Relationships between Frailty and the Risk of Glaucoma in Middle-aged and Older Adults.

PURPOSE: Increased frailty in older individuals increases health risks, but its relationship with glaucoma, the leading cause of irreversible blindness in middle-aged and older adults, is unclear. We investigated the association between frailty and glaucoma in a large-scale representative sample and explored possible causal relationships. DESIGN: Combined cross-sectional and Mendelian randomization (MR) study. PARTICIPANTS: In the cross-sectional analysis, we included 5744 participants of the US National Health and Nutrition Examination Surveys 2005-2008 aged ≥40. For the MR analysis, frailty genome-wide association study (GWAS) data were sourced from a UK Biobank and TwinGen meta-analysis, and GWAS data on glaucoma subtypes were derived from FinnGen. METHODS: According to the 49-item frailty index, we classified participants into nonfrail (≤0.10), prefrail (0.10-0.21), and frail (>0.21) groups. Using survey-weighted logistic regression models adjusted for multiple covariates, we explored the association between frailty and glaucoma. We further assessed causation using MR. MAIN OUTCOME MEASURES: The associations between different levels of frailty (nonfrail, prefrail, and frail) and glaucoma, as well as causal relationships between genetically predicted frailty and various subtypes of glaucoma (primary open-angle glaucoma, primary angle-closure glaucoma, normotensive glaucoma, exfoliation glaucoma, and suspected glaucoma). RESULTS: After adjusting for covariates, higher frailty levels were significantly associated with glaucoma in frail individuals (odds ratio [OR]=1.83, 95% confidence interval [CI]=1.05-3.19, P=0.036) but not prefrail (OR=1.90, 95% CI=0.99-3.64, P=0.052). The association was significantly stronger among male participants (P interaction=0.042). The variation in the association between frailty and glaucoma did not reach statistical significance across age groups (P interaction=0.575) or race groups (P interaction=0.092). MR revealed that genetically predicted frailty was linked to greater risks for primary open-angle glaucoma (OR=1.67, 95% CI=1.24-2.25, P=0.001), primary angle-closure glaucoma (OR=2.78, 95% CI=1.48-5.20, P=0.001), exfoliation glaucoma (OR=1.70, 95% CI=1.18-2.43, P=0.004), and suspected glaucoma (OR=1.74, 95% CI=1.30-2.34, P<0.001), but not for normotensive glaucoma (OR=1.01, 95% CI=0.61-1.68, P=0.956). CONCLUSIONS: Our study revealed an association between frailty and increased glaucoma risk and emphasized the significance of glaucoma screening in frail individuals. Targeted healthcare strategies can help prevent or delay irreversible blindness among middle-aged and older adults.

Characterization of extreme rainfall changes and response to temperature changes in Guizhou Province, China.

Different geographical zones have regional heterogeneity in underlying earth surface structure and microclimate which result in different evolution trends and their response to climate change varies in extreme rainfalls in these zones. In the Guizhou province of China, there are complex landforms, which lead to spatial redistribution of rainfall, frequent extreme rainfall, and disasters high risk of geologic disasters. Research on extreme climate in Guizhou mostly paid attention to its spatio-temporal characteristics and modeling, but lack of analysis on its characteristics of extreme rainfall variability and response to temperature changes under different subsurface conditions. This study investigated the characteristics of the extreme rainfall spatiotemporal and recurrence periods in Guizhou province and discussed the relationship between the response of extreme rainfall to temperature change. Daily rainfall data from 1990 to 2020 and 2021-2100 at 31 meteorological observation stations throughout the province were collected to calculate extreme precipitation. This research had the following results. (1) Both historical and future periods show an upward trend in extreme rainfall in Guizhou province, with a spatial distribution pattern of "high in the south and low in the north, high in the east and low in the west" and "high in the southeast and low in the northwest", respectively; the spatial distribution of extreme rainfall under each recurrence period is consistent with the non-recurrence period. (2) Both historical and future periods show an upward trend in temperature in Guizhou province, with a spatial distribution consistent with that of the extreme rainfall in the corresponding period. (3) The change in extreme rainfall intensity with increasing temperature is almost always greater than the C-C rate for different periods and underlying earth surface structure; Extreme rainfall has a Hook response structure to temperature change, and the climate response structure shifts to the right with climate warming. The results of the study can provide a basis for decision-making on regional disaster prevention and mitigation in the context of temperature change.

Comparison of Drug Therapy Efficacy in Patients With Hypertrophic Cardiomyopathy: A Network Meta-Analysis.

The aim of this network meta-analysis was to compare the efficacy of various commonly used drugs in treating patients with hypertrophic cardiomyopathy (HCM). Randomized controlled trials on drugs for HCM treatment were retrieved from PubMed, Embase, Cochrane Library, and Web of Science (search cutoff: January 10, 2024). Quality assessment was performed using the risk of bias tool, and data analysis used R software. Seventeen studies (1,133 patients with HCM) were included. The network meta-analysis indicated that mavacamten and perhexiline improved peak oxygen consumption compared with placebo. Mavacamten reduced N-terminal pro-B-type natriuretic peptide, left ventricular mass index, left atrial volume index, and septal E/e' ratio. Losartan decreased systolic blood pressure, whereas candesartan, mavacamten, and valsartan reduced maximum wall thickness. Perhexiline had better efficacy in increasing peak oxygen consumption, and candesartan in reducing maximum wall thickness. No drug significantly improved left ventricular ejection fraction compared with placebo. In conclusion, on the basis of current studies, commonly used drugs may effectively improve some of the outcome measures in patients with HCM, whereas the novel drug mavacamten showed significant therapeutic effects in most of the remaining outcome measures except for left ventricular ejection fraction.

Study on the Spatiotemporal Evolution and Driving Factors of Ecological Security in Stages Based on the DPSIRM-SBM Model: A Case Study of the Yangtze River Economic Belt.

Scientific assessment of urban ecological security (ES) is an important prerequisite to realize regional sustainable development. Previous studies lack the consideration of quality and poor systematic correlation, which could not reflect the internal dynamic relationship. On the basis of considering the time lag, this study divided the research process into the natural operation stage and the management feedback stage based on the driving forces, pressures, state, impacts, responses, management (DPSIRM) framework model and DEA theory, so as to effectively overcome the above shortcomings. Finally, we analyzed the spatio-temporal characteristics and influencing factors of the ES level of 108 cities in the Yangtze River Economic Belt (YREB) during 2005-2019. The results showed that: (a) both two stages showed a slow and fluctuating upward trend in time series, and the level of urban ES in the management feedback stage was significantly higher than that in the natural operation stage; (b) with the passage of time, the spatial distribution of ES in the natural operation stage gradually developed towards the middle and downstream of the YREB, while the management feedback stage mainly evolved from the midstream to the edge area; (c) the level of urban ES presented a different degree of spatial agglomeration phenomenon, and showed an increasing trend over time; and (d) the key influencing factors gradually changed from pressure to response during 2005-2019. This research aims to provide an innovative perspective for the measurement of urban ES, and provide scientific reference for improving urban ecological sustainable development.

Cortistatin protects against septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-NLRP3 pathway.

BACKGROUND: Although the pathophysiological mechanism of septic cardiomyopathy has been continuously discovered, it is still a lack of effective treatment method. Cortistatin (CST), a neuroendocrine polypeptide of the somatostatin family, has emerged as a novel cardiovascular-protective peptide, but the specific mechanism has not been elucidated. PURPOSE: The aim of our study is to explore the role of CST in cardiomyocytes pyroptosis and myocardial injury in sepsis and whether CST inhibits cardiomyocytes pyroptosis through specific binding with somastatin receptor 2 (SSTR2) and activating AMPK/Drp1 signaling pathway. METHODS AND RESULTS: In this study, plasma CST levels were significantly high and were negatively correlated with N-terminal pro-B type natriuretic peptide (NT-proBNP), a biomarker for cardiac dysfunction, in patients with sepsis. Exogenous administration of CST significantly improved survival rate and cardiac function in mouse models of sepsis by inhibiting the activation of the NLRP3 inflammasome and pyroptosis of cardiomyocytes (decreased cleavage of caspase-1, IL-1ß and gasdermin D). Pharmacological inhibition and genetic ablation revealed that CST exerted anti-pyroptosis effects by specifically binding to somatostatin receptor subtype 2 (SSTR2), thus activating AMPK and inactivating Drp1 to inhibit mitochondrial fission in cardiomyocytes. CONCLUSIONS: This study is the first to report that CST attenuates septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-Drp1-NLRP3 pathway. Importantly, CST specifically binds to SSTR2, which promotes AMPK phosphorylation, inhibits Drp1-mediated mitochondrial fission, and reduces ROS levels, thereby inhibiting NLRP3 inflammasome activation-mediated pyroptosis and alleviating sepsis-induced myocardial injury.

Agricultural drought-driven mechanism of coupled climate and human activities in the karst basin of southern China.

Timely and accurate agricultural drought monitoring and drought-driven mechanism analysis in karst basins in the context of global warming are highly important for drought disaster monitoring and sustainable ecological development in a basin. In this study, based on MODIS data, meteorological and topographic data and land use data from 2001 to 2020, we used the Sen slope, the Mann-Kendall test and a geographic detector to explore the driving mechanisms of agricultural drought caused by climate change and human activities in the karst basin of southern China from 2001 to 2020. The results showed that (1) the spatial distribution of the TVDI in the karst basin in southern China has obvious regional characteristics, showing a decreasing trend from west to east. (2) According to the interannual trend of drought, the degree of drought in the South China karst basin exhibited a weakening trend over the last 20 years, with the most severe drought occurring in 2003. Regarding the seasonal change in the TVDI, drought in spring, summer and autumn exhibited a decreasing trend, while that in winter exhibited an increasing trend, and the drought intensity decreased in the following order: spring (0.58) > autumn (0.53) > summer (0.5) > winter (0.48). (3) Single-factor detection the results showed that rainfall, temperature and elevation were the main factors driving aridification in the study area; multifactor coupling (mean) drove drought in descending order: rainfall (q = 0.424) > temperature (q = 0.340) > elevation (q = 0.219) > land use (q = 0.188) > population density (q = 0.061) > slope (q = 0.057). Therefore, revealing the mechanism of agricultural drought in karst basins through the study of this paper has important theoretical significance and provides technical guidance for drought relief in karst areas.

The allostery and modification of hGHRH molecules and specific dimer produced significant fertility effect by proliferating and activating in-situ ovarian mesenchymal stem cells.

The negative coordination of growth hormone secretagogue receptor (GHS-R) and growth hormone-releasing hormone receptor (GHRH-R) involves in the repair processes of cellular injury. The allosteric U- or H-like modified GHRH dimer Grinodin and 2Y were comparatively evaluated in normal Kunming mice and hamster infertility models induced by CPA treatment. 1-3-9 µg of Grinodin or 2Y per hamster stem-cell-exhaustion model was subcutaneously administered once a week, respectively inducing 75-69-46 or 45-13-50 % of birth rates. In comparison, the similar mole of human menopausal gonadotropin (hMG) or human growth hormone (hGH) was administered once a day but caused just 25 or 20 % of birth rates. Grinodin induced more big ovarian follicles and corpora lutea than 2Y, hMG, hGH. The hMG-treated group was observed many distorted interstitial cells and more connective tissues and the hGH-treated group had few ovarian follicles. 2Y had a plasma lifetime of 21 days and higher GH release in mice, inducing lower birth rate and stronger individual specificity in reproduction as well as only promoting the proliferation of mesenchymal-stem-cells (MSCs) in the models. In comparison, Grinodin had a plasma lifetime of 30 days and much lower GH release in mice. It significantly promoted the proliferation and activation of ovarian MSCs together with the development of follicles in the models by increasing Ki67 and GHS-R expressions, and decreasing GHRH-R expression in a dose-dependent manner. However, the high GH and excessive estrogen levels in the models showed a dose-dependent reduction in fertility. Therefore, unlike 2Y, the low dose of Grinodin specifically shows low GHS-R and high GHRH-R expressions thus evades GH and estrogen release and improves functions of organs, resulting in an increase of fertility.

Propagation thresholds and driving mechanism detection of karst meteorological- agricultural drought: A case study in Guizhou Province.

It is significant to systematically quantify the propagation thresholds of meteorological drought to different levels of agricultural drought in karst areas, and revealit's the propagation driving mechanisms. This can guide early warning and fine management of agricultural drought. In this study,we selected Guizhou Province as an example. The standardized precipitation evapotranspiration index (SPEI) and standardized soil moisture index (SSI) were used to characterize meteorological and agricultural drought. The run theory was used to identify, merge and eliminate drought events. The maximum correlation coefficient was used to capture the propagation time of meteorological-agricultural drought. The regression models were used to quantify the propagation intensity threshold from meteorological drought to different levels of agricultural drought. Finally, the propagation threshold driving mechanism was explored using geographical detectors. The results show that: (1) in terms of temporal variations during the past 21 years, regional meteorological drought had a shorter duration and a higher intensity than agricultural drought, Particularly, 2011 was a year of severe drought, and agricultural drought was significantly alleviated after 2014. (2) In terms of spatial variations, the "long duration area" of meteorological drought duration showed an "S" shaped distribution in the northeast, and the "short duration area" showed a point-like distribution. The overall duration of agricultural drought showed a spatial distribution of northeast to "medium-high in the northeast and low in the southwest. (3) The drought propagation time showed an alternating distribution of "valley-peak-valley-peak" from southeast to northwest. In terms of propagation intensity thresholds, light drought showed an overall spatial distribution of high in the east and low in the west. Moderate, severe, and extreme droughts showed a spatial distribution of low in the center north of southern Guizhou) and high in the borders. (4) There was a strong spatial coupling relationship between karst development intensity, altitude and meteorological-agricultural drought propagation thresholds. The interaction of different factors exhibited a two-factor enhancement and nonlinear enhancement on the propagation threshold. This indicates that synergistic effects of different factors on the propagation threshold were larger than single-factor effects.

Real-world experience of teriflunomide in relapsing multiple sclerosis: paramagnetic rim lesions may play a role.

Objectives: The aims of this study were to report the effectiveness and safety of teriflunomide in Chinese patients with relapsing-remitting multiple sclerosis (RRMS) and to explore the association of paramagnetic rim lesion (PRL) burden with patient outcome in the context of teriflunomide treatment and the impact of teriflunomide on PRL burden. Methods: This is a prospective observational study. A total of 100 RRMS patients treated with teriflunomide ≥3 months were included in analyzing drug persistence and safety. Among them, 96 patients treated ≥6 months were included in assessing drug effectiveness in aspects of no evidence of disease activity (NEDA) 3. The number and total volume of PRL were calculated in 76 patients with baseline susceptibility-weighted imaging (SWI), and their association with NEDA3 failure during teriflunomide treatment was investigated. Results: Over a treatment period of 19.7 (3.1-51.7) months, teriflunomide reduced annualized relapse rate (ARR) from 1.1 ± 0.8 to 0.3 ± 0.5, and Expanded Disability Status Scale (EDSS) scores remained stable. At month 24, the NEDA3% and drug persistence rate were 43.8% and 65.1%, respectively. In patients with a baseline SWI, 81.6% had at least 1 PRL, and 42.1% had ≥4 PRLs. The total volume of PRL per patient was 0.3 (0.0-11.5) mL, accounting for 2.3% (0.0%-49.0%) of the total T2 lesion volume. Baseline PRL number ≥ 4 (OR = 4.24, p = 0.009), younger onset age (OR = 0.94, p = 0.039), and frequent relapses in initial 2 years of disease (OR = 13.40, p = 0.026) were associated with NEDA3 failure. The PRL number and volume were not reduced (p = 0.343 and 0.051) after teriflunomide treatment for more than 24 months. No new safety concerns were identified in this study. Conclusion: Teriflunomide is effective in reducing ARR in Chinese patients with RRMS. Patients with less PRL burden, less frequent relapses, and relatively older age are likely to benefit more from teriflunomide, indicating that PRL might be a valuable measurement to inform clinical treatment decision.

Joint radiomics and spatial distribution model for MRI-based discrimination of multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin-oligodendrocyte-glycoprotein-IgG-associated disorder.

OBJECTIVE: To develop a discrimination pipeline concerning both radiomics and spatial distribution features of brain lesions for discrimination of multiple sclerosis (MS), aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD), and myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). METHODS: Hyperintensity T2 lesions were delineated in 212 brain MRI scans of MS (n = 63), NMOSD (n = 87), and MOGAD (n = 45) patients. To avoid the effect of fixed training/test dataset sampling when developing machine learning models, patients were allocated into 4 sub-groups for cross-validation. For each scan, 351 radiomics and 27 spatial distribution features were extracted. Three models, i.e., multi-lesion radiomics, spatial distribution, and joint models, were constructed using random forest and logistic regression algorithms for differentiating: MS from the others (MS models) and MOGAD from NMOSD (MOG-NMO models), respectively. Then, the joint models were combined with demographic characteristics (i.e., age and sex) to create MS and MOG-NMO discriminators, respectively, based on which a three-disease discrimination pipeline was generated and compared with radiologists. RESULTS: For classification of both MS-others and MOG-NMO, the joint models performed better than radiomics or spatial distribution model solely. The MS discriminator achieved AUC = 0.909 ± 0.027 and bias-corrected C-index = 0.909 ± 0.027, and the MOG-NMO discriminator achieved AUC = 0.880 ± 0.064 and bias-corrected C-index = 0.883 ± 0.068. The three-disease discrimination pipeline differentiated MS, NMOSD, and MOGAD patients with 75.0% accuracy, prominently outperforming the three radiologists (47.6%, 56.6%, and 66.0%). CONCLUSIONS: The proposed pipeline integrating multi-lesion radiomics and spatial distribution features could effectively differentiate MS, NMOSD, and MOGAD. CLINICAL RELEVANCE STATEMENT: The discrimination pipeline merging both radiomics and spatial distribution features of brain lesions may facilitate the differential diagnoses of multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin-oligodendrocyte-glycoprotein-IgG-associated disorder. KEY POINTS: • Our study introduces an approach by combining radiomics and spatial distribution models. • The joint model exhibited superior performance in distinguishing multiple sclerosis from aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorder and myelin-oligodendrocyte-glycoprotein-IgG-associated disorder as well as discriminating the latter two diseases. • The three-disease discrimination pipeline showcased remarkable accuracy, surpassing the performance of experienced radiologists, highlighting its potential as a valuable diagnostic tool.

Causal associations between prodromal infection and neuromyelitis optica spectrum disorder: A Mendelian randomization study.

BACKGROUND AND PURPOSE: Prodromal infections are associated with neuromyelitis optica spectrum disorder (NMOSD), but it remains unclear which type of infection has a causal association with NMOSD. We aimed to explore the causal associations between four herpesvirus infections (chickenpox, cold sores, mononucleosis and shingles) and NMOSD, as well as between other types of infections and NMOSD. METHODS: For data on infections, we used the genome-wide association study (GWAS) summary statistics from the 23andMe cohort. For outcomes, we used the GWAS data of participants of European ancestry, including 215 NMOSD patients (132 anti-aquaporin-4 antibody [AQP4-ab]-positive patients and 83 AQP4-ab-negative patients) and 1244 normal controls. Single-nucleotide polymorphism (SNP) identification and two-sample Mendelian randomization (MR) analyses were then performed. RESULTS: In the 23andMe cohort, we identified one SNP for chickenpox (rs9266089 in HLA-B gene), one SNP for cold scores (rs885950 in the POU5F1 gene), one SNP for mononucleosis (rs2596465 in the HCP5 gene), and three SNPs for shingles (rs2523591 in the HLA-B gene; rs7047299 in the IFNA21 gene; rs9260809 in the MICD gene). The association between cold sores and AQP4-ab-positive NMOSD reached statistical significance (odds ratio [OR] 745.318; 95% confidence interval [CI] 22.176, 25,049.53 [p < 0.001, Q < 0.001]). The association between shingles and AQP4-ab-positive NMOSD was also statistically significant (OR 21.073; 95% CI 4.271, 103.974 [p < 0.001, Q < 0.001]). No significant association was observed between other infections and AQP4-ab-positive or AQP4-ab-negative NMOSD. CONCLUSION: These findings suggest there are positive associations between cold sores and shingles and AQP4-ab-positive NMOSD, indicating there may be causal links between herpes simplex virus and varicella-zoster virus infection and AQP4-ab-positive NMOSD.

What were the spatiotemporal evolution characteristics and the influencing factors of urban land green use efficiency? A case study of the Yangtze River Economic Belt.

China's rapid urbanization has had a tremendous impact on the country's limited land resources, and one of the major issues of green development is how to utilize the limited land resources to maximize social, economic, and environmental advantages. From 2005 to 2019, the super epsilon-based measure model (EBM) was employed to assess the green land use efficiency of 108 prefecture-level and above cities in the Yangtze River Economic Belt (YREB), as well as investigate its spatial and temporal evolution and influential factors. The findings demonstrate that overall, urban land green use efficiency (ULGUE) in the YREB has been ineffective; in terms of city scale, megacities have the highest efficiency, followed by large cities and small and medium-sized cities; and at the regional level, downstream efficiency does have the greatest average value, followed by upstream efficiency and middle efficiency. The results of temporal and spatial evolution reveal that the number of cities with a high ULGUE is increasing in general but that their spatial characteristics are relatively dispersed. Population density, environmental regulation, industrial structure, technology input, and the intensity of urban land investment all have major beneficial effects on ULGUE, whereas urban economic development level and urban land use scale clearly have inhibitory effects. In light of the previous conclusions, some recommendations are made to continuously improve ULGUE.

Clinical feature and disease outcome in patients with myelin oligodendrocyte glycoprotein antibody-associated disorder: a Chinese study.

BACKGROUND: To identify factors associated with relapse risk and disability in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). METHOD: Between 2016 and 2021, 186 patients with MOGAD were included in the study. Factors associated with a relapsing course, annualised relapse rate (ARR), recurrent relapses under different maintenance treatments and unfavourable disability outcome were analysed. RESULTS: MOGAD affects women (53.8%) slightly more often than men. After a median disease duration of 51.0 months, 60.2% (112/186) relapsed, with an overall ARR of 0.5. The ARR (0.6 vs 0.4, p=0.049), median Expanded Disability Status Scale (EDSS) score (1 (range 0-9.5) vs 1 (range 0-3.5), p=0.005) and Visual Functional System Score (VFSS) (0 (range 0-6) vs 0 (range 0-3), p=0.023) at last visit were higher in adults than in children, and time to first relapse was shorter in adults than in children (4.1 (range 1.0-111.0) vs 12.2 (range 1.3-266.8) months, p=0.001). Myelin oligodendrocyte glycoprotein antibody (MOG-ab) persistence over 1 year was associated with a relapsing course (OR 7.41, 95% CI 2.46 to 22.33, p=0.000), while timely maintenance therapy was associated with a lower ARR (p=0.008). More than four attacks (OR 4.86, 95% CI 1.65 to 14.28, p=0.004) and poor recovery from the first attack (OR 75.28, 95% CI 14.45 to 392.05, p=0.000) were associated with an unfavourable outcome (EDSS score ≥2 including VFSS ≥2). CONCLUSIONS: The results underscored the importance of timely maintenance treatment to prevent further relapses, especially in adult patients with persistently positive MOG-ab and unsatisfactory recovery from the onset attack.

Numerical Simulation of Fatigue Cracking of Diaphragm Notch in Orthotropic Steel Deck Model.

Orthotropic steel deck (OSD) are widely used in steel bridges because of their many advantages, but the structures and stresses of OSD are complex and sensitive to fatigue. Based on the model test, the structural fatigue analysis of OSD is carried out by using the extended finite element method (XFEM) to understand and reveal the causes of fatigue detail cracks and the generation and propagation of fatigue cracks at the welding ends of diaphragms, U-ribs, and diaphragms, which are the main structural fatigue details of the deck. The results show that: the fatigue crack at the diaphragm opening is not caused by a single factor, but the horizontal relative displacement is the root-cause of the fatigue crack; the contribution of out-of-plane displacement to the fatigue crack is more significant than that of vertical displacement or in-plane stress, which often leads to the initiation and propagation of the fatigue crack; the crack-propagation direction is perpendicular to the contour of principal stress, and the crack propagates into the plate along the high-stress area in the horizontal direction, which is in accordance with the basic theory of crack propagation. The research methods can provide technical support for the design of similar structures.

Baseline retinal nerve fiber layer thickness as a predictor of multiple sclerosis progression: New insights from the FREEDOMS II study.

BACKGROUND AND PURPOSE: The aim was to evaluate the potential of retinal nerve fiber layer thickness (RNFLT) measured with optical coherence tomography in predicting disease progression in relapsing-remitting multiple sclerosis (RRMS). METHODS: Analyses were conducted post hoc of this 24-month, phase III, double-blind study, in which RRMS patients were randomized (1:1:1) to once daily oral fingolimod 0.5 mg, 1.25 mg or placebo. The key outcomes were the association between baseline RNFLT and baseline clinical characteristics and clinical/imaging outcomes up to 24 months. Change of RNFLT with fingolimod versus placebo within 24 months and time to retinal nerve fiber layer (RNFL) thinning were evaluated. RESULTS: Altogether 885 patients were included. At baseline, lower RNFLT was correlated with higher Expanded Disability Status Scale score (r = -1.085, p = 0.018), lower brain volume (r = 0.025, p = 0.006) and deep gray matter volume (r = 0.731, p < 0.0001), worse visual acuity (r = -19.846, p < 0.0001) and longer duration since diagnosis (r = -0.258, p = 0.018). At month 12, low baseline RNFLT (<86 µm) versus high baseline RNFLT (≥99 µm) was associated with a greater brain volume loss (percentage change -0.605% vs. -0.315%, p = 0.035) in patients without optic neuritis history. At month 24, low baseline RNFLT versus high baseline RNFLT was associated with a higher number of new or newly enlarged T2 lesions (mean number 4.0 vs. 2.8, p = 0.014) and a higher risk of subsequent RNFL thinning (hazard ratio 2.55; 95% confidence interval 1.84-3.53; p < 0.001). The atrophy of the RNFL in the inferior quadrant was alleviated with fingolimod 0.5 mg versus placebo at month 24 (Δ(least squares mean) = 1.8, p = 0.047). CONCLUSION: Retinal nerve fiber layer thickness could predict disease progression in RRMS. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00355134, https://clinicaltrials.gov/ct2/show/NCT00355134.

Deep learning-based relapse prediction of neuromyelitis optica spectrum disorder with anti-aquaporin-4 antibody.

Objective: We previously identified the independent predictors of recurrent relapse in neuromyelitis optica spectrum disorder (NMOSD) with anti-aquaporin-4 antibody (AQP4-ab) and designed a nomogram to estimate the 1- and 2-year relapse-free probability, using the Cox proportional hazard (Cox-PH) model, assuming that the risk of relapse had a linear correlation with clinical variables. However, whether the linear assumption fits real disease tragedy is unknown. We aimed to employ deep learning and machine learning to develop a novel prediction model of relapse in patients with NMOSD and compare the performance with the conventional Cox-PH model. Methods: This retrospective cohort study included patients with NMOSD with AQP4-ab in 10 study centers. In this study, 1,135 treatment episodes from 358 patients in Huashan Hospital were employed as the training set while 213 treatment episodes from 92 patients in nine other research centers as the validation set. We compared five models with added variables of gender, AQP4-ab titer, previous attack under the same therapy, EDSS score at treatment initiation, maintenance therapy, age at treatment initiation, disease duration, the phenotype of the most recent attack, and annualized relapse rate (ARR) of the most recent year by concordance index (C-index): conventional Cox-PH, random survival forest (RSF), LogisticHazard, DeepHit, and DeepSurv. Results: When including all variables, RSF outperformed the C-index in the training set (0.739), followed by DeepHit (0.737), LogisticHazard (0.722), DeepSurv (0.698), and Cox-PH (0.679) models. As for the validation set, the C-index of LogisticHazard outperformed the other models (0.718), followed by DeepHit (0.704), DeepSurv (0.698), RSF (0.685), and Cox-PH (0.651) models. Maintenance therapy was calculated to be the most important variable for relapse prediction. Conclusion: This study confirmed the superiority of deep learning to design a prediction model of relapse in patients with AQP4-ab-positive NMOSD, with the LogisticHazard model showing the best predictive power in validation.

HHcy Induces Pyroptosis and Atherosclerosis via the Lipid Raft-Mediated NOX-ROS-NLRP3 Inflammasome Pathway in apoE-/- Mice.

Lipid rafts play important roles in signal transduction, particularly in responses to inflammatory processes. The current study aimed to identify whether lipid raft-mediated inflammation contributes to hyperhomocysteinemia (HHcy)-accelerated atherosclerosis (AS), and to investigate the underlying mechanisms. THP-1-derived macrophages were used for in vitro experiments. ApoE-/- mice were fed a high-fat diet for 12 weeks to establish an AS model, and a high-fat plus high-methionine diet was used to induce HHcy. We found that homocysteine (Hcy) increased the expression of p22phox and p67phox and promoted their recruitment into lipid rafts (indicating the assembly of the NOX complex), thereby increasing ROS generation and NOX activity, NLRP3 inflammasome activation, and pyroptosis. Mechanistically, Hcy activated the NOX-ROS-NLRP3 inflammasome pathway and induced pyroptosis by increasing the expression of acid sphingomyelinase (ASM) to promote the formation of lipid raft clustering. Importantly, lipid raft-mediated pyroptosis was confirmed in HHcy mice, and HHcy-promoted macrophage recruitment in atherosclerotic lesions and HHcy-aggravated AS were blocked by the lipid raft disruptor methyl-ß-cyclodextrin. The study findings indicate that Hcy promotes lipid raft clustering via the upregulation of ASM, which mediates the assembly of the NOX complex, causing an increase in ROS generation, NLRP3 inflammasome activation, and pyroptosis, and contributes to HHcy-induced AS.

Analysis of Pregnancy-Related Attacks in Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Meta-Analysis.

Importance: Risk of relapse may be increased in the postpartum period of neuromyelitis optica spectrum disorder (NMOSD). Information regarding factors associated with pregnancy-related attacks is still lacking. Objectives: To identify factors associated with pregnancy-related NMOSD attacks, investigate the integrated annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score in each phase of pregnancy, and summarize pregnancy outcomes and complications in patients with NMOSD. Data Sources: An electronic search was performed in the MEDLINE, PubMed in-process and non-MEDLINE, EMBASE, Web of Science, and Cochrane databases using the OvidSP search platform, updated through December 30, 2021. Study Selection: All published and unpublished studies in English were considered, covering all patients with NMOSD with an informative pregnancy. Data Extraction and Synthesis: Two independent reviewers extracted the published data with a standardized procedure following MOOSE and PRISMA guidelines. The end points were calculated with the DerSimonian and Laird inverse variance (for random effects) method. Main Outcomes and Measures: The primary outcome was the rate of pregnancies with pregnancy-related NMOSD attacks, measured by risk ratios (RRs). The mean differences (MDs) in ARR and EDSS scores between each phase of pregnancy, pregnancy outcomes, and complications were defined as the secondary outcomes. Results: A total of 15 studies were analyzed, including 443 patients with NMOSD with 639 informative pregnancies. Patients receiving immunosuppressive treatment during pregnancy (RR, 0.43; 95% CI, 0.32-0.57; P < .001) and with older age at conception (RR, 0.67; 95% CI, 0.47-0.95; P = .02) had lower rates of pregnancy with pregnancy-related attacks. The increase in the ARR was highest in the first trimester after delivery compared with before pregnancy (MD, 1.28; 95% CI, 0.94-1.62; P < .001). The EDSS scores increased significantly both during pregnancy (MD, 0.44; 95% CI, 0.20-0.69; P < .001) and in the postpartum period (MD, 0.88; 95% CI, 0.51-1.26; P < .001) compared with before pregnancy. Conclusions and Relevance: This systematic review and meta-analysis found that receiving immunosuppressive treatment during pregnancy and older age at conception were associated with reduced risk of pregnancy-related NMOSD attacks, which mostly occurred in the first trimester of the postpartum period, although more high-quality prospective studies are needed.

The description of neuromyelitis optica spectrum disorder: Patient registry in Yangtze River Delta area of China.

OBJECTIVE: To describe the clinical features of neuromyelitis optica spectrum disorder (NMOSD) through patient registry in Yangtze River Delta area of China. METHODS: A total of 502 consecutive patients diagnosed with aquaporin-4 antibody (AQP4-ab)-positive NMOSD were registered between December 2018 to January 2021 in multiple tertiary referral centers within the framework of Yangtze River Delta of China. Their baseline data were reviewed, and follow-up clinical information were collected prospectively. RESULTS: The mean age at onset was 37.3 (range 3-80 years) years and the female-to-male ratio was 8.1:1. The median disease duration was 47 months (interquartile range [IQR] 25-84 months). A total of 1372 attacks of the 502 patients were recorded till the last follow-up, with a median annualized relapse rate of 0.4 (IQR 0.3-0.6). Nearly one-fourth (24.5%, 336/1372) of the attacks had prodromic events, including upper respiratory tract infection (36.3%, 122/336), fever (20.2%, 68/336) and pregnancy-related issues (17.9%, 60/336), etc. Myelitis was the most common attack type throughout the disease course (51.4%, 705/1372), followed by optic neuritis (ON, 43.1%, 592/1372). As for onset phenotype, ON (37.3%, 187/502) prevailed over myelitis (28.3%, 142/502). The median time to first relapse was 12 months (IQR 5-25 months). Patients with brainstem encephalitis at onset were more likely to have other anatomical region involved in subsequent attacks (p < 0.001), compared to other onset type. The median serum AQP4-ab titer measured by cell-based assays was 1:100 (IQR 1:32-1:320, range 1:10-1:10,000). The baseline AQP4-ab titer in cerebrospinal fluid (r = 0.542, p <0.001), overall ARR (r = 0.232, p< 0.001) and the EDSS scores at last follow-up (r = 0.119, p = 0.022) significantly correlated with baseline serum AQP4-ab titer. Antinuclear antibodies (48.4%), thyroid peroxidase antibodies (30.7%), and anti-SSA antibodies (26.2%) represented the most frequent concomitant antibodies, while autoimmune thyroid disorders (13.1%, 66/502) and Sjogren's syndrome (10.8%, 54/502) were the most common accompanying autoimmune diseases. Till the last follow-up, 403 patients received preventive treatments. Azathioprine represented the most common initial treatment, mycophenolate mofetil and rituximab was the most common second and third-line treatment, respectively. The EDSS score at the last follow-up ranged from 0 to 8.5 with a median of 2 (IQR 1-3). CONCLUSIONS: A comprehensive clinical picture of patients with AQP4-ab-positive NMOSD in Yangtze River Delta area of China was presented. More information on disease tragedy and predictive prognostic factors could be generated through long-term observations.