Improved green and red GRAB sensors for monitoring dopaminergic activity in vivo.

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.

Clinical assessment of cardiac impairment favored by two-dimensional speckle tracking echocardiology in patients with systemic sclerosis.

BACKGROUND: Cardiac involvement is a major cause of death in SSc, while early detection remains a challenge. OBJECTIVES: The purpose of this study was to investigate the prevalence and clinical implications of cardiac impairment in SSc. METHODS: Ninety-five consecutive SSc patients [55.6 (13.8) years old, 5.3 (8.1) years from diagnosis] were included in the study. Patients with heart diseases onset prior to SSc were excluded. All patients underwent two-dimensional speckle-tracking echocardiology (2D-STE) with measuring left and right ventricular global longitudinal strain (GLS/RGLS). Clinical manifestation, laboratory evaluation (CRP, cTnI, antibodies, etc.) and ECG were collected at the same time. Comparisons between the SSc subgroups (lcSSc and dcSSc) were performed using Student's t-test, Mann-Whitney U or Fisher's exact test. Binary logistic regression was applied to determine the independent effects of variables in cardiac impairment. RESULTS: Early left and right ventricular impairment measured by GLS and RGLS were detected in 22.1% and 24.2% of the SSc patients, respectively. In comparison, only 2.1% showed reduced left ventricular ejection fraction (LVEF). Impaired GLS was mainly observed in the basal and medial segments of anterior, lateral and posterior left ventricle walls, and more profound in dcSSc. Elevated CRP (OR 3.561 95% CI: 1.071, 11.839, P <0.05) was associated with reduced GLS/RGLS. The adoption of GLS/RGLS enhanced the efficacy of routine screening for cardiac impairment that 52.6% of patients showed potential cardiac impairment. CONCLUSIONS: Cardiac impairment is a common manifestation in SSc. Increasing awareness of early cardiac impairment is warranted with elevated CRP and dcSSc.

Association of central arterial blood pressure and left ventricular hypertrophy in patients with chronic kidney disease.

AIMS: In the general population, central arterial blood pressure has proved to be more closely related to left ventricular hypertrophy (LVH) than brachial arterial blood pressure. We aimed to investigate whether this relationship was true in patients with chronic kidney disease (CKD). METHODS: In this retrospective study, we reviewed the medical records of 289 adult patients with CKD from the Zhejiang Provincial People's Hospital in Zhejiang, China. Demographic, echocardiographic and brachial and central blood pressure parameters were retrieved from medical records. Central blood pressure was measured using the SphygmoCor® CvMS (AtCor, Australia) device and its corresponding software. Multivariate logistic regression analyses were performed to identify independent predictors of LVH. Receiver operating characteristic curves were used to determine the ability of central and brachial blood pressure to predict LVH. RESULTS: The left ventricular mass index was positively associated with both central and brachial blood pressures. However, multiple logistic regression analysis demonstrated that a central pulse pressure (CPP) ≥ 58 mm Hg was an independent risk factor for LVH (OR = 5.597, 95%CI 2.363-13.259, p < .001). Brachial pulse pressure is not superior to CPP in predicting LVH (area under the curve [AUC] = 0.695, 95%CI 0.634-0.756, p < .001 vs. AUC = 0.687, 95%CI: 0.626-0.748, p < .001, respectively; p = .4824). CONCLUSION: Our results suggested that, similarly to the general population, CPP is a better parameter for predicting the occurrence of LVH in patients with CKD.

A multi-predictor model to predict risk of scleroderma renal crisis in systemic sclerosis: a multicentre, retrospective, cohort study.

OBJECTIVES: Scleroderma renal crisis (SRC) is a life-threatening syndrome. The early identification of patients at risk is essential for timely treatment to improve the outcome. Therefore, it is of great interest to provide a personalised tool to predict risk of SRC in systemic sclerosis (SSc). METHODS: We tried to set up a SRC prediction model based on the PKUPH-SSc cohort of 302 SSc patients. The least absolute shrinkage and selection operator (Lasso) regression was used to optimise disease features. Multivariable logistic regression analysis was applied to build a SRC prediction model incorporating the features of SSc selected in the Lasso regression. Then, a multi-predictor nomogram combining clinical characteristics was constructed and evaluated by discrimination and calibration, with further assessment by external validation in a validation cohort composed of 400 consecutive SSc patients from other 4 tertiary hospitals. RESULTS: A multi-predictor nomogram for evaluating the risk of SRC was successfully developed. In the nomogram, four easily available predictors were contained, including disease duration <2 years, cardiac involvement, anaemia and corticosteroid >15mg/d exposure. The nomogram displayed good discrimination with an area under the curve (AUC) of 0.843 (95% CI: 0.797-0.882) and good calibration. High AUC value of 0.854 (95% CI: 0.690-1.000) could still be achieved in the external validation. The model is now available online for research use. CONCLUSIONS: The multi-predictor nomogram for SRC could be reliably and conveniently used to predict the individual risk of SRC in SSc patients, and be a step towards more personalised medicine.

The association between dyslipidemia and the incidence of chronic kidney disease in the general Zhejiang population: a retrospective study.

BACKGROUND: According to the "lipid nephrotoxicity hypothesis", there is now significant research being conducted in this area. By studying the role of hyperlipidemia in chronic kidney disease in the general Zhejiang population, we aimed to explore the correlation between changes in blood lipid levels and chronic kidney disease. METHODS: We collected and analyzed clinical data from ordinary residents who participated in the annual comprehensive physical examination with no overt kidney disease in Zhejiang Provincial People's Hospital, China from January 2011 to December 2016. According to triglyceride, total cholesterol and low-density lipoprotein levels, participants were respectively divided into 4 groups. Statistical methods were used to evaluate the correlation between different blood lipid profiles and chronic kidney disease. RESULTS: Five thousand one hundred eighty-three participants were included in our study. During the six-year follow-up period, 227 participants (4.4%) developed chronic kidney disease. The odds ratio for incident chronic kidney disease was 3.14 (95%CI: 1.53-6.43) in Q3, 3.84 (95%CI: 1.90-7.76) in Q4 according to the total cholesterol group and 1.17 (95%CI: 1.04-1.32) in Q3, 1.40 (95%CI: 1.11-2.48) in Q4 according to the low-density lipoprotein group, respectively, after multivariable-adjusted analyses. According to the triglyceride grouping, the odds ratio for incident chronic kidney disease was 2.88 (95%CI: 1.29-6.43) in Q2, 2.92 (95%CI: 1.44-6.57) in Q3 and 3.08 (95%CI: 1.11-6.69) in Q4, after multivariable-adjusted analyses. CONCLUSION: Increased triglycerides and high levels of total cholesterol and low-density lipoprotein were independently associated with an increased likelihood of estimated glomerular filtration rate (eGFR) decline and development of incident chronic kidney disease in the general Zhejiang population.

An octopamine-specific GRAB sensor reveals a monoamine relay circuitry that boosts aversive learning.

Octopamine (OA), analogous to norepinephrine in vertebrates, is an essential monoamine neurotransmitter in invertebrates that plays a significant role in various biological functions, including olfactory associative learning. However, the spatial and temporal dynamics of OA in vivo remain poorly understood due to limitations associated with the currently available methods used to detect it. To overcome these limitations, we developed a genetically encoded GPCR  activation-based (GRAB) OA sensor called GRABOA1.0. This sensor is highly selective for OA and exhibits a robust and rapid increase in fluorescence in response to extracellular OA. Using GRABOA1.0, we monitored OA release in the Drosophila mushroom body (MB), the fly's learning center, and found that OA is released in response to both odor and shock stimuli in an aversive learning model. This OA release requires acetylcholine (ACh) released from Kenyon cells, signaling via nicotinic ACh receptors. Finally, we discovered that OA amplifies aversive learning behavior by augmenting dopamine-mediated punishment signals via Octß1R in dopaminergic neurons, leading to alterations in synaptic plasticity within the MB. Thus, our new GRABOA1.0 sensor can be used to monitor OA release in real time under physiological conditions, providing valuable insights into the cellular and circuit mechanisms that underlie OA signaling.

An octopamine-specific GRAB sensor reveals a monoamine relay circuitry that boosts aversive learning.

Octopamine (OA), analogous to norepinephrine in vertebrates, is an essential monoamine neurotransmitter in invertebrates that plays a significant role in various biological functions, including olfactory associative learning. However, the spatial and temporal dynamics of OA in vivo remain poorly understood due to limitations associated with the currently available methods used to detect it. To overcome these limitations, we developed a genetically encoded GPCR activation-based (GRAB) OA sensor called GRABOA1.0. This sensor is highly selective for OA and exhibits a robust and rapid increase in fluorescence in response to extracellular OA. Using GRABOA1.0, we monitored OA release in the Drosophila mushroom body (MB), the fly's learning center, and found that OA is released in response to both odor and shock stimuli in an aversive learning model. This OA release requires acetylcholine (ACh) released from Kenyon cells, signaling via nicotinic ACh receptors. Finally, we discovered that OA amplifies aversive learning behavior by augmenting dopamine-mediated punishment signals via Octß1R in dopaminergic neurons, leading to alterations in synaptic plasticity within the MB. Thus, our new GRABOA1.0 sensor can be used to monitor OA release in real-time under physiological conditions, providing valuable insights into the cellular and circuit mechanisms that underlie OA signaling.

Monitoring norepinephrine release in vivo using next-generation GRABNE sensors.

Norepinephrine (NE) is an essential biogenic monoamine neurotransmitter. The first-generation NE sensor makes in vivo, real-time, cell-type-specific and region-specific NE detection possible, but its low NE sensitivity limits its utility. Here, we developed the second-generation GPCR-activation-based NE sensors (GRABNE2m and GRABNE2h) with a superior response and high sensitivity and selectivity to NE both in vitro and in vivo. Notably, these sensors can detect NE release triggered by either optogenetic or behavioral stimuli in freely moving mice, producing robust signals in the locus coeruleus and hypothalamus. With the development of a novel transgenic mouse line, we recorded both NE release and calcium dynamics with dual-color fiber photometry throughout the sleep-wake cycle; moreover, dual-color mesoscopic imaging revealed cell-type-specific spatiotemporal dynamics of NE and calcium during sensory processing and locomotion. Thus, these new GRABNE sensors are valuable tools for monitoring the precise spatiotemporal release of NE in vivo, providing new insights into the physiological and pathophysiological roles of NE.

The value of shear wave elastography in diagnosis and assessment of systemic sclerosis.

Objective: The aim was to determine the efficacy of shear wave elastography (SWE) in assessing skin stiffness and aiding in the diagnosis of patients with systemic sclerosis (SSc). Methods: A total of 66 patients with SSc, 100 healthy individuals and 27 patients with SSc-like disorders were included. SWE was performed at 17 modified Rodnan skin score (mRSS) measurement sites. The correlation between SWE and clinical profiles was assessed, and the diagnostic value of SSc was explored. Results: The SWE values at all 17 mRSS sites were significantly higher in SSc than in the healthy group [54.95 (45.95, 66.55) vs 41.10 (39.18, 45.45) m/s, P < 0.001]. For clinically uninvolved sites (mRSS = 0) of patients with SSc, 11 of 17 sites showed significantly higher SWE values compared with healthy controls. SWE was positively correlated with total mRSS (r = 0.783, P < 0.001), the European Scleroderma Study Group disease activity index (r = 0.707, P < 0.001) and histological collagen deposition (r = 0.749, P = 0.013). SWE effectively distinguished patients with SSc from patients with SSc-like disorders (area under the curve, AUC = 0.819). Use of SWE-detected skin sclerosis showed a significantly higher sensitivity compared with 1980 ACR criteria [0.818 (95% CI 0.709, 0.893) vs 0.727 (95% CI 0.610, 0.820), P = 0.031]. Conclusion: SWE correlates well with disease activity and collagen deposition in the skin, provides greater reliability than mRSS and aids in the diagnosis of SSc. SWE could be considered as a convenient and reliable quantitative tool for assessing skin sclerosis and disease progression in SSc.

Impact of targeted therapies on the risk of cardiovascular events in patients with psoriasis and psoriatic arthritis: A systematic review and aggregate data meta-analysis of randomized controlled trials.

OBJECTIVE: We aimed to investigate the effect of targeted therapies on cardiovascular risk in psoriasis (PsO) and psoriatic arthritis (PsA) via a meta-analysis of randomized controlled trials (RCTs). METHODS: Pubmed, Embase, Cochrane Library, and Scopus were searched for RCTs reporting targeted therapies in patients with PsO/PsA published until 28 October 2021. The primary and secondary outcomes included the relationship between targeted therapies and all cardiovascular events (CVEs), major adverse cardiovascular events (MACEs), myocardial infarction (MI), heart failure, and stroke in PsO/PsA. The outcome risk ratios (RRs) were calculated using the Mantel-Haenszel fixed-effect method. RESULTS: A total of 81 articles involving 88 RCTs were included. There was no statistically significant difference regarding the occurrence of all CVEs for all targeted therapies (RR = 1.03, 95% CI 0.74-1.43, P = .85) compared to placebo in PsO/PsA. No statistically significant difference existed between drugs and placebo in patients with PsA on all CVEs (RR = 0.81, 95% CI 0.48-1.36, P = .43). Surprisingly, the incidence of all CVEs was higher in the low dosage group compared to the high dosage group of all targeted therapies (RR = 1.97, 95% CI 1.19-3.27, P = .008) and prominently anti-interleukin-17 agent (RR = 2.20, 95% CI 1.05-4.58, P = .04). CONCLUSION: Current targeted therapies are not associated with the risk of CVEs. Based on the existing evidence, we reported here that a dosage reduction of targeted therapies was not recommended.

Detection of NDM-1 and OXA-10 Co-Producing Providencia rettgeri Clinical Isolate.

Background: The coexistence of blaNDM-1 with other resistance determinants is rarely reported for Providencia rettgeri. Therefore, this study investigates the phenotypic and genetic characteristics of a multidrug-resistant P. rettgeri strain YQ150713. Methods: P. rettgeri YQ150713 was identified as carrying blaNDM-1. S1-pulsed-field gel electrophoresis (S1-PFGE), Southern blotting, and conjugation experiments were used to determine plasmid characteristics. An antimicrobial susceptibility test was conducted. The complete genomic sequence of YQ150713 was obtained using Illumina NovaSeq 6000 and Oxford nanopore platforms. To further characterize the phylogenetic structure of P. rettgeri YQ150713, average nucleotide identity (ANI) and phylogenetic analyses were conducted. Results: The S1-PFGE, Southern blot, and conjugation assays have confirmed that the isolate P. rettgeri YQ150713 contains the blaNDM-1 gene on a conjugative plasmid pYQ150713-NDM-1. Antimicrobial susceptibility testing has indicated that strain YQ150713 was resistant to various common antibiotics, except aztreonam and fosfomycin. Bioinformatics analysis has further shown that pYQ150713-NDM-1 was a novel plasmid with a size of 265,883 bp, and blaNDM-1 and blaOXA-10 were co-located on it. Phylogenetic analysis suggesting P. rettgeri has spread widely throughout the world. Conclusion: In this study, blaNDM-1 and blaOXA-10 were co-localized on a novel plasmid pYQ150713-NDM-1 with a horizontal transfer function. To reduce the risk of the dissemination of such P. rettgeri isolates in clinical settings, more surveillance will be required in the future.

Improved dual-color GRAB sensors for monitoring dopaminergic activity in vivo.

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a vast network of dopaminergic projections. To fully dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent GPCR activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity, and signal-to-noise properties with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in freely moving mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala, and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.

Association Between Four Anthropometric Indexes and Metabolic Syndrome in US Adults.

Objective: To study the association between anthropometric indexes [lipid accumulation products (LAP), visceral obesity index (VAI), triglyceride and glucose index (TyG) and waist triglyceride index (WTI)] and metabolic syndrome (MetS) in a representative sample of American adult population surveyed by National Health and Nutrition Examination Survey (NHANES). Methods: Cross-sectional data from the NHANES were used. Participants were adults aged 18-80 y from 1996-2006. MetS were defined by the updated National Cholesterol Education Program/Adult Treatment Panel III criteria (NCEP-ATP III) for Americans. Receiver operating characteristic (ROC) curve was drawn and the areas under the curve (AUC) were used to assess the ability of these indexes in screening MetS. Statistical differences among the AUC values of these indexes were compared. The association between the anthropometric indexes and MetS was investigated using weighted multivariable-adjusted logistic regression. Results: 560 (35.2%) males and 529 (26.4%) females were diagnosed with MetS. LAP was the strongest predictor of MetS for men (AUC=0.87, 95% CI 0.85-0.89), and also was the strongest for women [AUC=0.85, 95% confidence interval (CI) 0.83-0.86], according to the ROC curve analysis. In men, differences in AUC values between LAP and other anthropometric indicators were also significant (all P<0.001). In women, there was a significant difference in AUC values between LAP and WTI (P<0.001), but differences in AUC values between LAP and TyG, VAI were not significant. Conclusion: The present study indicated that LAP is a better predictor in the clinical setting for identifying individuals with MetS in the American adult population.

A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo.

Endocannabinoids (eCBs) are retrograde neuromodulators with important functions in a wide range of physiological processes, but their in vivo dynamics remain largely uncharacterized. Here we developed a genetically encoded eCB sensor called GRABeCB2.0. GRABeCB2.0 consists of a circular-permutated EGFP and the human CB1 cannabinoid receptor, providing cell membrane trafficking, second-resolution kinetics with high specificity for eCBs, and shows a robust fluorescence response at physiological eCB concentrations. Using GRABeCB2.0, we monitored evoked and spontaneous changes in eCB dynamics in cultured neurons and acute brain slices. We observed spontaneous compartmentalized eCB transients in cultured neurons and eCB transients from single axonal boutons in acute brain slices, suggesting constrained, localized eCB signaling. When GRABeCB2.0 was expressed in the mouse brain, we observed foot shock-elicited and running-triggered eCB signaling in the basolateral amygdala and hippocampus, respectively. In a mouse model of epilepsy, we observed a spreading wave of eCB release that followed a Ca2+ wave through the hippocampus. GRABeCB2.0 is a robust probe for eCB release in vivo.

Mortality in chronic kidney disease patients with COVID-19: a systematic review and meta-analysis.

At the beginning of 2020, the outbreak of coronavirus disease 2019 (COVID-19) led to a worldwide pandemic and mass panic. The number of infected people has been increasing exponentially since, and the mortality rate has also been concomitantly increasing. At present, no study has summarized the mortality risk of COVID-19 in patients with chronic kidney disease (CKD). Therefore, the aim of the present study was to conduct a literature review and meta-analysis to understand the frequency of mortality among CKD patients infected with COVID-19. A comprehensive systematic search was conducted on the PubMed, Embase, and Cochrane databases to find articles published until May 15, 2020. Study quality was assessed using a modified version of the Newcastle-Ottawa Scale. After careful screening based on the inclusion and exclusion criteria, 3,867,367 patients from 12 studies were included. The mortality rate was significantly higher among CKD patients with COVID-19 infection than among CKD patients without COVID-19 infection, as indicated by a pooled OR of 5.81 (95% CI 3.78-8.94, P < 0.00001, I2 = 30%). The patients were then stratified into ≥ 70 and < 70 years, and subgroup analysis revealed that among CKD patients with COVID-19 infection, the mortality rate was higher in the < 70 years group (OR 8.69, 95% CI 7.56-9.97, P < 0.0001) than in the ≥ 70 years group (OR 2.44, 95% CI 0.75-6.63, P = 0.15). Thus, COVID-19 patients with CKD have a high mortality risk and require a comprehensive multidisciplinary management strategy.

The effects of written catharsis on anger relief.

Previous studies have found that "general catharsis", such as hitting sandbags, does not reduce but increases an individual's anger feeling and aggressive behavior. Although the "goal catharsis" that is directed at attacking targets can temporarily relieve anger, there is a risk of increasing the tendency of aggressive personality if it is used for a long time. These findings raise serious doubts and challenges to the traditional view that "anger must be released" held by the classic catharsis theory that many people still trust. The present study compared the effects of "general catharsis" and "goal catharsis" on anger-related responses among Chinese people, and the Chinese written form of catharsis was used in this study. The results showed that after participants were provoked, the aggressive behavior of participants who wrote down their dissatisfaction (general catharsis condition) was significantly higher than that of participants who wrote to attack someone who irritated them (goal catharsis condition) as well as that of participants who completed a simple recall task (control condition), and there was no significant difference in the aggressive behavior level between the latter two cases. These results suggest that the catharsis effect is no better than a simple recall task similar to attention distraction, that is, aggressive catharsis is not an effective way for anger relief.

Clinical outcomes of COVID-19 in patients with rheumatic diseases: A systematic review and meta-analysis of global data.

OBJECTIVES: The impact of rheumatic diseases on COVID-19 infection remains poorly investigated. Here we performed a systematic review and meta-analysis to evaluate the outcomes of COVID-19 in patients with rheumatic diseases. METHODS: We systematically searched PubMed, Embase, Cochrane Library, Scopus and preprint database up to 29th August 2020, for publications with confirmed COVID-19 infection in patients with rheumatic diseases. The primary outcomes were the rates of hospitalization, oxygen support, intensive care unit (ICU) admission and death. A meta-analysis of effect sizes using the random-effects models was performed, and meta-regression analyses were performed to explore heterogeneity. The data from the COVID-19 Global Rheumatology Alliance physician registry (the COVID-19 GRA) was used as a reference. RESULTS: A total of 31 articles involving 1138 patients were included in this systematic review and meta-analysis. The publications were from Europe, Asia and North America, but none from other continents. The overall rates of hospitalization, oxygen support, ICU admission and fatality among COVID-19 infected patients with rheumatic diseases were 0.58 (95% confidence interval (CI) 0.48-0.67), 0.33 (95% CI 0.21-0.47), 0.09 (95% CI 0.05-0.15) and 0.07 (95% CI 0.03-0.11), respectively. The rate of oxygen support in Europe (0.48, 95% CI 0.4-0.57) was higher than that in other continents. Among all hospitalized patients, the rates of oxygen support, ICU admission and fatality were 0.61 (95% CI 0.48-0.73), 0.13 (95% CI 0.07-0.21) and 0.13 (95% CI 0.09-0.18), respectively. The fatality rate was highest in Europe (0.19, 95% CI 0.15-0.24). The fatality rate was higher both in this meta-analysis and the COVID-19 GRA (7.0% and 6.7%, respectively) than that (3.4%) in WHO database, although the age, gender and comorbidity were not matched. CONCLUSION: Patients with rheumatic diseases remain vulnerable with substantial rates of severe outcomes and a geographic variation. More studies were urgently needed to elucidate the risk factors of severe outcomes in this population.

The safety and efficacy of low-dose mineralocorticoid receptor antagonists in dialysis patients: A meta-analysis.

INTRODUCTION: Our aim was to evaluate the safety and efficacy of low-dose mineralocorticoid receptor antagonists (MRAs) in dialysis patients. METHODS: We systematically searched PubMed, EMBASE, and Cochrane libraries for clinical trials on the use of MRAs in dialysis patients. Review Manager 5.3 software was used to analyze relevant data and evaluate the quality of evidence. RESULTS: We identified nine randomized controlled trials including 1128 chronic dialysis patients. In terms of safety, when hyperkalemia was defined as serum potassium level ≥5.5 mmol/L, low-dose MRAs were significantly associated with hyperkalemia (relative risk [RR] 1.76, 95% confidence intervals [CI] 1.07-2.89, P = .02); however, when hyperkalemia was defined as serum potassium level ≥6.0 mmol/L or serum potassium level ≥6.5 mmol/L, no significant association was observed between low-dose MRAs and hyperkalemia (RR 1.40, 95% CI 0.83-2.37, P = .20; RR 1.98, 95% CI 0.91-4.30, P = .09, respectively). Use of low-dose MRAs can reduce cardiovascular mortality by 54% compared with the control group (0.46, 95% CI 0.28-0.76, P = .003). Similarly, the RR of all-cause mortality for the low-dose MRAs group was 0.48 (95% CI 0.33-0.72, P = .0003). CONCLUSION: Low-dose MRAs may benefit dialysis patients without significantly increasing moderate to severe hyperkalemia.

Differential Expression of Urinary Exosomal Small RNAs in Idiopathic Membranous Nephropathy.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is a major cause of adult nephrotic syndromes, and reliable noninvasive biomarkers for diagnosis and monitoring are urgently needed. In this study, we performed small RNA (sRNA) sequencing to explore sRNA profiles of urinary exosomes derived from IMN patients and healthy controls (CON) to provide clues for identifying novel noninvasive sRNA biomarkers for IMN. METHODS: Urine samples were collected from five healthy controls and six patients with IMN. High-throughput sequencing was used to screen sRNA expression profiles of urinary exosomes from patients with IMN in two independent cohorts. RESULTS: Urinary exosomes were successfully isolated and used to obtain exosomal sRNAs. We screened 131 differentially expressed miRNAs, including 28 specifically expressed miRNAs, then explored the top 10 specifically expressed miRNAs in all IMN individuals. The specifically expressed miRNAs and differentially expressed miRNAs provide potential biomarkers for IMN. Additionally, we discovered numerous sRNAs derived from genomic repetitive sequences, which could represent an exciting new area of research. CONCLUSION: Herein, we revealed significant differences in expression profiles of urinary exosomal miRNAs and repetitive region-derived sRNAs between patients with IMN and healthy controls. The findings could facilitate the development of potential molecular targets for membranous nephropathy.