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Background and Purpose Moderate-intensity statin plus ezetimibe versus high-intensity statin alone may provide a greater low-density lipoprotein cholesterol (LDL-C) reduction in patients with recent ischemic stroke.Methods This randomized, open-label, controlled trial assigned patients with recent ischemic stroke P= 0.0003). LDL-C level P=0.0001). Multiple lipid goal achievement rate was 71.1% and 53.7% in the ROS10/EZT10 and ROS20 groups (PP=0.0091). The adverse event rates did not differ between the two groups.Conclusion Moderate-intensity rosuvastatin plus ezetimibe was superior to high-intensity rosuvastatin alone for intensive LDL-C reduction in patients with recent ischemic stroke. With the combination therapy, more than 70% of patients achieved LDL-C reduction ≥50% and 80% had an LDL-C

OBJECTIVE Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of patients with many tumor histologies. Simultaneously, stereotactic body radiotherapy (SBRT) provides excellent local control (LC) and plays an important role in the management of spine metastasis. Promising preclinical work suggests the potential therapeutic benefit of combining SBRT with ICI therapy, but the safety profile of combined therapy is unclear. This study aimed to evaluate the toxicity profile associated with ICI in patients receiving SBRT and, secondarily, whether ICI administration sequence with respect to SBRT affects LC or overall survival (OS) outcomes. METHODS The authors retrospectively reviewed patients with spine metastasis treated with SBRT at an academic center. Patients who received ICI at any point during their disease course were compared to those with the same primary tumor types who did not receive ICI by using Cox proportional hazards analyses. Primary outcomes were long-term sequelae, including radiation-induced spinal cord myelopathy, esophageal stricture, and bowel obstruction. Secondarily, models were created to evaluate OS and LC in the cohort. RESULTS Two hundred forty patients who received SBRT to 299 spine metastases were included in this study. The most common primary tumor types were non–small cell lung cancer (n = 59 [24.6%]) and renal cell carcinoma (n = 55 [22.9%]). One hundred eight patients received at least 1 dose of ICI, with the most common regimen being single-agent anti–PD-1 (n = 80 [74.1%]), followed by combination CTLA-4/PD-1 inhibitors (n = 19 [17.6%]). Three patients experienced long-term radiation-induced sequelae: 2 had esophageal stricture and 1 had bowel obstruction. No patients developed radiation-induced myelopathy. There was no association between receipt of ICI and development of any of these adverse events (p > 0.9). Similarly, ICI was not significantly associated with either LC (p = 0.3) or OS (p = 0.6). In the entire cohort, patients who received ICI prior to beginning SBRT had worse median survival, but ICI sequence with respect to SBRT was not significantly prognostic of either LC (p > 0.3) or OS (p > 0.07); instead, baseline performance status was most predictive of OS (HR 1.38, 95% CI 1.07–1.78, p = 0.012). CONCLUSIONS Treatment regimens that combine ICIs before, concurrent with, and after SBRT for spine metastases are safe, with minimal risk for increased rates of long-term toxicity.

Symptomatic thoracic disc herniations are a rare entity and their operative treatment is challenging. Open approaches, despite providing excellent access, are associated with significant access morbidity from thoracotomy, and this has led to an increased interest in minimally invasive techniques such as mini-open approach, thoracoscopic approach and the endoscopic approach. In this article, we describe the technical points for performing a transforaminal endoscopic thoracic discectomy and summarize its literature outcomes in the context of other minimally invasive approaches.

The extracellular matrix (ECM) has many functions, such as segregating tissues, providing support, and regulating intercellular communication. Cartilage-derived ECM (CECM) can be prepared via consecutive processes of chemical decellularization and enzyme treatment. The purpose of this study was to improve and treat osteoarthritis (OA) using porcine knee articular CECM.We assessed the rheological characteristics and pH of CECM solutions. Furthermore, we determined the effects of CECM on cell proliferation and cytotoxicity in the chondrocytes of New Zealand rabbits. The inhibitory effect of CECM on tumor necrosis factor (TNF)-α-induced cellular apoptosis was assessed using New Zealand rabbit chondrocytes and human synoviocytes. Finally, we examined the in vivo effects of CECM on inflammation control and cartilage degradation in an experimental OA-induced rat model. The rat model of OA was established by injecting monosodium iodoacetate into the intra-articular knee joint. The rats were then injected with CECM solution. Inflammation control and cartilage degradation were assessed by measuring the serum levels of proinflammatory cytokines and C-telopeptide of type II collagen and performing a histomorphological analysis.CECM was found to be biocompatible and non-immunogenic, and could improve cell proliferation without inducing a toxic reaction. CECM significantly reduced cellular apoptosis due to TNF-α, significantly improved the survival of cells in inflammatory environments, and exerted anti-inflammatory effects.Our findings suggest that CECM is an appropriate injectable material that mediates OA-induced inflammation.

Radiocarbon (14C) in natural samples undergoes changes due to variations in atmospheric CO2 resulting from anthropogenic activities. To analyze the variation of the 14C ratio in atmospheric CO2, deciduous tree leaves were collected in Gyeongju, a popular tourist city in South Korea. Leaf samples were collected from Prunus subg. Cerasus trees at five different sampling points throughout the city over 3 years (2018, 2020, and 2021). The 14C data of the samples were categorized into three groups (downtown, rural, and tourist sites) and analyzed for variations among the different years. The 14C ratio at downtown sites was stable after 2018, the rural site ratio increased between 2018 and 2020 and then decreased between 2020 and 2021, and the tourist site ratio increased after 2018. We theorize that the increased 14C ratio at the tourist site was caused by a decrease in tourism after 2018.

Background: Center of pressure (COP) is a useful measure for dynamic balance, which directly represents the ability of weight shift and control of the foot, however, there is no study analyzing COP during whole stance phase in the elderly with acute stroke.Methods: A total of 30 acute ischemic stroke patients (mean age±standard deviation [SD], 75.0±5.6 years; 11 females) and 30 propensity score matched controls (mean age±SD, 72.8±5.9 years; 17 females) using age, sex, and Korean version of Mini-Mental State Examination score were finally included. Participants performed barefoot walking trials on a pressure-sensitive mat until 20 footfalls in each limb were corrected. To evaluate gait function based on COP, mean and coefficient of variance as variability were calculated for 3 types of variables as followings: (1) durations of sub-phases in stance phase, (2) mean locations and displacement ranges of COP, and (3) velocities.Results: Significant difference was observed in many of both mean and variability variables. Especially, stroke patients had an increased duration, posterior location of COP, wide range of mediolateral and anteroposterior displacement range, and slow velocity in foot flat phase belonging to the double limb stance. In variability variables, stroke patients had significantly larger variabilities of COP velocities in all sub-phases except in foot flat phase and late propulsive phase were stood out.Conclusions: The elderly with acute ischemic stroke had inefficiency during double limb stance and reduced functional balance in single limb stance in both sides, implying impaired gait ability on COP excursion in these patients.

In this study, we designed two user interfaces for automated vehicles operated in the modes that correspond to the Society of Automotive Engineers automation levels 0–3. The first is a level-centred interface that allows the driver to increase or decrease the automation level step-by-step. The second is a function-centred interface that has independent driving controls in the longitudinal and lateral directions. We implemented prototypes for the two interfaces and conducted driver-in-the-loop experiments on a driving simulator to verify their effectiveness in the driver’s mode awareness. For events on the road, the participants took actions to control the vehicle, which might cause mode changes, and answered the modes he/she believed. The experimental results show that the mode confusion rate of the level-centred interface is twice higher than that of the function-centred interface. Also, visual feedbacks can reduce the mode confusion rate dramatically. The results show that a function-centred user interface combined with adequate visual and/or auditory feedback is essential to improve driver’s mode awareness when driving an automated vehicle.

Midbrain dopamine (DA) neurons are associated with locomotor and psychiatric disorders. DA phenotype is specified in ancestral neural precursor cells (NPCs) and maintained throughout neuronal differentiation. Here we show that endogenous expression of MeCP2 coincides with DA phenotype specification in mouse mesencephalon, and premature expression of MeCP2 prevents in vitro cultured NPCs from acquiring DA phenotype through interfering NURR1 transactivation of DA phenotype genes. By contrast, ectopic MeCP2 expression does not disturb DA phenotype in the DA neurons. By analyzing the dynamic change of DNA methylation along DA neuronal differentiation at the promoter of DA phenotype gene tyrosine hydroxylase (Th), we show that Th expression is determined by TET1-mediated de-methylation of NURR1 binding sites within Th promoter. Chromatin immunoprecipitation assays demonstrate that premature MeCP2 dominates the DNA binding of the corresponding sites thereby blocking TET1 function in DA NPCs, whereas TET1-mediated de-methylation prevents excessive MeCP2 binding in DA neurons. The significance of temporal DNA methylation status is further confirmed by targeted methylation/demethylation experiments showing that targeted de-methylation in DA NPCs protects DA phenotype specification from ectopic MeCP2 expression, whereas targeted methylation disturbs phenotype maintenance in MeCP2-overexpressed DA neurons. These findings suggest the appropriate timing of MeCP2 expression as a novel determining factor for guiding NPCs into DA lineage.

Post-traumatic epilepsy (PTE) and behavioral comorbidities frequently develop after traumatic brain injury (TBI). Aberrant neurogenesis of dentate granule cells (DGCs) after TBI may contribute to the synaptic reorganization that occurs in PTE, but how neurogenesis at different times relative to the injury contributes to feedback inhibition and recurrent excitation in the dentate gyrus is unknown. Thus, we examined whether DGCs born at different postnatal ages differentially participate in feedback inhibition and recurrent excitation in the dentate gyrus using the controlled cortical impact (CCI) model of TBI. Both sexes of transgenic mice expressing channelrhodopsin2 (ChR2) in postnatally born DGCs were used for optogenetic activation of three DGC cohorts: postnatally early born DGCs, or those born just before or after CCI. We performed whole-cell patch-clamp recordings from ChR2-negative, mature DGCs and parvalbumin-expressing basket cells (PVBCs) in hippocampal slices to determine whether optogenetic activation of postnatally born DGCs increases feedback inhibition and/or recurrent excitation in mice 8-10 weeks after CCI and whether PVBCs are targets of ChR2-positive DGCs. In the dentate gyrus ipsilateral to CCI, activation of ChR2-expressing DGCs born before CCI produced increased feedback inhibition in ChR2-negative DGCs and increased excitation in PVBCs compared with those from sham controls. This upregulated feedback inhibition was less prominent in DGCs born early in life or after CCI. Surprisingly, ChR2-positive DGC activation rarely evoked recurrent excitation in mature DGCs from any cohort. These results support that DGC birth date-related increased feedback inhibition in of DGCs may contribute to altered excitability after TBI. SIGNIFICANCE STATEMENT Dentate granule cells (DGCs) control excitability of the dentate gyrus through synaptic interactions with inhibitory GABAergic interneurons. Persistent changes in DGC synaptic connectivity develop after traumatic brain injury, contributing to hyperexcitability in post-traumatic epilepsy (PTE). However, the impact of DGC neurogenesis on synaptic reorganization, especially on inhibitory circuits, after brain injury is not adequately described. Here, upregulation of feedback inhibition in mature DGCs from male and female mice was associated with increased excitation of parvalbumin-expressing basket cells by postnatally born DGCs, providing novel insights into underlying mechanisms of altered excitability after brain injury. A better understanding of these inhibitory circuit changes can help formulate hypotheses for development of novel, evidence-based treatments for post-traumatic epilepsy by targeting birth date-specific subsets of DGCs.

Objectives: Video head impulse test (vHIT) can evaluate function of the vestibuloocular reflex for high frequency range of head rotation. We aimed to characterize the abnormal patterns of canal dysfunction by vHIT in vestibular migraine (VM) and evaluate the relationship between the presence of canal dysfunction and symptomatic improvement.Methods: Eighty-seven patients with VM were included. Abnormality of vHIT at the initial examination was determined by the vHIT gain and the degrees of the corrective saccades at each canal and each side. The relationship between the abnormal patterns and the symptomatic improvement (no need for preventive medication) after modification of life styles and preventive medications for 1, 3, and 6 months was evaluated.Results: Abnormal vHIT of the lateral canal was 13.8% when determined by the gain criteria and 31.0% when based on both gain and corrective saccade, regardless of the side. Abnormal vHIT of the superior and posterior canals were 18.4% and 27.6%, regardless of the side. Abnormal vHIT at any canal and side was observed in 47%. Patients showed symptomatic improvement in 29.9%, 71.3%, and 88.5% after modification of life styles and preventive medications for 1, 3, and 6 months. Abnormal vHIT results of canals were significantly related to the poor response to preventive mediations.Conclusions: Prolonged preventive medication was required for symptomatic improvement in VM patients when vHIT results of any canals were abnormal, suggesting that peripheral vestibular abnormality is closely related to the pathophysiology of vestibular migraine.

Nicotinamide mononucleotide (NMN) is a representative anti-aging drug that, after long-term administration in mice, causes an increase in energy and lipid metabolism, improves eye function, immune response, and increases insulin sensitivity. However, the effects of NMN on skin pigmentation are still unknown.In this study, we aimed to demonstrate the effects of NMN on melanogenesis.NMN was applied to both young and aged melanocytes, and melanin production, protein expression, and mRNA levels were analyzed. A reconstituted human skin model was used to validate the effect of NMN on melanogenesis in vivo.NMN treatment showed no apparent effects on young melanocytes, however, in aged melanocytes, a marked reduction in melanin production was observed. NMN treatment also efficiently reduced melanin production in a reconstituted human skin with aged melanocytes. Genome-wide analysis showed the downregulation of melanogenesis-related cyclic adenosine monophosphate (cAMP)/Wnt signaling in aged melanocytes. Moreover, NMN treatment downregulated forskolin-induced expression of melanogenesis-related proteins, tyrosinase (TYR), tyrosinase-related protein (TRP)- 1, and TRP-2. Nicotinamide adenine dinucleotide (NADNMN reduces melanogenesis in aged melanocytes by downregulating the signaling of melanogenesis-associated receptors. Therefore, NMN is a human-friendly anti-melanogenic agent with the potential to aid in aging-related hyperpigmentation therapy.

Tissue-resident macrophages (TRMs) are critical for tissue homeostasis/repair. We previously showed that dermal TRMs produce CCL24 (eotaxin2) which mediates their interaction with IL-4 producing eosinophils, required to maintain their number and M2-like properties in the TH1 environment of the Leishmania major infected skin. Here, we unveil another layer of TRM self-maintenance involving their production of TSLP, an alarmin typically characterized as epithelial cell-derived. Both TSLP signaling and IL-5+ innate lymphoid cell 2 (ILC2s) were shown to maintain the number of dermal TRMs and promote infection. Single cell RNA sequencing identified the dermal TRMs as the sole source of TSLP and CCL24. Development of Ccl24-cre mice permitted specific labeling of dermal TRMs, as well as interstitial TRMs from other organs. Genetic ablation of TSLP from dermal TRMs reduced the number of dermal TRMs, and disease was ameliorated. Thus, by orchestrating localized type 2 circuitries with ILC2s and eosinophils, dermal TRMs are self-maintained as a replicative niche for L. major.

Antibody blockade of programmed death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD-L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy. Using CRISPR/Cas9-induced loss-of-function approaches and overexpression gain-of-function techniques, we confirmed that PD-L1 on tumor cells is key to promoting tumor escape. In addition, the capacity of PD-L1 to suppress antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumor-associated macrophages (TAM), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was IFNγ-dependent and transient, but PD-L1 induction on TAMs was of greater magnitude, only partially IFNγ dependent, and was stable over time. Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from immune control, indicating that total PD-L1 expression in the immediate tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with monitoring PD-L1 expression on tumor cells alone. Cancer Immunol Res; 5(2); 106–17. ©2017 AACR.

Supplementary Figure S1. Genomic sequence of the PD-L1 locus and expression of immunogenic neoantigens in T3deltaPDL1 lines. Supplementary Figure S2. Expression of PD-L1 and neoantigens in the escape T3deltaPDL1 cells. Supplementary Figure S3. PD-L1 but not PD-L2 is upregulated on MCA sarcomas in vitro and in vivo following exposure to IFNgamma. Supplementary Figure S4. T9-PDL1 cells form progressively growing tumors in WT mice. Supplementary Figure S5. T9-PDL1ovr but not T9-PDL1phy cells inhibit antigen-specific T cell killing in vitro. Supplementary Figure S6. Extrinsic IFNgamma stimulation controls upregulation and maintenance of tumor PD-L1 expression. Supplementary Figure S7. Sixteen immune subsets in MCA sarcomas by flow cytometry. Supplementary Figure S8. Comprehensive analysis of cell types expressing PD-L1 in T3 tumors.

Supplementary Table S1. Staining panels for comprehensive analysis of cell types expressing PD-L1.

Figure Legends for Supplementary Data

Boundary-updating, a process of updating decision boundaries, has been known to induce a history effect on binary choices. However, the history effect that boundary-updating has on decision uncertainty has been previously overlooked. Our study revealed that boundary-updating can also impact decision uncertainty, as evidenced by changes in response time, pupil-size, and dACC response, suggesting that boundary-updating is a source of history effect not only on choice but also decision uncertainty.

Background: To prepare for future work stoppages in the medical industry, this study aimed to identify the effects of healthcare worker strikes on the mortality rate of patients visiting the emergency department (ED) at six training hospitals in Daegu, Korea. Methods: We used a retrospective, cross-sectional, multicenter design to analyze the medical records of patients who visited six training hospitals in Daegu (August 21–September 8, 2020). For comparison, control period 1 was set as the same period in the previous year (August 21–September 8, 2019) and control period 2 was set as July 1–19, 2020. Patient characteristics including age, sex, and time of ED visit were investigated along with mode of arrival, length of ED stay, and in-hospital mortality. The experimental and control groups were compared using t-tests, and Mann-Whitney U-test, chi-square test, and Fisher exact tests, as appropriate. Univariate logistic regression was performed to identify significant factors, followed by multivariate logistic regression analysis. Results: During the study period, 31,357 patients visited the ED, of which 7,749 belonged to the experimental group. Control periods 1 and 2 included 13,100 and 10,243 patients, respectively. No significant in-hospital mortality differences were found between study periods; however, the results showed statistically significant differences in the length of ED stay. Conclusion: The ED resident strike did not influence the mortality rate of patients who visited the EDs of six training hospitals in Daegu. Furthermore, the number of patients admitted and the length of ED stay decreased during the strike period.

Anti-cancer chemotherapy is an effective therapeutic approach. Milk extracellular vesicles (EVs) loaded with chemotherapeutics have a potential anticancer effect by acting as a drug delivery system. Thus, our study aimed to explore the effect of engineered milk extracellular vesicles.To treat epidermal growth factor receptor (EGFR) expressing solid tumors, we established oxaliplatin-loaded milk EV conjugated with GE11 peptide (Drug-loadedAnti-cancer drug-loaded engineered milk EVs might be a novel therapeutic approach for treating patients with EGFR expressing solid tumors.