Confined Ionic Environments Tailoring the Reactivity of Molecules in the Micropores of BEA-Type Zeolite.

In the presence of water, hydronium ions formed within the micropores of zeolite H-BEA significantly influence the surrounding environment and the reactivity of organic substrates. The positive charge of these ions, coupled with the zeolite's negatively charged framework, results in an ionic environment that causes a strongly nonideal solvation behavior of cyclohexanol. This leads to a significantly higher excess chemical potential in the initial state and stabilizes at the same time the charged transition state in the dehydration of cyclohexanol. As a result, the free-energy barrier of the reaction is lowered, leading to a marked increase in the reaction rates. Nonetheless, there is a limit to the reaction rate enhancement by the hydronium ion concentration. Experiments conducted with low concentrations of reactants show that beyond an optimal concentration, the required spatial rearrangement between hydronium ions and cyclohexanols inhibits further increases in the reaction rate, leading to a peak in the intrinsic activity of hydronium ions. The quantification of excess chemical potential in both initial and transition states for zeolites H-BEA, along with findings from HMFI, provides a basis to generalize and predict rates for hydronium-ion-catalyzed dehydration reactions in Brønsted zeolites.

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.

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.

Does the coronoid fracture in terrible triad injury always need to be fixed?

BACKGROUND: The ideal treatment of terrble triad injuries and whether fixation of coronoid process fractures is needed or not are still debated. Therefore, we aimed to investigate if terrible triad injuries necessitate coronoid fracture fixation and evaluate if non-fixation treatments have similar efficacies and outcomes as fixation-treatments in cases of terrible triad injuries. METHODS: From August 2011 to July 2020, 23 patients with acute terrible triad injuries without involvement of the anteromedial facet of the coronoid process were included to evaluate the postoperative clinical and radiological outcomes (minimum follow-up of 20 months). According to the preoperative height loss evaluation of the coronoid process and an intraoperative elbow stability test, seven patients underwent coronoid fracture fixation, and the other eight patients were treated conservatively. The elbow range of motion (ROM), Mayo Elbow Performance Score (MEPS), and modified Broberg-Morrey score were evaluated at the last follow-up. In addition, plain radiographs were reviewed to evaluate joint congruency, fracture union, heterotopic ossification, and the development of arthritic changes. RESULTS: At the last follow-up, the mean arcs of flexion-extension and supination-pronation values were 118.2° and 146.8° in the fixation group and 122.5° and 151.3° in the non-fixation group, respectively. The mean MEPSs were 96.4 in the fixation group (excellent, nine cases; good, tow cases) and 96.7 in the non-fixation group (excellent, ten cases; good, two cases). The mean modified Broberg-Morrey scores were 94.0 in the fixation group (excellent, sevev cases; good, four cases) and 94.0 in the non-fixation group (excellent, ten cases; good, tow cases). No statistically significant differences in clinical scores and ROM were identified between the two groups. However, the non-fixation group showed a significantly lower height loss of the coronoid process than the fixation group (36.3% versus 54.5%). CONCLUSIONS: There were no significant differences in clinical outcomes between the fixation and non-fixation groups in terrible triad injuries.

Chloride and Hydride Transfer as Keys to Catalytic Upcycling of Polyethylene into Liquid Alkanes.

Transforming polyolefin waste into liquid alkanes through tandem cracking-alkylation reactions catalyzed by Lewis-acid chlorides offers an efficient route for single-step plastic upcycling. Lewis acids in dichloromethane establish a polar environment that stabilizes carbenium ion intermediates and catalyzes hydride transfer, enabling breaking of polyethylene C-C bonds and forming C-C bonds in alkylation. Here, we show that efficient and selective deconstruction of low-density polyethylene (LDPE) to liquid alkanes is achieved with anhydrous aluminum chloride (AlCl3) and gallium chloride (GaCl3). Already at 60 °C, complete LDPE conversion was achieved, while maintaining the selectivity for gasoline-range liquid alkanes over 70 %. AlCl3 showed an exceptional conversion rate of 5000 g L D P E m o l c a t - 1 h - 1 ${{{\rm g}}_{{\rm L}{\rm D}{\rm P}{\rm E}}{{\rm \ }{\rm m}{\rm o}{\rm l}}_{{\rm c}{\rm a}{\rm t}}^{-1}{{\rm \ }{\rm h}}^{-1}}$ , surpassing other Lewis acid catalysts by two orders of magnitude. Through kinetic and mechanistic studies, we show that the rates of LDPE conversion do not correlate directly with the intrinsic strength of the Lewis acids or steric constraints that may limit the polymer to access the Lewis acid sites. Instead, the rates for the tandem processes of cracking and alkylation are primarily governed by the rates of initiation of carbenium ions and the subsequent intermolecular hydride transfer. Both jointly control the relative rates of cracking and alkylation, thereby determining the overall conversion and selectivity.

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.

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.

Outcome Prediction Model Following Proximal Femoral Osteotomy in Legg-Calvé-Perthes Disease Using Machine Learning Algorithms.

BACKGROUND: The purpose of the current study was (1) to analyze various factors that may be associated with the outcomes of Legg-Calvé-Perthes disease (LCPD), and (2) to develop and internally validate machine learning algorithms capable of providing patient-specific predictions of which patients with LCPD will achieve relevant improvement in radiologic outcomes after proximal femoral varus osteotomy (PFVO). We examined several variables, previously identified as factors, that may influence the outcome of LCPD and developed a machine learning algorithm based on them. METHODS: In this retrospective study, we analyzed patients aged older than  6 years at the time of LCPD diagnosis who underwent PFVO at our institution between 1979 and 2015. Univariate and multivariate logistic regression analyses were used to examine the effects of variables on the sphericity of the femoral head at skeletal maturity, including age at onset, sex, stage at operation, extent of epiphyseal involvement and collapse, presence of specific epiphyseal, metaphyseal, and acetabular changes, and postoperative neck shaft angle (NSA). Recursive feature selection was used to identify the combination of variables from an initial pool of 13 features that optimized the model performance. Five machine learning algorithms [extreme gradient boosting (XGBoost), multilayer perception, support vector machine, elastic-net penalized logistic regression, and random forest) were trained using 5-fold cross-validation 3 times and applied to an independent testing set of patients. RESULTS: Ninety patients with LCPD who underwent PFVO were included in this study. The mean age at diagnosis was 7.93 (range, 6.0 to 12.33) years. The average follow-up period was 10.11 (range, 5.25 to 22.92) years. A combination of 8 variables, optimized algorithm performance, and specific cutoffs were found to decrease the likelihood of achieving the 1 or 2 Stulberg classification: age at onset ≤ 8.06, lateral classification ≤ B, 12.40 < preoperative migration percentage (MP) ≤ 22.85, Catterall classification ≤ 2, 117.4 < postoperative NSA ≤ 122.90, -10.8 < postoperative MP ≤ 6.5, 139.65 < preoperative NSA ≤ 144.67, and operation at stage 1. The XGBoost model demonstrated the best performance (F1 score: 0.78; area under the curve: 0.84). CONCLUSIONS: The XGBoost machine learning algorithm achieved the best performance in predicting the postoperative radiologic outcomes in patients with LCPD who underwent PFVO. In our population, age at onset ≤ 8.06, lateral classification ≤ B, 12.40 < preoperative MP ≤ 22.85, Catterall classification ≤ 2, 117.4 < postoperative NSA ≤ 122.90, -10.8 < postoperative MP ≤ 6.5, 139.65 < preoperative NSA ≤ 144.67, and operation at an early stage had the likelihood of achieving the spherical femoral head for the patients with LCPD that underwent PFVO. After external validation, the online application of this model may enhance shared decision-making. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

APE1/Ref-1 Inhibits Adipogenic Transcription Factors during Adipocyte Differentiation in 3T3-L1 Cells.

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in DNA repair and redox regulation. The redox activity of APE1/Ref-1 is involved in inflammatory responses and regulation of DNA binding of transcription factors related to cell survival pathways. However, the effect of APE1/Ref-1 on adipogenic transcription factor regulation remains unknown. In this study, we investigated the effect of APE1/Ref-1 on the regulation of adipocyte differentiation in 3T3-L1 cells. During adipocyte differentiation, APE1/Ref-1 expression significantly decreased with the increased expression of adipogenic transcription factors such as CCAAT/enhancer binding protein (C/EBP)-α and peroxisome proliferator-activated receptor (PPAR)-γ, and the adipocyte differentiation marker adipocyte protein 2 (aP2) in a time-dependent manner. However, APE1/Ref-1 overexpression inhibited C/EBP-α, PPAR-γ, and aP2 expression, which was upregulated during adipocyte differentiation. In contrast, silencing APE1/Ref-1 or redox inhibition of APE1/Ref-1 using E3330 increased the mRNA and protein levels of C/EBP-α, PPAR-γ, and aP2 during adipocyte differentiation. These results suggest that APE1/Ref-1 inhibits adipocyte differentiation by regulating adipogenic transcription factors, suggesting that APE1/Ref-1 is a potential therapeutic target for regulating adipocyte differentiation.

Surface Wettability Prediction Using Image Analysis and an Artificial Neural Network.

In this study, a wettability-predicting method that uses an artificial neural network (ANN) by learning from digital images of the actual surface structures was developed. Polyester film surfaces were treated with oxygen plasma to realize various nanostructured surfaces. Surface structural characteristics from SEM images were quantified in a multifaceted way using a box-counting algorithm, a gray-level co-occurrence matrix algorithm, and binary image analysis. An ANN model that can predict wettability from surface structures was developed using the quantified surface structure and the resulting wettability as learning data. Furthermore, a surface with an optimal nanostructure to achieve superhydrophobicity was suggested by considering extracted surface structural parameters that significantly affect the surface wettability.

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.

Within- and between-person variability of urinary phthalate metabolites and bisphenol analogues over seven days: Considerations of biomonitoring study design.

Urine was used as a part of a human biomonitoring study based on the excretion kinetics of less-persistent contaminants, such as phthalates and bisphenol A (BPA). Despite the advantages of being non-invasive and easy to collect, urine can show a large variability of concentrations of phthalate metabolites and BPA within a person depending on sampling time. Therefore, it is essential to assess the variability of urinary concentrations for comprehensive sampling design in the context of exposure and risk assessments. In this study, 18 phthalate metabolites and eight BPs were measured in all spot urine (n = 401) collected from 12 participants for seven consecutive days to evaluate within- and between-person variabilities. The intraclass correlation coefficients (ICCs) for all spot urines were poor for monomethyl phthalate (ICC: 0.002) and BPA (0.121) but were moderate for monoethyl phthalate (0.514) and monobenzyl phthalate (0.462). Based on the results of di (2-ethylhexyl) phthalate (DEHP) metabolites, the half-life and differences in metabolic capability seem to affect the ICCs. Urinary mono (2-ethylhexyl) phthalate (MEHP), a primary metabolite of DEHP, was suggested as a short-term exposure marker of DEHP in our study. Creatinine- and specific gravity-adjusted concentrations of phthalate metabolites and BPs resulted in increased ICCs, implying requirements for randomly collected spot urine. Most analytes in the first morning voids (FMVs) were correlated significantly with those in the daily composites, suggesting the feasibility of FMVs to estimate the daily exposure dose. This study facilitates a more comprehensive sampling design and data interpretation strategy for human biomonitoring studies.