundred twenty-nine participants were enrolled at 5 hospital sites in South Korea. Healthy adults aged 19-75 without prior known exposure to COVID-19 were vaccinated intramuscularly on day 0 and day 21. Of the participants who received two vaccine doses according to protocol, 100 received high-dose ECV19 (20 µg RBD), 96 received low-dose ECV19 (10 µg RBD), and 27 received placebo. Local and systemic adverse events were monitored. Serum was assessed on days 0, 21, and 42 for immunogenicity analysis by ELISA and neutralizing antibody response by focus reduction neutralization test (FRNT). RESULTS: Low-grade injection site tenderness and pain were observed in most participants. Solicited systemic adverse events were less frequent, and mostly involved low-grade fatigue/malaise, myalgia, and headache. No clinical laboratory abnormalities were observed. Adverse events did not increase with the second injection and no serious adverse events were solicited by ECV19. On day 42, Spike IgG geometric mean ELISA titers were 0.8, 211, and 590 Spike binding antibody units (BAU/mL) for placebo, low-dose and high-dose ECV19, respectively (p < 0.001 between groups). Neutralizing antibodies levels of the low-dose and high-dose ECV19 groups had FRNT50 geometric mean values of 129 and 316, respectively. Boosting responses and dose responses were observed. Antibodies against the RBD correlated with antibodies against the Spike and with virus neutralization. CONCLUSIONS: ECV19 was generally well-tolerated and induced antibodies in a dose-dependent manner that neutralized SARS-CoV-2. The unique liposome display approach of ECV19, which lacks any immunogenic protein components besides the antigen itself, coupled with the lack of increased adverse events during boosting suggest the vaccine platform may be amenable to multiple boosting regimes in the future. Taken together, these findings motivate further investigation of ECV19 in larger scale clinical testing that is underway. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov as # NCT04783311.

Detection of paradoxical carbon dioxide gas embolism with opening of patent foramen ovale by perioperative transesophageal echocardiography during laparoscopic hepatectomy - A case report.

BACKGROUND: Due to its various advantages, laparoscopic surgery is preferred over laparotomy in patients who require hepatic resection. Carbon dioxide embolism -which occurs approximately ten times more often in laparoscopic hepatectomy than in general laparoscopic surgery-presents with insignificant symptoms and may be overlooked. CASE: A 70-year-old male with hepatic cell carcinoma underwent laparoscopic hepatectomy. Though his vital signs were stable during the initiation of surgery, they became unstable during the procedure. The surgeon detected portal vein rupture, and transesophageal echocardiography was subsequently performed. A large amount of gas in the heart chamber and paradoxical embolism through a patent foramen ovale due to a right-to-left shunt were observed. We treated the symptoms, and the surgery was completed without any further issues. CONCLUSIONS: Active use of transesophageal echocardiography to identify and monitor heart functions during a suspected carbon dioxide embolism can significantly reduce morbidity and mortality associated with that embolism.

Machine learning prediction of suicidal ideation, planning, and attempt among Korean adults: A population-based study.

Background: Suicide remains the leading cause of premature death in South Korea. This study aims to develop machine learning algorithms for screening Korean adults at risk for suicidal ideation and suicide planning or attempt. Methods: Two sets of balanced data for Korean adults aged 19-64 years were drawn from the 2012-2019 waves of the Korea Welfare Panel Study using the random down-sampling method (N = 3292 for the prediction of suicidal ideation, N = 488 for the prediction of suicide planning or attempt). Demographic, socioeconomic, and psychosocial characteristics were used to predict suicidal ideation and suicide planning or attempt. Four machine-learning classifiers (logistic regression, random forest, support vector machine, and extreme gradient boosting) were tuned and cross-validated. Results: All four algorithms demonstrated satisfactory classification performance in predicting suicidal ideation (sensitivity 0.808-0.853, accuracy 0.843-0.863) and suicide planning or attempt (sensitivity 0.814-0.861, accuracy 0.864-0.884). Extreme gradient boosting was the best-performing algorithm for predicting both suicidal outcomes. The most important predictors were depressive symptoms, self-esteem, income, consumption, and life satisfaction. The algorithms trained with the top two predictors, depressive symptoms and self-esteem, showed comparable classification performance in predicting suicidal ideation (sensitivity 0.801-0.839, accuracy 0.841-0.846) and suicide planning or attempt (sensitivity 0.814-0.837, accuracy 0.874-0.884). Limitations: Suicidal ideation and behaviors may be under-reported due to social desirability bias. Causality is not established. Discussion: More than 80% of individuals at risk for suicidal ideation and suicide planning or attempt could be predicted by a number of mental and socioeconomic characteristics of respondents. This finding suggests the potential of developing a quick screening tool based on the known risk factors and applying it to primary care or community settings for early intervention.

Cortisol secretory patterns in deep and moderate neuromuscular blockades in laparoscopic surgery under total intravenous anesthesia: A prospective, single-blinded, randomized controlled trial.

BACKGROUND: Neuroendocrine stress response induces physiological changes depending on the type of surgery and anesthesia. Although the optimal depth of neuromuscular blockade for reducing this response remains unknown, deep neuromuscular blockade is known to improve the surgical environment. Therefore, we hypothesized that a patient's stress response would be lower in surgical procedures under deep neuromuscular blockade than under moderate neuromuscular blockade. METHODS: This prospective, randomized, single-blind study enrolled 72 patients who underwent laparoscopic gynecological surgery under general anesthesia and were assigned to group D (deep blockade: target train-of-four 0 and posttetanic count ≥ 1) or group M (moderate blockade: target train-of-four count 1-3). The primary endpoints were changing patterns in cortisol and adrenocorticotrophic hormone levels; the secondary endpoints were patient outcomes, such as hemodynamic variables, serum glucose level, postoperative pain in the postanesthesia care unit, and hospital stay. RESULTS: The baseline characteristics were comparable between the 67 patients included in the 2 groups (34 in group M and 33 in group D). Cortisol and adrenocorticotrophic hormone levels increased perioperatively in both groups but without significant intergroup differences. Serum glucose level increased perioperatively and decreased postoperatively, but without a significant intergroup difference. Postoperative pain, fentanyl requirement in the postanesthesia care unit, and hospital stay were also comparable. CONCLUSIONS: Compared with moderate neuromuscular blockade, deep neuromuscular blockade improved the surgical environment without significant intergroup differences in the hormonal stress response.

PHF20 is crucial for epigenetic control of starvation-induced autophagy through enhancer activation.

Autophagy is a catabolic pathway that maintains cellular homeostasis under various stress conditions, including conditions of nutrient deprivation. To elevate autophagic flux to a sufficient level under stress conditions, transcriptional activation of autophagy genes occurs to replenish autophagy components. Thus, the transcriptional and epigenetic control of the genes regulating autophagy is essential for cellular homeostasis. Here, we applied integrated transcriptomic and epigenomic profiling to reveal the roles of plant homeodomain finger protein 20 (PHF20), which is an epigenetic reader possessing methyl binding activity, in controlling the expression of autophagy genes. Phf20 deficiency led to impaired autophagic flux and autophagy gene expression under glucose starvation. Interestingly, the genome-wide characterization of chromatin states by Assay for Transposase-Accessible Chromatin (ATAC)-sequencing revealed that the PHF20-dependent chromatin remodelling occurs in enhancers that are co-occupied by dimethylated lysine 36 on histone H3 (H3K36me2). Importantly, the recognition of H3K36me2 by PHF20 was found to be highly correlated with increased levels of H3K4me1/2 at the enhancer regions. Collectively, these results indicate that PHF20 regulates autophagy genes through enhancer activation via H3K36me2 recognition as an epigenetic reader. Our findings emphasize the importance of nuclear events in the regulation of autophagy.

Detailed visual assessment of striatal dopaminergic depletion in patients with idiopathic normal pressure hydrocephalus: unremarkable or not?

BACKGROUND: Dopamine transporter (DAT) imaging may enable clinicians to discriminate idiopathic normal pressure hydrocephalus (iNPH) from other parkinsonian disorders. However, a specific pattern of dopaminergic loss in DAT imaging of iNPH patients remains to be further elucidated. METHODS: In this preliminary study, 11 patients with iNPH in our hospital between March 2017 and February 2019 were finally enrolled. A diagnosis of iNPH was made according to the two established criteria. For visual analysis of DAT imaging, a striatum was divided into five domains. A semi-quantitative visual assessment was performed with a consensus between a nuclear medicine specialist and an experienced neurologist who were blinded to the clinical diagnosis. RESULTS: Striatal dopaminergic deficits were abnormal in 90.9% (10/11) of patients with iNPH. The degree of dopaminergic reduction was mild and heterogeneous. However, a tendency of preferential striatal DAT loss in the caudate nucleus (90.9%, 10/11) than in the putamen (72.7%, 8/11) was observed, whereas ventral portion (9.1%, 1/11) was relatively preserved. CONCLUSION: Striatal dopaminergic depletion might be mild and heterogeneous in patients with iNPH. These dopaminergic deficits were more common in the caudate nucleus than in the putamen, suggesting a pattern different from other degenerative parkinsonian disorders.

Differential Inhibitory Configurations Segregate Frequency Selectivity in the Mouse Inferior Colliculus.

Receptive fields and tuning curves of sensory neurons represent the neural substrates that allow animals to efficiently detect and distinguish external stimuli. They are progressively refined to create diverse sensitivity and selectivity for neurons along ascending central pathways. However, the neural circuitry mechanisms have not been directly determined for such fundamental qualities in relation to sensory neurons' functional organizations, because of the technical difficulty of correlating neurons' input and output. Here, we obtained spike outputs and synaptic inputs from the same neurons within characteristically defined neural ensembles, to determine the synaptic mechanisms driving their diverse frequency selectivity in the mouse inferior colliculus. We find that the synaptic strength and timing of excitatory and inhibitory inputs are configured differently and independently within individual neurons' receptive fields, which segregate sensitive and selective neurons and endow neural populations with broad receptive fields and sharp frequency tuning. By computationally modeling spike outputs from integrating synaptic inputs and comparing them with real spike responses of the same neurons, we show that space-clamping errors did not qualitatively affect the estimation of spike responses derived from synaptic currents in in vivo voltage-clamp recordings. These data suggest that heterogeneous inhibitory circuits coexist locally for a parallel but differentiated representation of incoming signals.SIGNIFICANCE STATEMENT Sensitivity and selectivity are functional qualities of sensory systems to facilitate animals' survival. There is little direct evidence for the synaptic basis of neurons' functional variance within neural ensembles. Here we adopted a novel framework to fill such a long-standing gap by uniting population activities with single cells' spike outputs and their synaptic inputs. Furthermore, the effects of space-clamping errors on subcortical synaptic currents were evaluated in vivo, by comparing recorded spike responses and simulated spike outputs from computationally integrating synaptic inputs. Our study illustrated that the synaptic strength and timing of inhibition relative to excitation can be configured differently for neurons within a defined neural ensemble, to segregate their selectivity. It provides new insights into coexisting heterogeneous local circuits.

Lack of association between dopamine transporter loss and non-motor symptoms in patients with Parkinson's disease: a detailed PET analysis of 12 striatal subregions.

INTRODUCTION: Patients with Parkinson's disease (PD) present a variety of non-motor symptoms. However, it remains unclear whether dopamine depletion is related to non-motor symptoms, and which non-motor symptoms are significantly dependent on dopaminergic deficit. METHODS: Forty-one patients with PD who underwent positron emission tomography imaging of dopamine transporters (DATs) were recruited for this study. The striatum was divided into 12 subregions, and DAT activity, as striatal dopaminergic concentration, was calculated in each subregion. In addition to measuring motor symptoms using the Unified Parkinson's Disease Rating Scale-part III (UPDRS-III), various non-motor symptoms were assessed using the Montreal cognitive assessment, frontal assessment battery, Beck depression inventory (BDI), Beck anxiety inventory, PD sleep scale (PDSS), PD fatigue scale, and non-motor symptoms scale (NMSS) for PD. RESULTS: For simple linear regression analyses, dopaminergic depletion in all striatal subregions was negatively correlated with the UPDRS-III score. The most relevant non-motor symptom assessment related to dopaminergic loss in the 12 subregions was NMSS, followed by BDI and PDSS. However, following multiple linear regression analyses, dopaminergic depletion in the 12 striatal subregions was not related with any of the non-motor symptoms. Conversely, dopaminergic deficit in the right anterior and posterior putamen was associated with the UPDRS-III score. CONCLUSIONS: Striatal dopaminergic depletion was not significantly correlated with any of the various non-motor symptoms in PD. Our findings suggest that non-dopaminergic systems are significantly implicated in the pathogenesis of non-motor symptoms in patients with PD.