Comparative analysis of glymphatic system alterations in multiple sclerosis and neuromyelitis optica spectrum disorder using MRI indices from diffusion tensor imaging.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Glymphatic system dysfunction has been observed in both multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), indicating the role of neuroinflammation in the glymphatic system. However, little is known about how the two diseases differently affect the human glymphatic system. The present study aims to evaluate the diffusion MRI-based measures of the glymphatic system by contrasting MS and NMOSD. METHODS: This prospective study included 63 patients with NMOSD (n = 21) and MS (n = 42) who underwent DTI. The fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging (DTI) along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. Age and EDSS scores were adjusted. RESULTS: Using Bayesian hypothesis testing, we show that the present data substantially favor the null model of no differences between MS and NMOSD for the diffusion MRI-based measures of the glymphatic system. The inclusion Bayes factor (BF10) of model-averaged probabilities of the group (MS, NMOSD) was 0.280 for FW and 0.236 for the ALPS index. CONCLUSION: Together, these findings suggest that glymphatic alteration associated with MS and NMOSD might be similar and common as an eventual result, albeit the disease etiologies differ. PRACTITIONER POINTS: Previous literature indicates important glymphatic system alteration in MS and NMOSD. We explore the difference between MS and NMOSD using diffusion MRI-based measures of the glymphatic system. We show support for the null hypothesis of no difference between MS and NMOSD. This suggests that glymphatic alteration associated with MS and NMOSD might be similar and common etiology.

Reconstruction of all hepatic arteries in right lobe grafts with 2 hepatic arteries and zero percent hepatic artery thrombosis.

Hepatic artery thrombosis (HAT) is a common cause of graft loss in living-donor liver transplantation, occurring in ~2.5%-8% of patients. Some right lobe grafts have 2 hepatic arteries (HAs), and the optimal reconstruction technique remains controversial. This study aimed to identify risk factors for HAT and to evaluate the efficacy of reconstructing 2 HAs in right lobe grafts. This retrospective, single-center study analyzed 1601 living-donor liver transplantation recipients with a right liver graft and divided them into 1 HA (n = 1524) and 2 HA (n = 77) groups. The reconstruction of all HAs was performed using a microscope with an interrupted suture. The primary outcome was any HAT event. Of the 1601 patients, 37.8% had a history of transcatheter arterial chemoembolization, and 130 underwent pretransplant hepatectomy. Extra-anatomical arterial reconstruction was performed in 38 cases (2.4%). HAT occurred in 1.2% of patients (20/1601) who underwent surgical revascularization. In the multivariate analysis, undergoing pretransplant hepatectomy ( p = 0.008), having a female donor ( p = 0.02), having a smaller graft-to-recipient weight ratio ( p = 0.002), and undergoing extra-anatomical reconstruction ( p = 0.001) were identified as risk factors for HAT. However, having 2 HA openings in right liver grafts was not a risk factor for HAT in our series. Kaplan-Meier survival analysis showed no significant difference in graft survival and patient survival rates between the 1 HA and 2 HA groups ( p = 0.09, p = 0.97). In our series, although the smaller HA in the 2 HA group should increase the risk of HAT, HAT did not occur in this group. Therefore, reconstructing both HAs when possible may be a reasonable approach in living-donor liver transplantation using a right liver graft with 2 HA openings.

Immunosuppressive therapy in elderly patients with neuromyelitis optica spectrum disorder: a retrospective multicentre study.

BACKGROUND: The risk-benefit relationship of immunosuppressive therapies (ISTs) for elderly patients with neuromyelitis optica spectrum disorder (NMOSD) is not well established. This study aimed to investigate the safety and efficacy of IST in elderly patients with NMOSD. METHODS: This retrospective study analysed IST efficacy and safety in 101 patients with aquaporin-4 antibody-positive NMOSD aged over 65 years, treated for at least 6 months at five Korean referral centres, focusing on relapse rates, infection events and discontinuation due to adverse outcomes. RESULTS: The mean age at disease onset was 59.8 years, and female-to-male ratio was 4:1. Concomitant comorbidities at NMOSD diagnosis were found in 87 patients (86%). The median Expanded Disability Status Scale score at the initiation of IST was 3.5. The administered ISTs included azathioprine (n=61, 60%), mycophenolate mofetil (MMF) (n=48, 48%) and rituximab (n=41, 41%). Over a median of 5.8 years of IST, 58% of patients were relapse-free. The median annualised relapse rate decreased from 0.76 to 0 (p<0.001), and 81% experienced improved or stabilised disability. Patients treated with rituximab had a higher relapse-free rate than those treated with azathioprine or MMF (p=0.022). During IST, 21 patients experienced 25 severe infection events (SIEs) over the age of 65 years, and 3 died from pneumonia. 14 patients (14%) experienced 17 adverse events that led to switching or discontinuation of IST. When comparing the incidence rates of SIEs and adverse events, no differences were observed among patients receiving azathioprine, MMF and rituximab. CONCLUSION: In elderly patients with NMOSD, IST offers potential benefits in reducing relapse rates alongside a tolerable risk of adverse events.

Prognostic factors of first-onset optic neuritis based on diagnostic criteria and antibody status: a multicentre analysis of 427 eyes.

BACKGROUND: Optic neuritis (ON) prognosis is influenced by various factors including attack severity, underlying aetiologies, treatments and consequences of previous episodes. This study, conducted on a large cohort of first ON episodes, aimed to identify unique prognostic factors for each ON subtype, while excluding any potential influence from pre-existing sequelae. METHODS: Patients experiencing their first ON episodes, with complete aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing, and clinical data for applying multiple sclerosis (MS) diagnostic criteria, were enrolled. 427 eyes from 355 patients from 10 hospitals were categorised into four subgroups: neuromyelitis optica with AQP4 IgG (NMOSD-ON), MOG antibody-associated disease (MOGAD-ON), ON in MS (MS-ON) or idiopathic ON (ION). Prognostic factors linked to complete recovery (regaining 20/20 visual acuity (VA)) or moderate recovery (regaining 20/40 VA) were assessed through multivariable Cox regression analysis. RESULTS: VA at nadir emerged as a robust prognostic factor for both complete and moderate recovery, spanning all ON subtypes. Early intravenous methylprednisolone (IVMP) was associated with enhanced complete recovery in NMOSD-ON and MOGAD-ON, but not in MS-ON or ION. Interestingly, in NMOSD-ON, even a slight IVMP delay in IVMP by >3 days had a significant negative impact, whereas a moderate delay up to 7-9 days was permissible in MOGAD-ON. Female sex predicted poor recovery in MOGAD-ON, while older age hindered moderate recovery in NMOSD-ON and ION. CONCLUSION: This comprehensive multicentre analysis on first-onset ON unveils subtype-specific prognostic factors. These insights will assist tailored treatment strategies and patient counselling for ON.

Analysis of clinical and genomic profiles of therapy-related myeloid neoplasm in Korea.

BACKGROUND: Therapy-related myeloid neoplasm (T-MN) rarely occurs among cancer survivors, and was characterized by poor prognosis. T-MN has germline predisposition in a considerable proportion. Here, clinical characteristics and germline/somatic variant profiles in T-MN patients were investigated, and the findings were compared with those of previous studies. METHODS: A review of medical records, cytogenetic study, targeted sequencing by next-generation sequencing, and survival analysis were performed on 53 patients with T-MN at a single institution in Korea. RESULTS: The patients were relatively younger compared to T-MN patients in other studies. Our T-MN patients showed a high frequency of complex karyotypes, -5/del(5q), and -7/del(7q), which was similar to the Japanese study group but higher than the Australian study group. The most common primary disease was non-Hodgkin lymphoma, followed by breast cancer. The detailed distributions of primary diseases were different across study groups. Seven patients (13.2%) harbored deleterious presumed/potential germline variants in cancer predisposition genes (CPG) such as BRIP1, CEBPA, DDX41, FANCM, NBN, NF1, and RUNX1. In the somatic variant profile, TP53 was the most frequently mutated gene, which was consistent with the previous studies about T-MN. However, the somatic variant frequency in our study group was lower than in other studies. Adverse factors for overall survival were male sex, older age, history of previous radiotherapy, previous longer cytotoxic therapy, and -5/del(5q). CONCLUSION: The findings of our study corroborate important information about T-MN patients. As well as a considerable predisposition to CPG, the clinical characteristics and somatic variant profile showed distinctive patterns. Germline variant testing should be recommended for T-MN patients. If the T-MN patients harbor pathogenic germline variants, the family members for stem cell donation should be screened for carrier status through germline variant testing to avoid donor-derived myeloid neoplasm. For the prediction of the prognosis in T-MN patients, sex, age, past treatment history, and cytogenetic findings can be considered.

Association between body composition and subsequent cardiovascular diseases among 5-year breast cancer survivors.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) remain one of the leading causes of mortality in breast cancer survivors. This study aimed to investigate the association between body composition and subsequent CVD in breast cancer survivors. METHODS AND RESULTS: A retrospective cohort study of more than 70 thousand 5-year breast cancer survivors aged 40 years or older was conducted using data from the National Health Insurance Service of South Korea. Based on the percentage of predicted lean body mass (pLBMP), appendicular skeletal muscle mass (pASMP), and body fat mass (pBFMP), which were calculated using prediction equations with anthropometric data and health habits, groups were equally divided into quartiles. The risk of CVD was evaluated using multivariate Cox proportional hazards regression. Compared to those with the lowest pLBMP and pASMP, those with the highest pLBMP and pASMP had a 38% and 42% lower risk of CVD, respectively. In contrast, those with the highest pBFMP had a 57% higher risk of CVD compared to those with the lowest pBFMP. Each 1 % increase in pLBMP and pASMP was associated with a decreased risk of CVD [pLBMP, adjusted hazard ratio (aHR): 0.96, 95% CI 0.94-0.98, p < 0.05; pASMP, aHR: 0.91, 95% CI 0.87-0.95, p < 0.05] while each 1 % increase in pBFMP was associated with the increased risk of CVD (aHR: 1.05, 95% CI 1.03-1.07, p < 0.01). CONCLUSION: In this cohort study, a high pLBMP, a high pASMP, and a low pBFMP were associated with a lower risk of CVD.

Association of parental depression with adolescent children's psychological well-being and health behaviors.

BACKGROUND: Parental depression is a significant problem that negatively affects parents' welfare and influences family dynamics, children's academic and health behaviors, and mental health. However, there is limited evidence regarding the impact of the parental depression into the children's' psychological and physical wellbeing on Asian cultures. This study examined the psychological burdens and health behaviors of adolescent children with parents with depression in the Republic of Korea. METHODS: We conducted a cross-sectional study using data from the Korean National Health and Nutrition Examination Survey (KNHANES) spanning 2013 to 2021 to compare health behaviors and mental health outcomes between 203 adolescent children with parents diagnosed with depression and 3,856 control adolescents aged 12-19 years. RESULTS: Following multivariate adjustments, the risk of depressive mood for more than two weeks was significantly increased in boys with parental depression (adjusted Odds Ratio [aOR] = 2.05, 95% Confidence Interval [CI] = 1.91-3.52) and adolescents with parents with moderate-to-severe depression (aOR = 2.60, 95% CI = 1.17-5.77). Adolescents with parental depression reported significantly worse subjective health status (aOR = 1.88, 95% CI = 1.05-3.36) and higher stress levels (aOR = 1.91, 95% CI = 1.33-2.76). Additionally, when parental depression was present and the time since depression diagnosis was more than five years, adolescents with parental depression exhibited even poorer subjective health status and higher stress levels. CONCLUSIONS: The study found that adolescents whose parents experienced depression had poorer mental health than those whose parents did not have mental health issues. These findings emphasize the importance of providing support for the mental health of adolescents in families affected by parental depression.

Characteristics and standards of severe sagittal imbalance in adult patients with spinal deformities: a retrospective analysis.

OBJECTIVE: To analyze the characteristics of "severe" dynamic sagittal imbalance (DSI) in patients with adult spinal deformity (ASD) and establish criteria for them. METHODS: We retrospectively analyzed 102 patients with ASD presenting four cardinal signs of lumbar degenerative kyphosis. All patients underwent deformity corrective surgery and were divided into three groups according to the diagnostic criteria based on the Oswestry disability index and dynamic features (△Timewalk: time until C7 sagittal vertical axis [C7SVA] reaches ≥ 20 cm after the start of walking) of sagittal imbalance. The paravertebral back muscles were analyzed and compared using T2-weighted axial imaging. We performed a statistically time-dependent spinopelvic sagittal parameter analysis of full standing lateral lumbar radiographs. Lumbar flexibility was analyzed using dynamic lateral lumbar radiography. RESULTS: The patients were classified into the mild (△Timewalk ≥ 180 s, 35 patients), moderate (180 s > △Timewalk ≥ 30 s, 38 patients), and severe (△Timewalk < 30 s, 29 patients) groups. The back muscles in the severe group exhibited a significantly higher signal intensity (533.4 ± 237.5, p < 0.05) and larger area of fat infiltration (35.2 ± 5.4, p < 0.05) than those in the mild (223.8 ± 67.6/22.9 ± 11.9) and moderate groups (294.4 ± 214.7/21.6 ± 10.6). The analysis of lumbar flexibility revealed significantly lower values in the severe group (5.8° ± 2.5°, p < 0.05) than in the mild and moderate groups (14.2° ± 12.4° and 11.4° ± 8.7°, respectively). The severe group had significantly lower lumbar lordosis (LL, 25.1° ± 22.7°, p < 0.05) and Pelvic incidence-LL mismatch (PI-LL, 81.5° ± 26.6°, p < 0.001) than those of the mild (8.2° ± 16.3°/58.7° ± 18.8°) and moderate (14.3° ± 28.6°/66.8° ± 13.4°) groups. On receiver operating characteristic curve analysis, PI-LL was statistically significant, with an area under the curve of 0.810 (95% confidence interval) when the baseline was set at 75.3°. The severe group had more postoperative complications than the other groups. CONCLUSIONS: Our results suggest the following criteria for severe DSI: C7SVA > 20 cm within 30 s of walking or standing, a rigid lumbar curve < 10° on dynamic lateral radiographs, and a PI-LL mismatch > 75.3°.

Recipient blood group does not affect hepatocellular carcinoma recurrence after living donor liver transplantation in Korea.

PURPOSE: This study assessed whether or not the ABO blood type affects the incidence of HCC recurrence after living donor liver transplantation (LDLT). METHODS: This retrospective observational study included 856 patients with hepatocellular carcinoma (HCC) who underwent LDLT between January 2006 and December 2016 at the Asan Medical Center. RESULTS: This study included 324 patients (37.9%) with blood type A, 215 (25.1%) with blood type B, 210 (24.5%) with blood type O, and 107 (12.5%) with blood type AB. ABO-incompatible LT was performed in 136 (15.9%) patients. The independent risk factors for the disease-free survival (DFS) were maximal tumor diameter, microvascular invasion, and Milan criteria. The only independent risk factor for the overall survival (OS) was microvascular invasion. The ABO blood group did not affect the DFS (P = 0.978) or OS (P = 0.261). The DFS according to the ABO blood group did not differ significantly between the ABO-compatible (p = 0.701) and ABO-incompatible LDLT recipients (p = 0.147). The DFS according to the ABO blood group did not differ significantly between patients within the Milan criteria (p = 0.934) and beyond the Milan criteria (p = 0.525). The DFS did not differ significantly between recipients with and without type A blood (p = 0.941). CONCLUSIONS: This study demonstrated that the ABO blood group system had no prognostic impact on the oncological outcomes of patients undergoing LT for HCC.

Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.

BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.

AXL+SIGLEC6+ dendritic cells in cerebrospinal fluid and brain tissues of patients with autoimmune inflammatory demyelinating disease of CNS.

Inflammatory demyelinating disease of the CNS (IDD) is a heterogeneous group of autoimmune diseases, and multiple sclerosis is the most common type. Dendritic cells (DCs), major antigen-presenting cells, have been proposed to play a central role in the pathogenesis of IDD. The AXL+SIGLEC6+ DC (ASDC) has been only recently identified in humans and has a high capability of T cell activation. Nevertheless, its contribution to CNS autoimmunity remains still obscure. Here, we aimed to identify the ASDC in diverse sample types from IDD patients and experimental autoimmune encephalomyelitis (EAE). A detailed analysis of DC subpopulations using single-cell transcriptomics for the paired cerebrospinal fluid (CSF) and blood samples of IDD patients (total n = 9) revealed that three subtypes of DCs (ASDCs, ACY3+ DCs, and LAMP3+ DCs) were overrepresented in CSF compared with their paired blood. Among these DCs, ASDCs were also more abundant in CSF of IDD patients than in controls, manifesting poly-adhesional and stimulatory characteristics. In the brain biopsied tissues of IDD patients, obtained at the acute attack of disease, ASDC were also frequently found in close contact with T cells. Lastly, the frequency of ASDC was found to be temporally more abundant in acute attack of disease both in CSF samples of IDD patients and in tissues of EAE, an animal model for CNS autoimmunity. Our analysis suggests that the ASDC might be involved in the pathogenesis of CNS autoimmunity.

Efficacy and safety of adhesion barrier in living-donor liver transplantation with right liver graft to prevent delayed gastric emptying.

Delayed gastric emptying (DGE) is a common complication of liver transplantation. This study aimed to clarify the efficacy and safety of the application of an adhesion barrier for preventing DGE in living-donor liver transplantation. This retrospective study included 453 patients who underwent living-donor liver transplantation using a right lobe graft between January 2018 and August 2019, and the incidence of postoperative DGE and complications was compared between patients in whom adhesion barrier was used (n=179 patients) and those in whom adhesion barrier was not used (n=274 patients). We performed 1:1 propensity score matching between the 2 groups, and 179 patients were included in each group. DGE was defined according to the International Study Group for Pancreatic Surgery classification. The use of adhesion barrier was significantly associated with a lower overall incidence of postoperative DGE in liver transplantation (30.7 vs. 17.9%; p =0.002), including grades A (16.8 vs. 9.5%; p =0.03), B (7.3 vs. 3.4%; p =0.08), and C (6.6 vs. 5.5%; p =0.50). After propensity score matching, similar results were observed for the overall incidence of DGE (29.6 vs. 17.9%; p =0.009), including grades A (16.8 vs. 9.5%; p =0.04), B (6.7 vs. 3.4%; p =0.15), and C (6.1 vs. 5.0%; p =0.65). Univariate and multivariate analyses showed a significant correlation between the use of adhesion barrier and a low incidence of DGE. There were no statistically significant differences in postoperative complications between the 2 groups. The application of an adhesion barrier could be a safe and feasible method to reduce the incidence of postoperative DGE in living-donor liver transplantation.

Favorable Prognostic Factors for Survival Outcomes of Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis After Hepatectomy.

BACKGROUND: This study aimed to investigate prognostic factors of recurrence and survival associated with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). PATIENTS AND METHODS: This retrospective study included 161 patients with HCC with PVTT who underwent hepatectomy between January 2003 and January 2014 at the Asan Medical Center. Regression analyses were conducted to identify favorable predictive factors for overall survival (OS) and recurrence-free survival (RFS). RESULTS: The median follow-up was 15.9 months, while 1-, 3-, and 5-year OS was 65.0%, 38.4%, and 36.0%, respectively, and 1-year RFS was 25.5%. There were no significant differences in OS and RFS between the patients with portal vein invasion (Vp) 1-2 and Vp3-4 PVTT. Patients with intrahepatic recurrence had significantly better overall survival than patients with extrahepatic recurrence. Transcatheter arterial chemoembolization and radiofrequency ablation were the most effective treatments for intrahepatic metastasis, and surgery was the most effective treatment for extrahepatic metastasis. On multivariate analysis, absence of esophageal varices, maximal tumor size < 5 cm, tumor location in single lobe, and anatomical resection were favorable prognostic factors for OS and R0 resection, and absence of microvascular invasion was a favorable prognostic factor for RFS. CONCLUSION: The long-term outcome of patients with HCC with PVTT can be improved under consideration of favorable prognostic factors including absence of esophageal varices, maximal tumor size < 5 cm, tumor location in single lobe, and anatomical resection, R0 resection, and absence of microvascular invasion. In addition, recurrent HCC required aggressive management to prolong overall survival.

MOG antibody-associated encephalitis in adult: clinical phenotypes and outcomes.

BACKGROUND: We investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients. METHODS: From an institutional cohort, we analysed adult patients with MOGAE followed-up for more than 1 year. Disease severity was assessed using the modified Rankin scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis scores. Immunotherapy profiles, outcomes and disease relapses were evaluated along with serial brain MRI data. RESULTS: A total of 40 patients were enrolled and categorised into cortical encephalitis (18 patients), limbic encephalitis (LE, 5 patients) and acute disseminated encephalomyelitis (ADEM, 17 patients). 80.0% of patients achieved good clinical outcomes (mRS 0‒2) and 40.0% relapsed. The LE subtype was associated with an older onset age (p=0.004) and poor clinical outcomes (p=0.014) than the other subtypes but with a low rate of relapse (0.0%). 21/25 (84.0%) relapse attacks were associated with an absence or short (≤6 months) immunotherapy maintenance. On MRI, the development of either diffuse cerebral or medial temporal atrophy within the first 6 month was correlated with poor outcomes. MOG-antibody (MOG-Ab) was copresent with anti-N-methyl-D-aspartate receptor (NMDAR)-antibody in 13 patients, in whom atypical clinical presentation (cortical encephalitis or ADEM, p<0.001) and disease relapse (46.2% vs 0.0%, p<0.001) were more frequent compared with conventional NMDAR encephalitis without MOG-Ab. CONCLUSIONS: Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.

Early rituximab treatment reduces long-term disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) causes relapsing inflammatory attacks in the central nervous system, leading to disability. As rituximab, a B-lymphocyte-depleting monoclonal antibody, is an effective in preventing NMOSD relapses, we hypothesised that earlier initiation of rituximab can also reduce long-term disability of patients with NMOSD. METHODS: This multicentre retrospective study involving 19 South Korean referral centres included patients with NMOSD with aquaporin-4 antibodies receiving rituximab treatment. Factors associated with the long-term Expanded Disability Status Scale (EDSS) were assessed using multivariable regression analysis. RESULTS: In total, 145 patients with rituximab treatment (mean age of onset, 39.5 years; 88.3% female; 98.6% on immunosuppressants/oral steroids before rituximab treatment; mean disease duration of 121 months) were included. Multivariable analysis revealed that the EDSS at the last follow-up was associated with time to rituximab initiation (interval from first symptom onset to initiation of rituximab treatment). EDSS at the last follow-up was also associated with maximum EDSS before rituximab treatment. In subgroup analysis, the time to initiation of rituximab was associated with EDSS at last follow-up in patients aged less than 50 years, female and those with a maximum EDSS score ≥6 before rituximab treatment. CONCLUSIONS: Earlier initiation of rituximab treatment may prevent long-term disability worsening in patients with NMOSD, especially among those with early to middle-age onset, female sex and severe attacks.

Smoking cessation after diagnosis of COPD is associated with lower all-cause and cause-specific mortality: a nationwide population-based cohort study of South Korean men.

BACKGROUND: The most effective way to halt the advancement of COPD is smoking cessation. However, limited data are available on the question of whether quitting smoking within two years after COPD diagnosis reduces the risk of mortality. The goal of our research was to analyze the relationship between quitting smoking after COPD diagnosis and the risks of all-cause and cause-specific mortality, using the Korean National Health Insurance Service (NHIS) database. METHODS: This study included 1,740 male COPD patients aged 40 years or more who had been newly diagnosed within the 2003-2014 time period and had smoked prior to their COPD diagnosis. The patients were categorized into two groups according to their smoking status after COPD diagnosis: (i) persistent smokers (ii) quitters (smoking cessation within two years of COPD diagnosis). Multivariate Cox proportional hazard regression was performed to determine the adjusted hazard ratio (HR) and 95% confidence interval (CI) for both all-cause and cause-specific mortality. RESULTS: Among 1,740 patients (mean age, 64.6 years; mean follow-up duration, 7.6 years), 30.5% stopped smoking after COPD diagnosis. Quitters gained a 17% risk reduction in all-cause mortality (aHR, 0.83; 95% CI, 0.69-1.00) and a 44% risk reduction in cardiovascular mortality (aHR, 0.56; 95% CI, 0.33-0.95) compared with persistent smokers. CONCLUSION: Our study found that patients who quit smoking within two years after COPD diagnosis had lower risks of all-cause and cardiovascular mortality relative to persistent smokers. These results can be used to encourage newly diagnosed COPD patients to stop smoking.

Increased risk of suicidality in patients with psoriasis: A Nationwide cohort study in Korea.

BACKGROUND: Psoriasis has a devastating psychological impact on patients' quality of life. However, the relationship between suicidality and psoriasis remains unclear. OBJECTIVE: This study analysed and compared the risk of suicidality (suicidal ideation, suicide attempt and completed suicide) between patients with psoriasis and the general population. METHODS: This nationwide, population-based, retrospective, cohort study analysed the Korean National Health Insurance Service claim data from 2005 to 2018. RESULTS: The study included 348,439 patients with psoriasis aged over 18 years and with age- and sex-matched controls. The risk of suicidality was higher in the psoriasis group than in the control group [adjusted hazard ratio (aHR) 1.21; 95% confidence interval (CI), 1.18-1.24]. The aHR of suicidality was higher in the psoriatic arthritis group (aHR, 1.46; 95% CI, 1.39-1.54) than in the psoriasis-alone group (aHR, 1.17; 95% CI, 1.13-1.20). However, the severity of psoriasis and suicidality showed no correlation (mild psoriasis group: aHR, 1.22; 95% CI, 1.18-1.25; moderate-to-severe psoriasis group: aHR, 1.16; 95% CI, 1.10-1.23). CONCLUSION: Patients with psoriasis have an increased risk of suicidality. In particular, the presence of arthritis in patients had a more significant effect on the risk of suicidality.

Natural Cyclophilin A Inhibitors Suppress the Growth of Cancer Stem Cells in Non-Small Cell Lung Cancer by Disrupting Crosstalk between CypA/CD147 and EGFR.

Non-small cell lung cancer (NSCLC) is a fatal malignant tumor with a high mortality rate. Cancer stem cells (CSCs) play pivotal roles in tumor initiation and progression, treatment resistance, and NSCLC recurrence. Therefore, the development of novel therapeutic targets and anticancer drugs that effectively block CSC growth may improve treatment outcomes in patients with NSCLC. In this study, we evaluated, for the first time, the effects of natural cyclophilin A (CypA) inhibitors, including 23-demethyl 8,13-deoxynargenicin (C9) and cyclosporin A (CsA), on the growth of NSCLC CSCs. C9 and CsA more sensitively inhibited the proliferation of epidermal growth factor receptor (EGFR)-mutant NSCLC CSCs than EGFR wild-type NSCLC CSCs. Both compounds suppressed the self-renewal ability of NSCLC CSCs and NSCLC-CSC-derived tumor growth in vivo. Furthermore, C9 and CsA inhibited NSCLC CSC growth by activating the intrinsic apoptotic pathway. Notably, C9 and CsA reduced the expression levels of major CSC markers, including integrin α6, CD133, CD44, ALDH1A1, Nanog, Oct4, and Sox2, through dual downregulation of the CypA/CD147 axis and EGFR activity in NSCLC CSCs. Our results also show that the EGFR tyrosine kinase inhibitor afatinib inactivated EGFR and decreased the expression levels of CypA and CD147 in NSCLC CSCs, suggesting close crosstalk between the CypA/CD147 and EGFR pathways in regulating NSCLC CSC growth. In addition, combined treatment with afatinib and C9 or CsA more potently inhibited the growth of EGFR-mutant NSCLC CSCs than single-compound treatments. These findings suggest that the natural CypA inhibitors C9 and CsA are potential anticancer agents that suppress the growth of EGFR-mutant NSCLC CSCs, either as monotherapy or in combination with afatinib, by interfering with the crosstalk between CypA/CD147 and EGFR.

Vagococcus allomyrinae sp. nov. and Enterococcus larvae sp. nov., isolated from larvae of Allomyrina dichotoma.

The taxonomic positions of two novel strains isolated from larvae of an insect (Allomyrina dichotoma) collected in Jeju, Republic of Korea, were determined by a polyphasic approach. Strain BWB3-3T was closely related to the type strain of Vagococcus salmoninarum, having 97.2 % 16S rRNA gene sequence similarity, whereas strain BWM-S5T formed an independent cluster within the genus Enterococcus in the 16S rRNA gene phylogeny and the closest relative was the type strain of Enterococcus canis (98.1 % sequence similarity). The core gene analysis supported the phylogenetic positions of the isolates revealed by 16S rRNA gene phylogeny. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain BWB3-3T and the type strain of V. salmoninarum were 73.2 and 20.0 %, respectively, whereas strain BWM-S5 T showed an ANI value of 70.9 % with the type strain of Enterococcus canis. The dDDH values between strain BWM-S5T and all the type strains of Enterococcus species were ≤25.1 %. On the basis of the results obtained here, the two isolates are considered to constitute two novel species of the family Enterococcaceae, for which the names Vagococcus allomyrineae sp. nov. and Enterococcus larvae sp. nov. are proposed, with the type strains BWB3-3T (=KCTC 43277T=CCM 9080T) and BWM-S5T (=KACC 22156T=CCM 9075T), respectively.

Aeromicrobium stalagmiti sp. nov., isolated from a lava cave.

A Gram-reaction-positive, strictly aerobic, non-sporulating, non-motile, rod-shaped bacterium, designated YC3-14T, was isolated from pieces of stalagmite collected in a lava cave in Jeju, Republic of Korea. Cells showed growth at 15-35 °C, pH 6.0-9.0 and with 0-3 % (w/v) NaCl. Colonies of the cells were circular, smooth, convex and cream in colour. A 16S rRNA gene-based neighbour-joining tree indicated that the organism belonged to the genus Aeromicrobium and formed a sublineage between an Aeromicrobium endophyticum-Aeromicrobium fastidiosum cluster and an Aeromicrobium yanjiei-Aeromicrobium chenweiae cluster. The highest 16S rRNA gene similarity values of strain YC3-14T were with the type strains of A. yanjiei (99.2 %), A. endophyticum (99.1 %), A. fastidiosum (98.8 %), A. ginsengisoli (98.8 %) and A. chenweiae (98.7 %). The cell-wall peptidoglycan contained ll-diaminopimelic acid as the diagnostic diamino acid. The major menaquinone was MK-9(H4). The predominant fatty acids were C18 : 0.10-methyl, C18 : 1 ω9c and C16 : 0. The polar lipids comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, an unidentified phospholipid and two unidentified lipids. The G+C content of the genome DNA was 69.9 mol%. These chemotaxonomic features of the isolate were typical for the genus Aeromicrobium. The genome-based phylogeny showed the same tree topology as the 16S rRNA gene phylogeny. The average nucleotide identity (≤84.5 %) and digital DNA-DNA hybridization (≤27.5 %) values supported that the isolate belongs to a novel species of the genus Aeromicrobium. On the basis of data obtained by a polyphasic approach, strain YC3-14T (=KCTC 49469T=NBRC 114653T) represents a novel species of the genus Aeromicrobium, for which the name Aeromicrobium stalagmiti sp. nov. is proposed.