Amyloid pathology mediates the associations between plasma fibrinogen and cognition in non-demented adults.

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.

Predictive Value of CT Enterography Index for Postoperative Intra-abdominal Septic Complications in Patients With Crohn's Disease: Implications for Surgical Decision-Making.

BACKGROUND: Postoperative intra-abdominal septic complications in patients with Crohn's disease undergoing intestinal resection and anastomosis are frequent and difficult to manage. OBJECTIVE: This study sought to explore the value of preoperative CT enterography to predict intra-abdominal septic complications. DESIGN: This was a retrospective and prospective observational study. SETTINGS: This study was conducted in a tertiary referral hospital. PATIENTS: Patients with Crohn's disease undergoing primary intestinal resection were enrolled in our study. MAIN OUTCOME MEASURES: The CT enterography severity index was calculated and its ability to predict intra-abdominal septic complications evaluated by multivariate analyses. A prospective study was then performed to assess the reliability of this CT enterography index. RESULTS: The incidence of postoperative intra-abdominal septic complications in patients undergoing a 1-stage procedure was significantly higher than those undergoing a 2-stage procedure (3/103 vs 24/241; 2.9% vs 10.0%; p = 0.026). A multivariate analysis identified 5 CT enterography parameters, including mesenteric fibrofatty proliferation, intra-abdominal abscess or phlegmon, intestinal fistula, peritoneal effusion, and intestinal dilatation with stricture to be independent predictors of intra-abdominal septic complications (p < 0.001). A nomogram model based on these 5 parameters was constructed. A receiver operating characteristic analysis identified a CT enterography nomogram score cutoff of 175 as a predictor of intra-abdominal septic complications with a sensitivity of 83.3% and a specificity of 85.3%. In the prospective study, those patients with a CT enterography nomogram score >175 were assigned to the 2-stage group, which resulted in a similar intra-abdominal septic complication incidence in those undergoing intestinal resection with or without anastomosis (2/82 vs 2/34; p = 0.355). LIMITATIONS: This study was limited by its single-center scope. CONCLUSIONS: Preoperative CT enterography findings may predict postoperative outcomes and help determine surgical approach in Crohn's disease. Patients with worse intra-abdominal findings confirmed by CT enterography may benefit from stoma creation after intestinal resection. See Video Abstract at http://links.lww.com/DCR/B588. EL VALOR PREDICTIVO DEL NDICE ENTEROGRFICO POR TOMOGRAFA COMPUTADA PARA LAS COMPLICACIONES SPTICAS INTRAABDOMINALES POSTOPERATORIAS EN PACIENTES CON ENFERMEDAD DE CROHN IMPLICACIONES PARA LA TOMA DE DECISIONES QUIRRGICAS: ANTECEDENTES:Las complicaciones sépticas intra-abdominales postoperatorias en pacientes con enfermedad de Crohn sometidos a resección intestinal y anastomosis son frecuentes y difíciles de manejar.OBJETIVO:Este estudio buscó explorar el valor del índice enterográfico por tomografía computada en el pré-operatorio y así poder predecir futuras complicaciones sépticas intra-abdominales.DISEÑO:Estudio observacional retro-prospectivo.AJUSTE:Investigación realizada en un hospital de referencia terciaria.PACIENTES:Se incluyeron en nuestro estudio pacientes con enfermedad de Crohn sometidos a una resección intestinal primaria.PRINCIPALES MEDIDAS DE RESULTADO:Se calculó el índice de gravedad de la enterografía por tomografía axial computada y se evaluó su capacidad para predecir las complicaciones sépticas intra-abdominales mediante un análisis multivariado. Luego se realizó un estudio prospectivo para evaluar la confiabilidad del índice enterográfico por tomografía axial computada.RESULTADOS:La incidencia de complicaciones sépticas intra-abdominales postoperatorias en pacientes sometidos a un procedimiento de un solo tiempo fue significativamente mayor que aquellos sometidos a un procedimiento de dos tiempos (3/103 frente a 24/241; 2,9% frente a 10,0%; p = 0,026). El análisis multivariado identificó cinco parámetros enterográficos por tomografía axial computada, incluidos la proliferación fibrograsa mesentérica, el absceso o flegmón intra-abdominal, la fístula entérica, el derrame peritoneal y la dilatación intestinal debido a estenosis como predictores independientes de complicaciones sépticas intra-abdominales (p <0,001). Se construyó un modelo de Nomograma basado en estos cinco parámetros. Un análisis de las características operatorias del receptor identificó una puntuación de cohortes del nomograma de la enterografía por tomografía axial computada de 175 como predictor de complicaciones sépticas intra-abdominales con una sensibilidad del 83,3% y una especificidad del 85,3%. En el estudio prospectivo, los pacientes con puntuación de nomograma enterográfico por tomografía axial computada superior a 175 fueron asignados al grupo en dos tiempos, lo que resultó en una incidencia similar de complicaciones sépticas intra-abdominales en aquellos sometidos a resección intestinal con o sin anastomosis (2/82 vs. 2/34; p = 0,355).LIMITACIONES:Este estudio estuvo limitado por su alcance unicéntrico.CONCLUSIÓN:Los hallazgos enterográficos por tomografía axial computada pré-operatoria pueden predecir ciertos resultados postoperatorios y ayudar a determinar el abordaje quirúrgico en la enfermedad de Crohn. Los pacientes con peores hallazgos intra-abdominales confirmados por enterografía en la tomografía axial computada podrían beneficiarse de la creación de un estoma después de la resección intestinal. Consulte Video Resumen en http://links.lww.com/DCR/B588. (Traducción-Dr Xavier Delgadillo).

Associations of the neutrophil to lymphocyte ratio with intracranial artery stenosis and ischemic stroke.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has emerged as an inflammatory marker. However, the associations of NLR with intracranial artery stenosis (ICAS) and ischemic stroke remain unclear. This study aimed to examine the associations of NLR with ICAS and ischemic stroke among a large and high-risk population. METHODS: Participants with records of clinical characteristics were prospectively recruited from the Neurology Department and Health & Physical Examination Center of Qingdao Municipal Hospital. Logistic regression analysis was used to examine the associations of NLR with ICAS and ischemic stroke. Moreover, we also conducted parametric mediation analysis to estimate the effect of NLR on the risk of ischemic stroke mediated through ICAS. RESULTS: A total of 2989 participants were enrolled in this study. After adjusting for covariates, NLR (OR = 1.125, 95%CI 1.070-1.183) and ICAS (OR = 1.638, 95%CI 1.364-1.967) were significantly associated with ischemic stroke. Compared with the first quartile NLR, the second, third and fourth quartiles NLR were independent risk predictors for ischemic stroke (P for trend < 0.001); the third and fourth quartiles were independent predictors for ICAS (P for trend < 0.001). The mediation analysis showed that ICAS partially mediated the association between NLR and ischemic stroke, accounting for 14.4% of the total effect (P < 0.001). CONCLUSIONS: NLR was significantly associated with ICAS and ischemic stroke. Besides, ICAS partially mediated the association between NLR and ischemic stroke.

Biometric indicators of eyes with occult lens subluxation inducing secondary acute angle closure.

BACKGROUND: To compare the anterior biometrics in eyes with secondary acute angle closure induced by occult lens subluxation (ASAC-LS), misdiagnosed as acute primary angle closure (APAC) at the first visit with APAC, chronic primary angle closure glaucoma (CPACG), and cataract. METHODS: This retrospective case study included 17 eyes with angel closure due to occult LS, who were misdiagnosed as APAC on their first visit, 56 APAC eyes, 54 CPACG eyes, and 56 cataract eyes. Axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), aqueous depth (AD) and lens thickness (LT) were recorded. Lens position (LP), relative lens position (RLP), corrected lens position (CLP) were calculated. Quantitative data were subject to one-way analysis of variance and correlation analysis. Categorical data were analyzed using the chi-squared test. Receiver operating characteristic (ROC) curves were plotted to obtain a suitable cutoff value of ocular biometrics. RESULTS: The ASAC-LS patients had a longer ocular axial length than APAC and CPACG patients. Central corneal thickness of the ASAC-LS patients was not significantly different from APAC patients, but was significantly different from CPACG and cataract patients. The APAC patients had the smallest ACD, while the ASAC-LS patients had the smallest AD. The ASAC-LS patients had the largest lens thickness. According to ROC curve analysis, RLP, ACD, AD, CLP, LP had high power of discrimination. CONCLUSIONS: This study revealed that LS secondary PAC patients had a shallower AD, thicker CCT comparing to those of APAC, CPACG and cataract patients. For patients with acute angle-closure glaucoma, it is necessary to exclude lens zonula relaxation. TRIAL REGISTRATION: NCT03752710, retrospectively registered.

Risk factors for cognitive decline in non-demented elders with amyloid-beta positivity.

BACKGROUND: As a currently incurable but preventable disease, the prevention and early diagnosis of Alzheimer's disease (AD) has long been a research hotspot. Amyloid deposition has been shown to be a major pathological feature of AD. Notably, not all the people with amyloid-beta (Aß) pathology will have significant cognitive declines and eventually develop AD. Therefore, the aim of this study was to explore the risk factors for cognitive decline in Aß-positive participants. METHODS: We included 650 non-demented participants who were Aß-positive at baseline from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Mixed effects and COX regression models were applied to assess 37 potential risk factors. Mixed effects models were employed to assess the temporal associations between potential risk factors and four cognitive assessment scales. COX regression models were used to assess the impact of potential risk factors on cognitive diagnosis conversion. Univariate and multivariate analyses were applied to the above models. Additionally, we used the Cochran-Armitage trend test to examine whether the incidence of cognitive decline increased with the number concurrent of risk factors. RESULTS: Six factors (low diastolic pressure, low body mass index, retired status, a history of drug abuse, Parkinsonism, and depression) were the identified risk factors and four factors (a history of urinary disease, musculoskeletal diseases, no major surgical history, and no prior dermatologic-connective tissue diseases) were found to be suggestive risk factors. The incidence of cognitive decline in the Aß-positive participants gradually increased as the number of concurrent risk factors increased (p for trend = 0.0005). CONCLUSIONS: Our study may facilitate the understanding of the potential pathological processes in AD and provide novel targets for the prevention of cognitive decline among participants with Aß positivity.

The interrelationships of CSF sTREM2, AD pathology, minimal depressive symptoms, and cognition in non-demented adults.

BACKGROUND: Microglial activation has been suggested to be involved in the pathogenesis of depression and Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a marker of microglial activation. The purpose of this study was to investigate the interrelationships of cerebrospinal fluid (CSF) sTREM2, AD pathology, as well as minimal depressive symptoms (MDSs), and cognition. METHODS: A total of 545 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative cohort were included in our study. The average age of the total population was 72.6 years and the percentage of females was 42.6%. Linear regression models were conducted to investigate the linear relationships of MDSs with CSF sTREM2, AD pathology, cognition, and brain structure. Mediation models and structural equation models (SEM) were conducted to examine whether CSF sTREM2 mediated the relationships of MDSs with AD pathology and cognition. RESULTS: Results revealed that individuals with MDSs had lower CSF sTREM2 levels than normal controls. Linear regression showed that MDSs were linearly associated with CSF sTREM2 (PFDR = 0.012) and amyloid biomarkers (PFDR < 0.05), as well as cognitive scores (PFDR < 0.05) and hippocampal volume (PFDR = 0.003). Mediation analyses revealed that CSF sTREM2 mediated the association between MDSs and amyloid pathology, with the mediating proportions ranging from 6.030 to 18.894%. However, SEM failed to reveal that MDS affected cognition through CSF amyloid pathology and CSF sTREM2. CONCLUSIONS: MDSs are associated with amyloid pathology and cognition. CSF sTREM2 may potentially be an intervenable target between depression and AD pathology.

Identifying modifiable factors and their joint effect on brain health: an exposome-wide association study.

Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.

CAIDE Score, Alzheimer's Disease Pathology, and Cognition in Cognitively Normal Adults: The CABLE Study.

Background: Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score serves as a credible predictor of an individual's risk of dementia. However, studies on the link of the CAIDE score to Alzheimer's disease (AD) pathology are scarce. Objective: To explore the links of CAIDE score to cerebrospinal fluid (CSF) biomarkers of AD as well as to cognitive performance. Methods: In the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, we recruited 600 cognitively normal participants. Correlations between the CAIDE score and CSF biomarkers of AD as well as cognitive performance were probed through multiple linear regression models. Whether the correlation between CAIDE score and cognitive performance was mediated by AD pathology was researched by means of mediation analyses. Results: Linear regression analyses illustrated that CAIDE score was positively associated with tau-related biomarkers, including pTau (p < 0.001), tTau (p < 0.001), as well as tTau/Aß42 (p = 0.008), while it was in negative association with cognitive scores, consisting of MMSE score (p < 0.001) as well as MoCA score (p < 0.001). The correlation from CAIDE score to cognitive scores was in part mediated by tau pathology, with a mediation rate varying from 3.2% to 13.2%. Conclusions: A higher CAIDE score, as demonstrated in our study, was linked to more severe tau pathology and poorer cognitive performance, and tau pathology mediated the link of CAIDE score to cognitive performance. Increased dementia risk will lead to cognitive decline through aggravating neurodegeneration.

Associations between cardiometabolic multimorbidity and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

BACKGROUND: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. METHODS: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. RESULTS: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: ß = 0.165, P = 0.037) and neuronal injury (CSF T-tau: ß = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aß42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. CONCLUSIONS: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.

How far has the globe gone in achieving One Health? Current evidence and policy implications based on global One Health index.

Background: In the 21st century, as globalization accelerates and global public health crises occur, the One Health approach, guided by the holistic thinking of human-animal-environment and emphasizing interdisciplinary collaboration to address global health issues, has been strongly advocated by the international community. An immediate requirement exists for the creation of an assessment tool to foster One Health initiatives on both global and national scales. Methods: Built upon extensive expert consultations and dialogues, this follow-up study enhances the 2022 global One Health index (GOHI) indicator system. The GOHI framework is enriched by covering three indices, e.g. external drivers index (EDI), intrinsic drivers index (IDI), and core drivers index (CDI). The comprehensive indicator system incorporates 13 key indicators, 50 indicators, and 170 sub I-indicators, utilizing a fuzzy analytic hierarchy process to ascertain the weight for each indicator. Weighted and summed, the EDI, IDI, and CDI scores contribute to the computation of the overall GOHI 2022 score. By comparing the ranking and the overall scores among the seven regions and across 160 countries/territories, we have not only derived an overall profile of the GOHI 2022 scores, but also assessed the GOHI framework. We also compared rankings of indicators and sub I-indicators to provide greater clarity on the strengths and weaknesses of each region within the One Health domains. Results: The GOHI 2022 performance reveals significant disparities between countries/territories ranged from 39.03 to 70.61. The global average score of the GOHI 2022 is 54.82. The average score for EDI, IDI, and CDI are 46.57, 58.01, and 57.25, respectively. In terms of global rankings, countries from North America, Europe and Central Asia, East Asia and Pacific present higher scores. In terms of One Health domains of CDI, the lowest scores are observed in antimicrobial resistance (median: 43.09), followed by food security (median: 53.78), governance (median: 54.77), climate change (median: 64.12) and zoonotic diseases (median: 69.23). Globally, the scores of GOHI vary spatially, with the highest score in North America while lowest in sub-Saharan Africa. In addition, evidence shows associations between the socio-demographic profile of countries/territories and their GOHI performance in certain One Health scenarios. Conclusion: The objective of GOHI is to guide impactful strategies for enhancing capacity building in One Health. With advanced technology and an annually updated database, intensifying efforts to refine GOHI's data-mining methodologies become imperative. The goal is to offer profound insights into disparities and progressions in practical One Health implementation, particularly in anticipation of future pandemics.

Optimized production of biodiesel from waste cooking oil by lipase immobilized on magnetic nanoparticles.

Biodiesel, a non-toxic and biodegradable fuel, has recently become a major source of renewable alternative fuels. Utilization of lipase as a biocatalyst to produce biodiesel has advantages over common alkaline catalysts such as mild reaction conditions, easy product separation, and use of waste cooking oil as raw material. In this study, Pseudomonas cepacia lipase immobilized onto magnetic nanoparticles (MNP) was used for biodiesel production from waste cooking oil. The optimal dosage of lipase-bound MNP was 40% (w/w of oil) and there was little difference between stepwise addition of methanol at 12 h- and 24 h-intervals. Reaction temperature, substrate molar ratio (methanol/oil), and water content (w/w of oil) were optimized using response surface methodology (RSM). The optimal reaction conditions were 44.2 °C, substrate molar ratio of 5.2, and water content of 12.5%. The predicted and experimental molar conversions of fatty acid methyl esters (FAME) were 80% and 79%, respectively.

PUFAs add fuel to Crohn's disease-associated AIEC-induced enteritis by exacerbating intestinal epithelial lipid peroxidation.

Polyunsaturated fatty acids (PUFAs) have been shown to exacerbate Crohn's disease (CD) by promoting lipid peroxidation (LPO) of intestinal epithelial cells (IECs). Dysbiosis of the gut microbiota may play a crucial role in this process. CD patients often exhibit an increased abundance of Escherichia coli (E. coli) in the gut, and the colonization of adherent-invasive E. coli (AIEC) is implicated in the initiation of intestinal inflammation in CD. However, the impact of AIEC on LPO remains unclear. In this study, we observed that AIEC colonization in the terminal ileum of CD patients was associated with decreased levels of glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH) in the intestinal epithelium, along with elevated levels of 4-Hydroxynonenal (4-HNE). In vitro experiments demonstrated that AIEC infection reduced the levels of GPX4 and FTH, increased LPO, and induced ferroptosis in IECs. Furthermore, arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation in AIEC-infected IECs significantly aggravated LPO and ferroptosis. However, overexpression of GPX4 rescued AIEC-induced LPO and ferroptosis in IECs. Our results further confirmed that AIEC with AA supplementation, associated with excessive LPO and cell death in IECs, worsened colitis in the DSS mouse model and induced enteritis in the antibiotic cocktail pre-treatment mouse model in vivo. Moreover, treatment with ferrostatin-1, a ferroptosis inhibitor, alleviated AIEC with AA supplementation-induced enteritis in mice, accompanied by reduced LPO and cell death in IECs. Our findings suggest that AIEC, in combination with PUFA supplementation, can induce and exacerbate intestinal inflammation, primarily through increased LPO and ferroptosis in IECs.

Hypoxic ASCs-derived Exosomes Attenuate Colitis by Regulating Macrophage Polarization via miR-216a-5p/HMGB1 Axis.

BACKGROUND: Exosomes derived from mesenchymal stem cells have shown therapeutic effects for colitis. As a more clinically accessible resource, the therapeutic potential of exosomes from adipose-derived stem cells (ASCs) has not been fully elucidated, and whether hypoxia precondition could improve the therapeutic effect of ASC-derived exosomes in colitis remains elusive. METHODS: In this study, exosomes were derived from ASCs under normoxia (NExos) and hypoxia (HExos) and were identified by detecting their morphology, size distribution, and exosome surface markers. The concentration of inflammation-related cytokines was detected by ELISA, and macrophage phenotype-related genes were determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blot, and immunofluorescence. A miRNA microarray sequencing analysis was conducted to confirm the differentially expressed miRNAs. Dextran sulfate sodium-induced colitis was employed as an in vivo assay. RESULTS: Administration of NExos alleviated inflammation by modulating the balance of macrophages both in cellular assays and in vivo experiments, and HExos showed higher therapeutic efficiency than NExos. The miR-216a-5p in HExos was significantly enriched and promoted macrophage M2 polarization through transfer to macrophages by exosomes. The miR-216a-5p was confirmed to target the 3'-UTR of HMGB1. Mechanistically, hypoxia-induced ASCs release miR-216a-5p in an exosomal way that induced macrophage M2 polarization by regulating the HMGB1/TLR4/NF-κB signaling pathway. CONCLUSIONS: Exosomal miR-216a-5p released from hypoxia-prime ASCs showed higher therapeutic efficiency than NExos in experimental colitis by promoting the M2 macrophage phenotype, which indicated that hypoxia prime may represent a promising approach to optimizing the function of ASC-derived exosomes.

Exosomal miR-216a-5p released from hypoxia-prime ASCs showed higher therapeutic efficiency than NExos in experimental colitis by promoting the M2 macrophage phenotype, which indicated that hypoxia prime may represent a promising approach to optimize the function of ASC-derived exosomes.

Cerebral Small Vessel Disease Burden Predicts Neurodegeneration and Clinical Progression in Prodromal Alzheimer's Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: This study aimed to comprehensively investigated the associations of CSVD burden with cognition and AD pathologies. METHODS: A total of 546 non-demented participants (mean age, 72.1 years, range, 55-89; 47.4% female) were included. The longitudinal neuropathological and clinical correlates of CSVD burden were assessed using linear mixed-effects and Cox proportional-hazard models. Partial least squares structural equation model (PLS-SEM) was used to assess the direct and indirect effects of CSVD burden on cognition. RESULTS: We found that higher CSVD burden was associated with worse cognition (MMSE, ß= -0.239, p = 0.006; MoCA, ß= -0.493, p = 0.013), lower cerebrospinal fluid (CSF) Aß level (ß= -0.276, p < 0.001) and increased amyloid burden (ß= 0.048, p = 0.002). In longitudinal, CSVD burden contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. Furthermore, as the results of PLS-SEM, we observed both significant direct and indirect impact of advanced age (direct, ß= -0.206, p < 0.001; indirect, ß= -0.002, p = 0.043) and CSVD burden (direct, ß= -0.096, p = 0.018; indirect, ß= -0.005, p = 0.040) on cognition by Aß-p-tau-tau pathway. CONCLUSION: CSVD burden could be a prodromal predictor for clinical and pathological progression. Simultaneously, we found that the effects were mediated by the one-direction-only sequence of pathological biomarker changes starting with Aß, through abnormal p-tau, and neurodegeneration.

Exosomal miR-103a-3p from Crohn's Creeping Fat-Derived Adipose-Derived Stem Cells Contributes to Intestinal Fibrosis by Targeting TGFBR3 and Activating Fibroblasts.

BACKGROUND AND AIMS: Mesenteric adipose tissue hypertrophy is a hallmark of Crohn's disease [CD], and creeping fat [CF] is unique to CD. Adipose-derived stem cells [ASCs] from inflammatory tissue exhibited altered biological functions. The role of ASCs isolated from CF in intestinal fibrosis and the potential mechanism remain unclear. METHODS: ASCs were isolated from CF [CF-ASCs] and disease-unaffected mesenteric adipose tissue [Ctrl-ASCs] of patients with CD. A series of in vitro and in vivo experiments were conducted to study the effects of exosomes from CF-ASCs [CF-Exos] on intestinal fibrosis and fibroblast activation. A micro-RNA microarray analysis was performed. Western blot, luciferase assay and immunofluorescence were performed to further detect the underlying mechanisms. RESULTS: The results indicated that CF-Exos promoted intestinal fibrosis by activating fibroblasts in a dose-dependent manner. They continuously promoted progression of intestinal fibrosis even after dextran sulphate sodium withdrawal. Further analysis showed that exosomal miR-103a-3p was enriched in CF-Exos and participated in exosome-mediated fibroblast activation. TGFBR3 was identified as a target gene of miR-103a-3p. Mechanistically, CF-ASCs released exosomal miR-103a-3p and promoted fibroblast activation by targeting TGFBR3 and promoting Smad2/3 phosphorylation. We also found that the expression of miR-103a-3p in diseased intestine was positively associated with the degree of CF and fibrosis score. CONCLUSION: Our findings show that exosomal miR-103a-3p from CF-ASCs promotes intestinal fibrosis by activating fibroblasts via TGFBR3 targeting, suggesting that CF-ASCs are potential therapeutic targets for intestinal fibrosis in CD.

Renal function and neurodegenerative diseases : a two-sample Mendelian randomization study.

BACKGROUND: Observational studies showed renal function had associations with Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD) and multiple sclerosis (MS). However, it is unknown whether these associations are causal. METHODS: We use a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between renal function and 6 neurodegenerative diseases (NDDs): AD (including familial AD), PD, LBD, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and MS. Blood urea nitrogen (BUN), chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) were used to measure renal function. The inverse-variance weighted (IVW) was the predominant estimation method. The results were further validated using sensitivity analysis (i.e. MR Egger regression, Cochran Q statistic of IVW, and leave-one-out method). RESULTS: There was no indication of any causative relationship of BUN, CKD, or eGFR with AD, familial AD, PD, LBD, FTD and ALS (all P values >0.05). The IVW analysis demonstrated a causal relationship between eGFR and MS [odds ratio (OR), 4.89; 95% confidence interval (CI), 1.43 to 16.71; P = 0.01] that was not verified in the MR-Egger and weighted median (all P values >0.05). However, no causal association of MS with BUN (OR, 0.91; 95% CI, 0.40-2.07; P = 0.82) and CKD (OR,1.04; 95% CI, 0.88-1.23; P = 0.66) was found. There was no single SNP that affects the overall trend. CONCLUSIONS: Our study showed that reduced eGFR was related to MS. The value of this study is that it provides a direction for further research on the relationship between reduced eGFR and MS.

Associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease: a Mendelian randomization study.

Previous observational studies reported that midlife clustering of cardiovascular risk factors and lifestyle behaviors were associated with neurodegenerative disease; however, these findings might be biased by confounding and reverse causality. This study aimed to investigate the causal associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease, using the two-sample Mendelian randomization design. Genetic variants for the modifiable risk factors and neurodegenerative disease were extracted from large-scale genome-wide association studies. The inverse-variance weighted method was used as the main analysis method, and MR-Egger regression and leave-one-out analyses were performed to identify potential violations. Genetically predicted diastolic blood pressure (DBP: OR per 1 mmHg, 0.990 [0.979-1.000]), body mass index (BMI: OR per 1 SD, 0.880 [0.825-0.939]), and educational level (OR per 1 SD, 0.698 [0.602-0.810]) were associated with lower risk of late-onset Alzheimer's disease (LOAD), while genetically predicted low-density lipoprotein (LDL: OR per 1 SD, 1.302 [1.066-1.590]) might increase LOAD risk. Genetically predicted exposures (including LDL and BMI) applied to familial AD showed the same effect. The association of LDL was also found with Amyotrophic lateral sclerosis (ALS) (LDL: OR per 1 SD, 1.180 [1.080-1.289]). This MR analysis showed that LDL, BMI, BP, and educational level were causally related to AD; a significant association between LDL and ALS risk, as well as the potential effect of sleep duration on PD risk, were also revealed. Targeting these modifiable factors was a promising strategy of neurodegenerative disease prevention.

Plasma ß2-microglobulin and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study.

BACKGROUND: Previous studies have suggested a correlation between elevated levels of ß2-microglobulin (B2M) and cognitive impairment. However, the existing evidence is insufficient to establish a conclusive relationship. This study aims to analyze the link of plasma B2M to cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers and cognition. METHODS: To track the dynamics of plasma B2M in preclinical AD, 846 cognitively healthy individuals in the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups (suspected non-AD pathology [SNAP], 2, 1, 0) according to the NIA-AA criteria. Multiple linear regression models were employed to examine the plasma B2M's relationship with cognitive and CSF AD biomarkers. Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of AD pathology on cognition. RESULTS: We found that the levels of plasma B2M were increased in stages 1 (P = 0.0007) and 2 (P < 0.0001), in contrast to stage 0. In total participants, higher levels of B2M were associated with worse cognitive performance (P = 0.006 for MMSE; P = 0.012 for MoCA). Moreover, a higher level of B2M was associated with decreases in Aß1-42 (P < 0.001) and Aß1-42/Aß1-40 (P = 0.015) as well as increases in T-tau/Aß1-42 (P < 0.001) and P-tau/Aß1-42 (P < 0.001). The subgroup analysis found B2M correlated with Aß1-42 in non-APOE ε4 individuals (P < 0.001) but not in APOE ε4 carriers. Additionally, the link between B2M and cognition was partially mediated by Aß pathology (percentage: 8.6 to 19.3%), whereas tau pathology did not mediate this effect. CONCLUSIONS: This study demonstrated the association of plasma B2M with CSF AD biomarkers as well as a possible important role of Aß pathology in the association between B2M and cognitive impairment, particularly in cognitively normal individuals. The results indicated that B2M could be a potential biomarker for preclinical AD and might have varied functions throughout various stages of preclinical AD progression.

Recognizing and monitoring infectious sources of schistosomiasis by developing deep learning models with high-resolution remote sensing images.

BACKGROUND: China is progressing towards the goal of schistosomiasis elimination, but there are still some problems, such as difficult management of infection source and snail control. This study aimed to develop deep learning models with high-resolution remote sensing images for recognizing and monitoring livestock bovine, which is an intermediate source of Schistosoma japonicum infection, and to evaluate the effectiveness of the models for real-world application. METHODS: The dataset of livestock bovine's spatial distribution was collected from the Chinese National Platform for Common Geospatial Information Services. The high-resolution remote sensing images were further divided into training data, test data, and validation data for model development. Two recognition models based on deep learning methods (ENVINet5 and Mask R-CNN) were developed with reference to the training datasets. The performance of the developed models was evaluated by the performance metrics of precision, recall, and F1-score. RESULTS: A total of 50 typical image areas were selected, 1125 bovine objectives were labeled by the ENVINet5 model and 1277 bovine objectives were labeled by the Mask R-CNN model. For the ENVINet5 model, a total of 1598 records of bovine distribution were recognized. The model precision and recall were 81.9% and 80.2%, respectively. The F1 score was 0.81. For the Mask R-CNN mode, 1679 records of bovine objectives were identified. The model precision and recall were 87.3% and 85.2%, respectively. The F1 score was 0.87. When applying the developed models to real-world schistosomiasis-endemic regions, there were 63 bovine objectives in the original image, 53 records were extracted using the ENVINet5 model, and 57 records were extracted using the Mask R-CNN model. The successful recognition ratios were 84.1% and 90.5% for the respectively developed models. CONCLUSION: The ENVINet5 model is very feasible when the bovine distribution is low in structure with few samples. The Mask R-CNN model has a good framework design and runs highly efficiently. The livestock recognition models developed using deep learning methods with high-resolution remote sensing images accurately recognize the spatial distribution of livestock, which could enable precise control of schistosomiasis.

Crohn's disease-associated AIEC inhibiting intestinal epithelial cell-derived exosomal let-7b expression regulates macrophage polarization to exacerbate intestinal fibrosis.

The interaction between adherent-invasive Escherichia coli (AIEC) and intestinal macrophages is implicated in the pathogenesis of Crohn's disease (CD). However, its role in intestinal fibrogenesis and the underlying molecular mechanisms are poorly understood. In addition, miRNAs such as let-7b may participate in AIEC-macrophage interactions. In this study, we identified that the colonization of AIEC in the ileum was associated with enhanced intestinal fibrosis and reduced let-7b expression by enrolling a prospective cohort of CD patients undergoing ileocolectomy. Besides, AIEC-infected IL-10-/- mice presented more severe intestinal fibrosis and could be improved by exogenous let-7b. Mechanistically, intestinal macrophages were found to be the main target of let-7b. Transferring let-7b-overexpressing macrophages to AIEC-infected IL-10-/- mice significantly alleviated intestinal fibrosis. In vitro, AIEC suppressed exosomal let-7b derived from intestinal epithelial cells (IECs), instead of the direct inhibition of let-7b in macrophages, to promote macrophages to a fibrotic phenotype. Finally, TGFßR1 was identified as one target of let-7b that regulates macrophage polarization. Overall, the results of our work indicate that AIEC is associated with enhanced intestinal fibrosis in CD. AIEC could inhibit exosomal let-7b from IECs to promote intestinal macrophages to a fibrotic phenotype and then contributed to fibrogenesis. Thus, anti-AIEC or let-7b therapy may serve as novel therapeutic approaches to ameliorate intestinal fibrosis.

What is the context?Adherent-invasive Escherichia coli (AIEC) plays an important role in the pathogenesis of Crohn's disease (CD) and has a strong association with intestinal fibrosis in animal models. However, how these bacteria contribute to intestinal fibrosis in CD patients is still unclear.The plasticity of macrophages is crucial in immune tolerance and tissue repair in the gastrointestinal tract, and the abnormal interaction between macrophages and gut bacteria triggers the fibrogenesis in the intestine.The association between the miRNA let-7b and fibrosis process has been widely reported in many tissues, except the intestine.What is new?AIEC colonization in the terminal ileum is associated with severe intestinal fibrosis in CD patients and the let-7b plays an anti-fibrotic role in intestinal fibrosis.Intestinal macrophages are the key modulator of AIEC-induced fibrosis and can be promoted to an antifibrotic phenotype through let-7b-targeted TGFßR1 inhibition.AIEC suppresses intestinal epithelial cell-derived exosomal let-7b to promote intestinal macrophages to a fibrotic phenotype, rather than a direct effect on macrophage regulation.What is the impact? Anti-AIEC and let-7b therapy may serve as potential therapeutic strategies to reduce intestinal fibrosis in CD in the future.