Individualized Risk for CKD Progression among US Adults.

BACKGROUND: Chronic kidney disease (CKD) is currently defined using glomerular filtration rate (GFR) or albuminuria. This is based on the relative risk of mortality and kidney outcomes compared to a healthy population and does not consider an individual's absolute risk of CKD progression. METHODS: Using National Health and Nutrition Examination Survey data from 1999-2020, we characterized the individual-level absolute 3-year risk of ≥40% decline in estimated GFR (eGFR, mL/min/1.73 m2) or kidney failure (3-year risk) among US adults. We categorized the 3-year risk and considered ≥5% high risk. RESULTS: Among 199.81 million US adults, 8.42 million (4%) had a 3-year risk ≥5%, including 1.04 million adults without CKD (eGFR ≥60 and albuminuria <30 mg/g). These high-risk adults without CKD as currently defined had risk factors including hypertension (98%), heart failure (72%), and diabetes (44%). 15.51 million adults had CKD with preserved eGFR (eGFR ≥60 and albuminuria ≥30 mg/g)-3.73 million had a 3-year risk ≥5%, 41% of whom did not have diabetes and thus would not be screened for albuminuria using current screening recommendations. The 3-year risk of CKD progression was low (risk <5%) in 94% of the 5.66 million US adults with CKD stage G3a-A1 (eGFR 45 to <60 and albuminuria <30 mg/g). CONCLUSIONS: Assessment of the individual's absolute risk of CKD progression allows further risk stratification of patients with CKD and identifies individuals without CKD, as currently defined, that are at high risk of CKD progression.

Ankle-Brachial Index and Risk of Sudden Cardiac Death in the Community: The ARIC Study.

BACKGROUND: Sudden cardiac death (SCD) is a significant global public health problem accounting for 15% to 20% of all deaths. A great majority of SCD is associated with coronary heart disease, which may first be detected at autopsy. The ankle-brachial index (ABI) is a simple, noninvasive measure of subclinical atherosclerosis. The purpose of this study was to examine the relationship between ABI and SCD in a middle-aged biracial general population. METHODS AND RESULTS: Participants of the ARIC (Atherosclerosis Risk in Communities) study with an ABI measurement between 1987 and 1989 were included. ABI was categorized as low (≤0.90), borderline (0.90-1.00), normal (1.00-1.40), and noncompressible (>1.40). SCD was defined as a sudden pulseless condition presumed to be caused by a ventricular tachyarrhythmia in a previously stable individual and was adjudicated by a committee of cardiac electrophysiologists, cardiologists, and internists. Cox proportional hazards models were used to evaluate the associations between baseline ABI and incident SCD. Of the 15 081 participants followed for a median of 23.5 years, 556 (3.7%) developed SCD (1.96 cases per 1000 person-years). Low and borderline ABIs were associated with an increased risk of SCD (demographically adjusted hazard ratios [HRs], 2.27 [95% CI, 1.64-3.14] and 1.52 [95% CI, 1.17-1.96], respectively) compared with normal ABI. The association between low ABI and SCD remained significant after adjustment for traditional cardiovascular risk factors (HR, 1.63 [95% CI, 1.15-2.32]). CONCLUSIONS: Low ABI is independently associated with an increased risk of SCD in a middle-aged biracial general population. ABI could be incorporated into future SCD risk prediction models.

Regulation of depressive-like behaviours by palmitoylation: Role of AKAP150 in the basolateral amygdala.

BACKGROUND AND PURPOSE: Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe that A-kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive-like behaviours in mice via a palmitoylation-dependent mechanism. EXPERIMENTAL APPROACH: Depressive-like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl-biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2-mediated AKAP150 palmitoylation signalling pathway in depressive-like behaviours. Electrophysiological recording, western blotting and co-immunoprecipitation were performed to define the mechanistic pathway. KEY RESULTS: Chronic stress successfully induced depressive-like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150-PKA interaction with the peptide Ht-31 abolished the CRS-induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS-induced depressive-like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS-treated mice. CONCLUSION AND IMPLICATIONS: These results delineate that DHHC2 modulates chronic stress-induced depressive-like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.

Risk communication in multistakeholder engagement: A novel spatial econometric model.

Existing studies on the environmental Kuznets curve (EKC) neglect the inverse effect of pollution transfer from environmental regulation interactions on pollution reduction from a risk analysis perspective. Based on the regional differentiated attitudes on the environmental regulation reached in risk communication by the risk awareness biases of multiple interest groups, this article clarifies the causality between risk communication and risk transfer based on multistakeholder engagement processes; furthermore, the article incorporates the simultaneous action of the technological innovation effect and pollution risk transfer effect to construct a spatial environmental hyperbolic model with a bidirectional correlation between pollution emissions and economic growth in different regions. To verify our model, we select the pollution from agricultural watersheds in China as a sample to examine the two inverse effects. The results demonstrate that (1) agricultural watershed pollution and economic growth show an inverted U-shaped relation and a U-shaped relation in the local region and adjacent regions, respectively; (2) the pollution reduction assessment of the classical EKC model can be largely attributed to pollution risk transfer behavior; and (3) the turning point of the U-shaped curve appears earlier than that of the inverted U-shaped curve in the spatial hyperbola model. The findings suggest that stakeholders should consider the risk awareness bias caused by the imbalance of regional economic development and the scenarios that provide a "haven" for pollution risk transfer. Moreover, our study expands the theoretical connotation of the classical EKC hypothesis and is more suitable for pollution reduction scenarios in developing countries.

DHHC2 regulates fear memory formation, LTP, and AKAP150 signaling in the hippocampus.

Palmitoyl acyltransferases (PATs) have been suggested to be involved in learning and memory. However, the underlying mechanisms have not yet been fully elucidated. Here, we found that the activity of DHHC2 was upregulated in the hippocampus after fear conditioning, and DHHC2 knockdown impaired fear induced memory and long-term potentiation (LTP). Additionally, the activity of DHHC2 and its synaptic expression were increased after high frequency stimulation (HFS) or glycine treatment. Importantly, fear learning selectively augmented the palmitoylation level of AKAP150, not PSD-95, and this effect was abolished by DHHC2 knockdown. Furthermore, 2-bromopalmitic acid (2-BP), a palmitoylation inhibitor, attenuated the increased palmitoylation level of AKAP150 and the interaction between AKAP150 and PSD-95 induced by HFS. Lastly, DHHC2 knockdown reduced the phosphorylation level of GluA1 at Ser845, and also induced an impairment of LTP in the hippocampus. Our results suggest that DHHC2 plays a critical role in regulating fear memory via AKAP150 signaling.

Ultralow background one-pot detection of Lead(II) using a non-enzymatic double-cycle system mediated by a hairpin-involved DNAzyme.

A double-cycle system has been developed for specifically detecting trace amounts of Pb2+ by significantly decreasing the background signal. The detection involves two types of RNA cleavage reactions: one using a Pb2+-specific GR5 DNAzyme (PbDz) and the other utilizing a newly constructed 10-23 DNAzyme with two hairpins embedded in its catalytic center (hpDz). The ring-structured hpDz (c-hpDz) exhibits significantly lower activity compared to the circular 10-23 DNAzyme without hairpin structures, which plays a crucial role in reducing the background signal. When Pb2+ is present, PbDz cleaves c-hpDz to its active form, which then disconnects the molecular beacon to emit the fluorescent signal. The method allows for rapid and sensitive Pb2+ detection within 40 min for 10 fM of Pb2+ and even as short as 10 min for 100 nM of Pb2+. Additionally, visual detection is possible through the non-crosslinking assembly of Au nanoparticles. The entire process can be performed in one pot and even one step, making it highly versatile and suitable for a wide range of applications, including food safety testing and environmental monitoring.

Factors Associated with Poor Olfaction and Olfactory Decline in Older Adults in the ARIC Neurocognitive Study.

Olfactory function has significant implications for human health, but few risk factors for olfactory decline have been identified. We examined the factors associated with olfactory status and decline over five years in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. A 12-item odor identification test was used to assess olfaction in 6053 participants in 2011-2013 (ARIC visit 5, mean age: 75.6, 41% male, 23% Black race) and in 3235 participants in 2016-2017 (visit 6). We used Poisson regression models to examine cross-sectional associations of a range of potential factors with the total odor identification errors (mean errors: 2.8 ± 2.4) in visit 5 participants. We used mixed-effect Poisson regression to examine associations with olfactory decline between visits 5 and 6. We also examined associations with visit 5 anosmia prevalence (847 cases, 14%) and incident anosmia between the two visits (510 cases, 16%) using Poisson models. Older age, male sex, lower education, Black race, APOE ε4 alleles, and diabetes were associated with higher odor identification errors and higher anosmia prevalence, and greater physical activity and hypertension with better olfaction. Age, male sex, lower education, Black race, APOE ε4 allele, and vitamin B12 levels were associated with incident anosmia over 5 years. Older age was associated with faster olfactory decline. Future studies with longer follow-ups are warranted.

Association of Olfaction and Microstructural Integrity of Brain Tissue in Community-Dwelling Adults: Atherosclerosis Risk in Communities Neurocognitive Study.

BACKGROUND AND OBJECTIVES: Research on olfaction and brain neuropathology may help understand brain regions associated with normal olfaction and dementia pathophysiology. To identify early regional brain structures affected in poor olfaction, we examined cross-sectional associations of microstructural integrity of the brain with olfaction in the Atherosclerosis Risk in Communities Neurocognitive Study. METHODS: Participants were selected from a prospective cohort study of community-dwelling adults; selection criteria included the following: evidence of cognitive impairment, participation in a previous MRI study, and a random sample of cognitively normal participants. Microstructural integrity was measured by 2 diffusion tensor imaging (DTI) measures, fractional anisotropy (FA) and mean diffusivity (MD), and olfaction by a 12-item odor identification test at the same visit. Higher FA and MD values indicate better and worse microstructural integrity, respectively, and higher odor identification scores indicate better olfaction. We used brain region-specific linear regression models to examine associations between DTI measures and olfaction, adjusting for potential confounders. RESULTS: Among 1,418 participants (mean age 76 ± 5 years, 41% male, 21% Black race, 59% with normal cognition), the mean olfaction score was 9 ± 2.3. Relevant to olfaction, higher MD in the medial temporal lobe (MTL) regions, namely the hippocampus (ß -0.79 [95% CI -0.94 to -0.65] units lower olfaction score per 1 SD higher MD), amygdala, entorhinal area, and some white matter (WM) tracts connecting to these regions, was associated with olfaction. We also observed associations with MD and WM FA in multiple atlas regions that were not previously implicated in olfaction. The associations between MD and olfaction were particularly stronger in the MTL regions among individuals with mild cognitive impairment (MCI) compared with those with normal cognition (e.g., ßhippocampus -0.75 [95% CI -1.02 to -0.49] and -0.44 [95% CI -0.63 to -0.26] for MCI and normal cognition, respectively, p interaction = 0.004). DISCUSSION: Neuronal microstructural integrity in multiple brain regions, particularly the MTL (the regions known to be affected in early Alzheimer disease), is associated with odor identification ability. Differential associations in the MTL regions among cognitively normal individuals compared with those with MCI may reflect the earlier vs later effects of the dementia pathogenesis. It is likely that some of the associated regions may not have any functional relevance to olfaction.

Association of Lung Function With Cognitive Decline and Incident Dementia in the Atherosclerosis Risk in Communities Study.

We examined the associations between lung function and incident dementia and cognitive decline in 12,688 participants in the ARIC Study who provided lung function measurements in 1990-1992. Cognitive tests were administered up to 7 times, and dementia was ascertained through 2019. We used shared parameter models to jointly fit proportional hazard models and linear mixed-effect models to estimate lung-function-associated dementia rate and cognitive change, respectively. Higher forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were associated with reduced dementia (n = 2,452 persons developed dementia); hazard ratios per 1-L increase in FEV1 and FVC were 0.79 (95% confidence interval (CI): 0.71, 0.89) and 0.81 (95% CI: 0.74, 0.89), respectively. Each 1-L increase in FEV1 and FVC was associated with a 0.08-standard deviation (SD) (95% CI: 0.05, 0.12) and a 0.05-SD (95% CI: 0.02, 0.07) attenuation of 30-year cognitive decline, respectively. A 1% increase in FEV1/FVC ratio was associated with 0.008-SD (95% CI: 0.004, 0.012) less cognitive decline. We observed statistical interaction between FEV1 and FVC, suggesting that cognitive declines depended on values of specific FEV1 and FVC (as compared with FEV1, FVC, or FEV1/FVC ratio models that suggested linear incremental associations). Our findings may have important implications for reducing the burden of cognitive decline that is attributable to environmental exposures and associated lung function impairment.

Macrocyclization of linear molecules by deep learning to facilitate macrocyclic drug candidates discovery.

Interest in macrocycles as potential therapeutic agents has increased rapidly. Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds, which can contribute to the improvement of the biological activity and physicochemical properties of these molecules. In this study, we propose a computational macrocyclization method based on Transformer architecture (which we name Macformer). Leveraging deep learning, Macformer explores the vast chemical space of macrocyclic analogues of a given acyclic molecule by adding diverse linkers compatible with the acyclic molecule. Macformer can efficiently learn the implicit relationships between acyclic and macrocyclic structures represented as SMILES strings and generate plenty of macrocycles with chemical diversity and structural novelty. In data augmentation scenarios using both internal ChEMBL and external ZINC test datasets, Macformer display excellent performance and generalisability. We showcase the utility of Macformer when combined with molecular docking simulations and wet lab based experimental validation, by applying it to the prospective design of macrocyclic JAK2 inhibitors.

Vertex Strategy in Layered 2D MOFs: Simultaneous Improvement of Thermodynamics and Kinetics for Record C2H2/CO2 Separation Performance.

Developing adsorbents with multiple merits in capacity, selectivity, mass transfer, and stability toward C2H2/CO2 separation is crucial and challenging for producing high-purity C2H2 for advanced polymers and the electronic industry. Here, we demonstrate a vertex strategy to create adsorbents combining these merits through rationally designing the vertex groups of a wavy-shaped framework in layered 2D metal-organic frameworks (MOFs) to finely regulate the local conformation and stacking interactions, which creates the optimal inter- and intralayer space to realize simultaneous improvement of adsorption thermodynamics and kinetics. Two new hydrolytically stable MOFs, ZUL-330 and ZUL-430, were prepared, and diverse experiments and modeling on both adsorption equilibrium and diffusion were performed. Record separation selectivities coupled with extraordinary dynamic C2H2 capacities were achieved for C2H2/CO2 mixtures with different proportions (50/50 or 10/5, v/v), along with a small diffusion barrier and fast mass transfer. Consequently, polymer-grade (99.9%) and electronic-grade (99.99%) C2H2 were obtained with excellent productivities of up to ∼6 mmol cm-3.

Quantified multidimensional public sentiment characteristics on social media for public opinion management: Evidence from the COVID-19 pandemic.

Background: Public sentiments arising from public opinion communication pose a serious psychological risk to public and interfere the communication of nonpharmacological intervention information during the COVID-19 pandemic. Problems caused by public sentiments need to be timely addressed and resolved to support public opinion management. Objective: This study aims to investigate the quantified multidimensional public sentiments characteristics for helping solve the public sentiments issues and strengthen public opinion management. Methods: This study collected the user interaction data from the Weibo platform, including 73,604 Weibo posts and 1,811,703 Weibo comments. Deep learning based on pretraining model, topics clustering and correlation analysis were used to conduct quantitative analysis on time series characteristics, content-based characteristics and audience response characteristics of public sentiments in public opinion during the pandemic. Results: The research findings were as follows: first, public sentiments erupted after priming, and the time series of public sentiments had window periods. Second, public sentiments were related to public discussion topics. The more negative the audience sentiments were, the more deeply the public participated in public discussions. Third, audience sentiments were independent of Weibo posts and user attributes, the steering role of opinion leaders was invalid in changing audience sentiments. Discussion: Since the COVID-19 pandemic, there has been an increasing demand for public opinion management on social media. Our study on the quantified multidimensional public sentiments characteristics is one of the methodological contributions to reinforce public opinion management from a practical perspective.

Combination of Low-Polar and Polar Binding Sites in Aliphatic MOFs for the Efficient C2H6/C2H4 Separation.

The selective capture of C2H6 from C2H6/C2H4 mixtures is of critical importance to realize the efficient one-step purification of C2H4 but remains challenging due to their similar properties and smaller quadrupole moment of C2H6 that usually result in C2H4-preferring adsorption. Herein, we reported two isostructural pillared-layer metal-organic frameworks, ZUL-C3 and ZUL-C4, which were constructed by mixed polycycloalkane-type ligands. Their low-polar pore environment along with more accessible low-polar C-H binding sites on the pore surface are conducive to generate more van der Waals interactions with C2H6 while the carboxylic groups distributed at four corners of pores form stronger and more dipolar interactions with C2H6, cooperatively resulting in a good C2H6/C2H4 uptake ratio of 1.50 for ZUL-C3 and 1.72 for ZUL-C4 in static adsorption experiments and a high C2H4 (>99.99% purity) productivity of 10.1 L/kg for ZUL-C3 and 14.6 L/kg for ZUL-C4 from an equimolar C2H6/C2H4 mixture in breakthrough experiments.

Exposure to acrylamide inhibits testosterone production in mice testes and Leydig cells by activating ERK1/2 phosphorylation.

Acrylamide (ACR) is formed during the cooking of starchy foods at high temperatures. Accumulating evidence has shown that ACR has toxic effects, but the mechanism of its potential reproductive toxicity remains unclear. In this study, we observed that ACR caused weight loss in mice. There was no significant difference in the weight of testis and epididymis between the low/medium-dose ACR group and the control group. And the number of epididymal sperms, testicular Leydig cells, serum testosterone level, testicular steroidogenic genes and enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1) and cytochrome P450 family 17 subfamily A member 1 (CYP17A1), were decreased in the medium/high-dose ACR group. Additional cell experiments showed that the apoptosis rate and the level of reactive oxygen species (ROS) were increased, and testosterone levels and CYP17A1 protein expression were reduced in Leydig cells with treated ACR. Furthermore, the phosphorylation levels of extracellular signal-regulated kinases (ERK1/2) increased significantly; however, there was no significant difference in the levels of serine-threonine protein kinase (AKT) phosphorylation in the testis of mice and Leydig cells treated with ACR. These results suggest that ACR exposure leads to the damage of testicular structure and function and a decline in testosterone synthesis in Leydig cells and mouse testis, which may be related to the activated phosphorylation of ERK1/2.

Prognostic significance of examined lymph node count in older patients with stage T1N0M0 pulmonary carcinoid tumours: a population-based propensity score-matched analysis.

BACKGROUND: The optimal number of examined lymph nodes (ELNs) for older early-stage pulmonary carcinoid tumour (PC) patients is unknown. AIMS: To explore the prognostic effect of the ELN count in older patients with stage T1N0M0 PC resection. METHODS: Clinical data from the Surveillance, Epidemiology, and End Results database on stage T1N0M0 PC older patients (age ≥ 65 years) who underwent sublobar resection and lobectomy between 2000 and 2018 were retrospectively analysed for two ELNs-stratified (≥ 7 vs. < 7 ELNs) propensity score-matched (PSM) groups. Overall survival (OS) was calculated and compared with Kaplan-Meier analysis and log-rank test, respectively, and the independent prognostic factors were estimated using a Cox proportional hazard model. RESULTS: Among 1077 participants (median dissected LN 4; mean ELNs 6.19 ± 7.04), 393 (36.49%) in the ≥ 7 ELNs group had better 5- and 10-year OS than the < 7 ELNs group (before PSM: 5-year OS = 93.01 vs. 85.22%, 10-year OS = 72.38 vs. 58.99%, p < 0.001; after PSM: 5-year OS = 93.12 vs. 85.97%, 10-year OS = 75.25 vs. 60.03%, p = 0.001). Subgroup analysis stratified by histologic type and surgical method showed a similar survival trend. Age-stratified analysis showed that, compared with the < 7 ELNs group, the ≥ 7 ELNs group had better 5- and 10-year OS but only better 5-year OS in participants > 75 years. Compared with the < 7 ELNs group, subgroup analysis by tumour size showed superior OS with 1.1-3.0 cm tumours in the ≥ 7 ELNs group, but no significant intergroup difference with tumours < 1.0 cm. Multivariate Cox analysis showed ≥ 7 ELNs was associated with improved OS. CONCLUSION: Higher ELNs correlated with increased long-term survival in older early­stage PC patients, and a minimum of 7 ELNs are recommended for prognostication in these patients (especially those aged 65-75 years, with tumour size 1.1-3.0 cm).

Concurrent hearing and vision impairment and 8-year memory decline in community-dwelling older adults.

BACKGROUND: Hearing and vision impairments are risk factors for cognitive decline; less is known about dual sensory impairment. This study quantifies the association between dual sensory impairment and 8-year change in memory among older adults. METHODS: Data (N = 5552) were from the National Health and Aging Trends Study. Memory (immediate/delayed word recall, subjective memory) was measured annually (2011 to 2019). Hearing and vision impairments were measured by self-report. Association between dual sensory impairment and 8-year change in memory was assessed using multivariate linear mixed effect models and generalized logistic mixed models. RESULTS: Rate of memory decline was most accelerated among participants with dual sensory impairment. For example, 8-year decline in delayed word recall was -1.03 (95% confidene interval: -1.29, -0.77) for dual sensory impairment versus -0.79 (-0.92, -0.67) for single and -0.56 (-0.63, -0.48) for no impairment. CONCLUSION: Older adults with dual sensory impairment may be at particularly higher risk for cognitive decline.

Traditions and innovations in assessment of glomerular filtration rate using creatinine to cystatin C.

PURPOSE OF REVIEW: Glomerular filtration rate (GFR) is the best index for kidney function and estimated GFR (eGFR) calculated from endogenous filtration markers like serum creatinine and cystatin C is widely used in clinical practice for chronic kidney disease diagnosis and prognostication. We sought to review the evolution of GFR estimating equations, nuances of eGFR interpretation, and utility of eGFR in drug dosing. RECENT FINDINGS: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) serum creatinine eGFR equation was recently updated to exclude the race variable and the CKD-EPI creatinine-cystatin C equation demonstrated the highest reliability. Although calculated creatinine clearance by Cockcroft Gault has been traditionally used for drug dosing, the use of eGFR is slowly being adapted by the Food and Drug Administration for pharmacokinetic studies. However, the individual-level accuracy of eGFR using the CKD-EPI 2021 equations remained low, with the distribution of measured GFR at a given eGFR value spanning several CKD stages. SUMMARY: Although current methods of estimating GFR have improved in population measures of reliability, all have significant individual-level inaccuracies that can be an issue when clinical decision-making is contingent on the actual level of GFR. Modern methods of GFR measurements should be made widely available to enhance individualized patient decision-making.

Quantifying Individual-Level Inaccuracy in Glomerular Filtration Rate Estimation : A Cross-Sectional Study.

BACKGROUND: Although the population-level differences between estimated glomerular filtration rate (eGFR) and measured glomerular filtration rate (mGFR) are well recognized, the magnitude and potential clinical implications of individual-level differences are unknown. OBJECTIVE: To quantify the magnitude and consequences of the individual-level differences between mGFRs and eGFRs. DESIGN: Cross-sectional study. SETTING: Four U.S. community-based epidemiologic cohort studies with mGFR. PATIENTS: 3223 participants in 4 studies. MEASUREMENTS: The GFRs were measured using urinary iothalamate and plasma iohexol clearance; the eGFR was calculated from serum creatinine concentration alone (eGFRCR) and with cystatin C. All GFR results are presented as mL/min/1.73 m2. RESULTS: The participants' mean age was 59 years; 32% were Black, 55% were women, and the mean mGFR was 68. The population-level differences between mGFR and eGFRCR were small; the median difference (mGFR - eGFR) was -0.6 (95% CI, -1.2 to -0.2); however, the individual-level differences were large. At an eGFRCR of 60, 50% of mGFRs ranged from 52 to 67, 80% from 45 to 76, and 95% from 36 to 87. At an eGFRCR of 30, 50% of mGFRs ranged from 27 to 38, 80% from 23 to 44, and 95% from 17 to 54. Substantial disagreement in chronic kidney disease staging by mGFR and eGFRCR was present. Among those with eGFRCR of 45 to 59, 36% had mGFR greater than 60 whereas 20% had mGFR less than 45; among those with eGFRCR of 15 to 29, 30% had mGFR greater than 30 and 5% had mGFR less than 15. The eGFR based on cystatin C did not provide substantial improvement. LIMITATION: Single measurement of mGFR and serum markers without short-term replicates. CONCLUSION: A substantial individual-level discrepancy exists between the mGFR and the eGFR. Laboratories reporting eGFR should consider including the extent of this uncertainty to avoid misinterpretation of eGFR as an mGFR replacement. PRIMARY FUNDING SOURCE: National Institutes of Health.

UC-MSCs promote frozen-thawed ovaries angiogenesis via activation of the Wnt/ß-catenin pathway in vitro ovarian culture system.

BACKGROUND: Ovarian tissue cryopreservation and transplantation are novel therapeutic approaches for fertility preservation. However, follicle loss caused by ischemic and hypoxic damage is one of the issues after frozen-thawed ovarian tissue transplantation. Promoting angiogenesis in grafts is the key to restore cryopreserved ovarian function. Mesenchymal stem cells (MSCs) have been reported to facilitate angiogenesis in the cryopreserved ovarian tissue transplantation. However, the risk of embolization, immunogenic effect and tumorigenesis hinders the clinical application of MSCs to human organ transplantation. In this study, we established an in vitro ovarian culture system to restore frozen-thawed ovarian function before transplantation with the application of umbilical cord mesenchymal stem cells (UC-MSCs), and explored the effects of UC-MSCs on frozen-thawed ovaries in vitro ovarian culture system and the mechanisms of UC-MSCs on the angiogenesis of frozen-thawed ovaries. METHODS: A simple in vitro three dimensional (3D) ovarian culture system using Matrigel was established to support to an ideal niche, and ovary was alone cultured in the 24-well plate as a control. We also evaluated the effects of UC-MSCs treatment on ovarian function with or without Matrigel support. All thawed ovaries were randomly divided into control group (Matrigel-/UC-MSCs-), Matrigel group (Matrigel+/UC-MSCs-), UC-MSCs group (Matrigel-/UC-MSCs+) and UC-MSCs + Matrigel group (Matrigel+/UC-MSCs+). HE staining was used to detect the histological structure of follicles and TUNEL staining was used to detect cell apoptosis. The number of microvessels was counted to evaluate neovascularization. The mRNA expression of VEGFA, IGF1 and ANGPT2 were detected by RT-PCR. Western blotting was used to measure the expression of GSK-3ß, ß-catenin and p-ß-catenin. RESULTS: In the absence of UC-MSCs, 3D culture system supported by Matrigel showed significantly improved follicular development and microvascular number. Additionally, UC-MSCs were also found to effectively improve follicular development and microvascular number regardless of the culture condition used. However, alleviated follicular apoptosis, increased mRNA expression of angiogenesis-related gene and activated Wnt/ß-catenin pathway occurred only in the UC-MSCs + Matrigel group. Besides, with the application of IWP-2 in UC-MSCs + Matrigel group, Wnt//ß-catenin pathway could be blocked by IWP-2 serving as one of Wnt/ß-catenin pathway inhibitors. CONCLUSIONS: This in vitro study showed the beneficial effects of UC-MSCs on thawed ovaries and explored a potential mechanism inducing angiogenesis. In particular, 3D ovarian culture system supported by Matrigel further improved UC-MSCs treatment. The in vitro culture system using Matrigel and UC-MSCs may provide a potential treatment strategy for improving the success rate of thawed ovaries transplantation.