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Objective: The purpose of this study was to evaluate the effectiveness of middle meningeal artery embolization (MMAE) in elderly high-risk patients with symptomatic chronic subdural hematoma (CSDH) in terms of reduction in hematoma volume and recurrence rate.Methods: We retrospectively reviewed data prospectively collected from nine patients who underwent 13 MMAE for CSDH between June 2017 and May 2022. The volume of the subdural hematoma was measured using a computer-aided volumetric analysis program. Hematoma volume changes during the follow-up period were analyzed and clinical outcomes were evaluated.Results: The mean follow-up period was 160 days (range, 46−311 days). All procedures were technically successful and there were no procedure-related complications. Of the 13 MMAE, 84% (11 out of 13 hemispheres) showed mean 88% of reduction on follow-up volumetric study with eight cases of complete resolution. There was one refractory case with MMAE which had been performed multiple burr-hole trephinations, for which treatment was completed by craniotomy and meticulous resection of multiple pseudomembranes. There was no recurrent case during the follow-up period, except for refractory case.Conclusions: MMAE for CSDH in selected high-risk elderly patients and relapsed patients might be effective. Despite the small cohort, our findings showed a high rate of complete resolution with no complications. Further prospective randomized trials are warranted to evaluate its usefulness as a primary treatment option for CSDH.

Dendritic spines are dynamic, submicron-scale protrusions on neuronal dendrites that receive neuronal inputs. Morphological changes in the dendritic spine often reflect alterations in physiological conditions and are indicators of various neuropsychiatric conditions. However, owing to the highly dynamic and heterogeneous nature of spines, accurate measurement and objective analysis of spine morphology are major challenges in neuroscience research. Most conventional approaches for analyzing dendritic spines are based on two-dimensional (2D) images, which barely reflect the actual three-dimensional (3D) shapes. Although some recent studies have attempted to analyze spines with various 3D-based features, it is still difficult to objectively categorize and analyze spines based on 3D morphology. Here, we propose a unified visualization framework for an interactive 3D dendritic spine analysis system, DXplorer, that displays 3D rendering of spines and plots the high-dimensional features extracted from the 3D mesh of spines. With this system, users can perform the clustering of spines interactively and explore and analyze dendritic spines based on high-dimensional features. We propose a series of high-dimensional morphological features extracted from a 3D mesh of dendritic spines. In addition, an interactive machine learning classifier with visual exploration and user feedback using an interactive 3D mesh grid view ensures a more precise classification based on the spine phenotype. A user study and two case studies were conducted to quantitatively verify the performance and usability of the DXplorer. We demonstrate that the system performs the entire analytic process effectively and provides high-quality, accurate, and objective analysis.

Purpose The purpose of this phase II trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, to preoperative chemoradiotherapy (CRT) with capecitabine confers a clinical benefit to patients with locally advanced rectal cancer (LARC).Materials and Methods Patients with LARC (defined by clinical stage T3/4 and/or lymph node positivity) received preoperative radiation (45-50.4 Gy in 25-28 daily fractions) with concomitant capecitabine (825 mg/m2 twice per day) and simvastatin (80 mg, daily). Curative surgery was planned 4-8 weeks after completion of the CRT regimen. The primary endpoint was pathologic complete response (pCR). The secondary endpoints included sphincter-sparing surgery, R0 resection, disease-free survival, overall survival, the pattern of failure, and toxicity.Results Between October 2014 and July 2017, 61 patients were enrolled; 53 patients completed CRT regimen and underwent total mesorectal excision. The pCR rate was 18.9% (n=10) by per-protocol analysis. Sphincter-sparing surgery was performed in 51 patients (96.2%). R0 resection was achieved in 51 patients (96.2%). One patient experienced grade 3 liver enzyme elevation. No patient experienced additional toxicity caused by simvastatin.Conclusion The combination of 80 mg simvastatin with CRT and capecitabine did not improve pCR in patients with LARC, although it did not increase toxicity.

In this randomized phase II study, we evaluated the efficacy and safety of sorafenib in combination with capecitabine and cisplatin (XP) as first-line chemotherapy in advanced gastric cancer.Patients with metastatic gastric or gastroesophageal junction adenocarcinoma were randomized (1:1) to receive either sorafenib plus XP (S + XP) or XP alone. In cases of disease progression in the XP arm, crossover to sorafenib alone was allowed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), response rates, safety profiles, and biomarkers, and the response rates and PFS with secondline sorafenib alone after progression in the XP arm.Between Jan 2011 and Feb 2013, a total of 195 patients were accrued (97 in the S + XP arm and 98 in the XP alone arm). The overall response rate was 54% with S + XP, and 52% with XP alone (p = 0.83). With a median follow-up of 12.6 months (range, 0.1-29.2), the median PFS assessed by independent review was 5.6 months in the S + XP arm and 5.3 months in the XP arm (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.67-1.27, p = 0.61). Overall survival was not different between the two arms (median 11.7 vs. 10.8 months; HR 0.93, 95% CI 0.65-1.31, p = 0.66). Frequencies of grade 3/4 toxicities were similar between the S + XP and XP alone arms, except for neutropenia (21% vs. 37%), anorexia (0% vs. 5%), and hand-foot skin reaction (7% vs. 1%). Among 51 patients who crossed over to sorafenib alone after disease progression in the XP arm, there was no objective response and their median PFS was 1.3 months (95% CI, 1.2-1.7).The addition of sorafenib to XP chemotherapy was safe but not more effective than XP alone for first-line treatment of metastatic gastric cancer.

The proliferation and migration of vascular smooth muscle cells (VSMCs) after vascular injury lead to neointimal hyperplasia, thus aggravating vascular diseases. However, the molecular mechanisms underlying neointima formation are not fully elucidated. Extracellular vesicles (EVs) are mediators of various intercellular communications. The potential of EVs as regulators in cardiovascular diseases has raised significant interest. In the current study we investigated the role of circulating small extracellular vesicles (csEVs), the most abundant EVs (10

Anti-Müllerian hormone (AMH) is one of the most reliable markers of ovarian reserve. Automated AMH assays are widely used in clinical laboratories, but reference intervals for the Elecsys AMH assay for Asian populations have not yet been determined. We aimed to determine reference intervals in healthy Korean women.The study included 1,450 women aged 19 to 54 years who participated in the Korea National Health and Nutrition Examination Survey between 2013 and 2016. The study participants were divided into seven 5-year age groups. AMH and progesterone concentrations were measured using Roche Elecsys assays, and bone morphogenetic protein-15 (The mean age was 37.4 years. AMH concentrations decreased with increasing age, especially after 40 years, with the median AMH decreasing from 30.9 pmol/L in participants of 19-24 years to 0.071 pmol/L in participants of 50-54 years. The mid-95 percentile AMH reference intervals decreased from 7.93-81.21 pmol/L in participants of 19-24 years to 0.07-3.86 pmol/L in participants of 50-54 years. Disease-associatedWe determined Elecsys AMH assay reference intervals in healthy Korean women. The results may provide basic information for the interpretation of AMH concentrations and assessment of ovarian reserve in Korean women.

The top-down (TD) approach using internal quality control (IQC) data is regarded a practical method for estimating measurement uncertainty (MU) in clinical laboratories. We estimated the MU of 14 clinical chemistry analytes using the TD approach and evaluated the effect of lot changes on the MU.MU values were estimated using subgrouping by reagent lot changes or using the data as a whole, and both methods were compared. Reagent lot change was simulated using randomly generated data, and the mean values and MU for two IQC datasets (different QC material lots) were compared using statistical methods.All MU values calculated using subgrouping were lower than the total values; however, the average differences were minimal. The simulation showed that the greater the increase in the extent of the average shift, the larger the difference in MU. In IQC data comparison, the mean values and MU exhibited statistically significant differences for most analytes. The MU calculation methods gave rise to minimal differences, suggesting that IQC data in clinical laboratories show no significant shift. However, the simulation results demonstrated that notable differences in the MU can arise from significant variations in IQC results before and after a reagent lot change. Additionally, IQC material lots should be treated separately when IQC data are collected for MU estimation.Lot changes in IQC data are a key factor affecting MU estimation and should not be overlooked during MU estimation.

Adding anti-PD1 antibodies to 5-FU/platinum chemotherapy improves survival in a subset of advanced gastroesophageal adenocarcinoma (GEA) patients. Beyond PD-L1 expression and mismatch repair status we have limited insight into molecular predictors of response, or the relative contribution of PD-1 blockade. We conducted an investigator sponsored phase II trial (n = 47) sequentially adding pembrolizumab to standard 5-FU/platinum in previously untreated advanced GEA (ClinicalTrials.gov: NCT04249739). With an overall response rate of 67% the activity paralleled phase III chemoimmunotherapy trials. To understand on-treatment tumor and immune adaptations patients underwent serial biopsy of the primary tumor, including baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab. We leveraged transcriptional profiling from 358,067 cells to identify multicellular networks of malignant, stromal, and immune cells after chemotherapy and concurrent chemoimmunotherapy. The relative usage of pro-tumor and anti-tumor interaction hubs differed between fast and slow progressing patients. Chemotherapy induced early on-treatment formation of hubs centered on tumor-reactive T-cell and M1-oriented macrophage interactions with pro-inflammatory cytokines in slow progressors. Faster progression was characterized by increased MUC5A and MSLN containing programs in tumor cells and M2-oriented macrophages with immunosuppressive stromal interactions. After adding pembrolizumab we observed increased CD8 T-cell infiltration by scRNAseq and multiplex immunofluorescence and development of an immunity hub involving co-variation of the tumor-reactive CXCL13 program and epithelial interferon-stimulated gene programs enriched in slow progressors. Together this data provides prospective evidence of differential early on-treatment evolution of the gastric immune microenvironment and nominates candidate cellular interactions for clinical targeting.

We established high-sensitivity cardiac troponin I (hsTnI) 99th percentile upper reference limits (URLs) for the Centaur XPT High-Sensitivity Troponin I assay (Centaur hsTnI; Siemens, Erlangen, Germany) and Atellica IM High-Sensitivity Troponin I assay (Atellica hsTnI; Siemens) and assessed the effect of outlier elimination.The reference population comprised 380 men and 387 women, satisfying the strict systematic reference population criteria. After reference population verification by the N-terminal pro-B-type natriuretic peptide (NT-proBNP) assay, 99th percentile URLs for Centaur hsTnI and Atellica hsTnI were calculated before and after outlier elimination.The 99th percentile URL for Centaur hsTnI was 60.4 (men, 74.7; women, 57.5) ng/L and that for Atellica hsTnI was 59.6 (men, 75.2; women, 55.1) ng/L. After the elimination of 61 (8.0%) outlier samples in Centaur hsTnI and 58 (7.6%) in Atellica hsTnI, the 99th percentile URLs were 13.5 ng/L (men, 15.3 ng/L; women, 11.9 ng/L) and 13.4 ng/L (men, 15.5 ng/L; women, 12.9 ng/L), respectively, significantly lower than those before outlier elimination. The CVs at the 99th percentile URLs were 5.2% and 3.5%, respectively. The measurable fractions among the reference population were 91.5% and 93.4%, respectively. Performance evaluation of Atellica B-type natriuretic peptide (BNP), Atellica NT-proBNP, Centaur hsTnI, and Atellica hsTnI showed outstanding results.The Korean hsTnI 99th percentile URLs calculated in this study were significantly lower after outlier elimination than before. Centaur hsTnI and Atellica hsTnI meet the "Guideline acceptable" and "Level 3 (second generation, high sensitivity)" requirements, satisfying international standards.

PurposeThe purpose of this study is to develop an integrative concept of perceived authenticity that captures a more nuanced perception of authenticity among LGBTQ stakeholders and to examine the effects of perceived organizational authenticity on Pride campaign evaluations.Design/methodology/approachWith 400 LGBTQ/non-LGBTQ participants, we developed a perceived organizational authenticity (POA) scale - adapted from marketing literature - adding representativeness as the fifth dimension to the context of LGBTQ communication. We also examined the differences between LGBTQ participants and non-LGBTQ participants in perceiving authenticity and evaluating the Pride 2020 campaign in terms of brand attitude, skepticism and purchase intention.FindingsOur scale development resulted in a 20-item POA scale measuring five dimensions: continuity, credibility, integrity, symbolism and representativeness. We also found that POA increases brand attitude and purchase intention while mitigating skepticism toward the Pride 2020 campaign.Research limitations/implicationsThis study provides not only empirical support for perceived authenticity literature across communication disciplines including marketing as well as public relations, but it also propels an interdisciplinary approach to POA scale development.Practical implicationsThe POA scale can be used to measure the effectiveness of organizational communication as well as stakeholder perception of authenticity. This research provides guidelines regarding how POA of LGBTQ communication might be enhanced.Originality/valueThis study developed a POA scale in the context of LGBTQ communication. This study is innovative in developing a POA scale that can be used to measure the effectiveness of public relations and communication efforts, as well as perceived authenticity of LGBTQ communication.

The aim of this study is to determine the optimal indications for preoperative pelvic radiotherapy (RT) in patients with metastatic rectal cancer who underwent curative-intent surgical resection and/or ablation.Between January 2000 and October 2019, 246 patients who met our inclusion criteria were enrolled. Preoperative RT was performed in 22 patients (8.9%). Lower margin below the peritoneal reflection (p0.001), mesorectal fascia (MRF) invasion (p = 0.02), and lateral pelvic lymph node (LPLN) involvement (p = 0.005) were more frequent in the preoperative RT group.During the median follow-up period of 13.3 months (interquartile range [IQR]: 6.0-36.3 months), local recurrence (LR) was identified in 60 patients (24.4%). It was the first site of recurrence in 45 of them (18.3%). Among them, three patients were in the preoperative RT group. On multivariable analysis, lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, carcinoembryonic antigen (CEA) level ≥ 10 ng/mL before treatment, and preoperative RT were significant prognostic factors for LR-free survival (LRFS). In the patient group without any risk factors, the 2-year LRFS rate was 94.9% without preoperative RT. In the patient group with one or more risk factors, the 2-year LRFS was 64.4% without and 95.2% with preoperative RT.LR developed in about 25% of patients within 2 years. Preoperative RT should be considered, especially in patients with a risk factor for LR, including lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, or CEA ≥ 10 ng/mL before treatment.

Aberrations in the fibroblast growth factor receptor2 (FGFR2) gene, including genetic alterations and chromosomal rearrangements, lead to the development and progression of cancer with poor prognosis. However, the mechanisms underlying the FGFR2 signaling pathway to facilitate the development of FGFR2-targeted therapies have not been fully explored. Here, we examined the clinicopathological features of FGFR2 amplification and fusion in gastrointestinal tract/genitourinary tract cancers. FGFR2 amplification and fusion were identified in approximately 1.5% and 1.1% of all cancer types in 1,373 patients, respectively, with both FGFR2 amplification and fusion occurring together at a rate of approximately 0.6%. Of all cancer types screened, gastric cancer (GC) was the most common cancer type with FGFR2 amplification (87.5% of all FGFR2 amplification case) or fusion (46.7% of all cases). In addition, FGFR2 alteration had poorer overall survival (OS, 13.7 months vs. 50.2 months, P = 0.0001 ) and progression-free survival (PFS, 5.6 months vs. 11.4 months, P = 0.0005 ) than did those without FGFR2 alteration, respectively. Taken together, our data underscore to screen solid cancer patients for FGFR2 aberrations in oncology clinic.

Background/aims Heme oxygenase-1 (HO-1) plays a central role in cellular defense against inflammatory insults, and its induction in macrophages potentiates their efferocytic activity. In this study, we explored the potential role of macrophage HO-1 in the resolution of experimentally induced colitis. Methods To induce colitis, male C57BL/6 mice were treated with 2% dextran sulfate sodium (DSS) in the drinking water for 7 days. To investigate efferocytosis, apoptotic colon epithelial CCD 841 CoN cells were coincubated with bone marrow-derived macrophages (BMDMs). Results Administration of the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blunted the resolution of DSS-induced intestinal inflammation and expression of the proresolving M2 macrophage marker CD206. BMDMs treated with apoptotic colonic epithelial cells showed significantly elevated expression of HO-1 and its regulator Nrf2. Under the same experimental conditions, the proportion of CD206-expressing macrophages was also enhanced. ZnPP treatment abrogated the upregulation of CD206 expression in BMDMs engulfing apoptotic colonic epithelial cells. This result was verified with BMDMs isolated from HO-1-knockout mice. BMDMs, when stimulated with lipopolysaccharide, exhibited increased expression of CD86, a marker of M1 macrophages. Coculture of lipopolysaccharide-stimulated BMDMs with apoptotic colonic epithelial cell debris dampened the expression of CD86 as well as the pro-inflammatory cytokines in an HO-1-dependent manner. Genetic ablation as well as pharmacologic inhibition of HO-1 significantly reduced the proportion of efferocytic BMDMs expressing the scavenger receptor CD36. Conclusions HO-1 plays a key role in the resolution of experimentally induced colitis by modulating the polarization of macrophages.

Octocrylene (OC) is an extensively prescribed organic ultraviolet B filter used in sunscreen products. Due to its extensive use, a significant level of OC is detected in marine and freshwater environments. Notably, the bioaccumulation of OC in aquatic biota may affect human health. In this study, the effect of OC on metabolism was investigated using the adipogenesis model of human bone marrow mesenchymal stem cells (hBM-MSCs). OC promoted adiponectin production during adipogenesis in hBM-MSCs compared to the vehicle-treated control (EC

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.F Hoffmann-La Roche.