Serum biomarkers and disease progression in CT-negative mild traumatic brain injury.

Blood proteins are emerging as potential biomarkers for mild traumatic brain injury (mTBI). Molecular pathology of mTBI underscores the critical roles of neuronal injury, neuroinflammation, and vascular health in disease progression. However, the temporal profile of blood biomarkers associated with the aforementioned molecular pathology after CT-negative mTBI, their diagnostic and prognostic potential, and their utility in monitoring white matter integrity and progressive brain atrophy remain unclear. Thus, we investigated serum biomarkers and neuroimaging in a longitudinal cohort, including 103 CT-negative mTBI patients and 66 matched healthy controls (HCs). Angiogenic biomarker vascular endothelial growth factor (VEGF) exhibited the highest area under the curve of 0.88 in identifying patients from HCs. Inflammatory biomarker interleukin-1ß and neuronal cell body injury biomarker ubiquitin carboxyl-terminal hydrolase L1 were elevated in acute-stage patients and associated with deterioration of cognitive function from acute-stage to 6-12 mo post-injury period. Notably, axonal injury biomarker neurofilament light (NfL) was elevated in acute-stage patients, with higher levels associated with impaired white matter integrity in acute-stage and progressive gray and white matter atrophy from 3- to 6-12 mo post-injury period. Collectively, our findings emphasized the potential clinical value of serum biomarkers, particularly NfL and VEGF, in diagnosing mTBI and monitoring disease progression.

Rh(III)-Catalyzed Diastereo- and Enantioselective Regiodivergent (Hetero)Arylamidation of (Homo)Allylic Sulfides.

A rhodium-catalyzed 3-component conjunctive diastereo- and regioselective arylamidation of (homo)allylic sulfides, organon boronic acids, and dioxazolones is reported. These reactions deliver the 1,2-insertion and 2,1-insertion arylamidation products, respectively, for allylic sulfides and homoallylic sulfides. The enantioselective arylamidation of terminal and internal allylic sulfides is achieved, furnishing various 1,3-N,S compounds featuring one or two contiguous stereocenters in high yields and with high diastereo- and enantioselectivities. Mechanistic studies suggest a change in the turnover-limiting and selectivity-determining steps induced by the native and easily removable sulfide group.

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed "variants of uncertain significance" (VUS). To systematically resolve their functional status, we performed a massively parallel screen in human cells to identify loss-of-function missense variants in the key DNA mismatch repair factor MSH2. The resulting functional effect map is substantially complete, covering 94% of the 17,746 possible variants, and is highly concordant (96%) with existing functional data and expert clinicians' interpretations. The large majority (89%) of missense variants were functionally neutral, perhaps unexpectedly in light of its evolutionary conservation. These data provide ready-to-use functional evidence to resolve the ∼1,300 extant missense VUSs in MSH2 and may facilitate the prospective classification of newly discovered variants in the clinic.

Hierarchical brain structural-functional coupling associated with cognitive impairments in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) disrupts the integrity of white matter microstructure, which affects brain functional connectivity supporting cognitive function. Although the relationship between structural and functional connectivity (SC and FC), here called SC-FC coupling, has been studied on global level in brain disorders, the long-term disruption of SC-FC coupling in mTBI at regional scale was still unclear. The current study investigated the alteration pattern of regional SC-FC coupling in 104 acute mTBI patients (41 with 6-12 months of follow-up) and 56 healthy controls (HCs). SC and FC networks were constructed to measure regional, intra-network, and inter-network SC-FC coupling. Compared with HCs, acute mTBI exhibited altered SC-FC coupling of the sensorimotor network (SMN). The coupling laterality indicators of the SMN can identify mTBI from controls. The persistent SC-FC decoupling of the SMN and the additional decoupling of the default mode network (DMN) were observed in chronic mTBI. Crucially, decoupling of the SMN and DMN predicted better cognitive outcomes. The findings revealed the SC-FC coupling alternations exhibited hierarchical trend originating from the sensorimotor cortex to high-order cognitive regions with the progression of mTBI. The regional and hierarchical SC-FC coupling may be a prognostic biomarker to provide insights into the pathophysiology mechanism of mTBI.

Brain dynamics in triple-network interactions and its relation to multiple cognitive impairments in mild traumatic brain injury.

Traumatic brain injury (TBI) disrupt the coordinated activity of triple-network and produce impairments across several cognitive domains. The triple-network model posits a key role of the salience network (SN) that regulates interactions with the central executive network (CEN) and default mode network (DMN). However, the aberrant dynamic interactions among triple-network and associations with neurobehavioral symptoms in mild TBI was still unclear. In present study, we used brain network interaction index (NII) and dynamic functional connectivity to examine the time-varying cross-network interactions among the triple-network in 109 acute patients, 41 chronic patients, and 65 healthy controls. Dynamic cross-network interactions were significantly increased and more variable in mild TBI compared to controls. Crucially, mild TBI exhibited an increased NII as enhanced integrations between the SN and CEN while reduced coupling of the SN with DMN. The increased NII also implied much severer and multiple domains of cognitive impairments at both acute and chronic mild TBI. Abnormities in time-varying engagement of triple-network is a clinically relevant neurobiological signature of psychopathology in mild TBI. The findings provided align with and advance an emerging perspective on the importance of aberrant brain dynamics associated with highly disparate cognitive and behavioral outcomes in trauma.

Medication burden in patients with dialysis-dependent CKD: a systematic review.

This systematic review aimed to statistically profile the medication burden and associated influencing factors, and outcomes in patients with dialysis-dependent chronic kidney disease (DD-CKD). Studies of medication burden in patients with DD-CKD in the last 10 years from 1 January 2013 to 31 March 2024 were searched from PubMed, Embase, and Cochrane databases. Newcastle-Ottawa Scale (NOS) or Agency for Healthcare Research and Quality (AHRQ) methodology checklist was used to evaluate quality and bias. Data extraction and combining from multiple groups of number (n), mean, and standard deviation (SD) were performed using R programming language (version4.3.1; R Core Team, Vienna, Austria). A total of 10 studies were included, and the results showed a higher drug burden in patients with DD-CKD. The combined pill burden was 14.57 ± 7.56 per day in hemodialysis (HD) patients and 14.63 ± 6.32 in peritoneal dialysis (PD) patients. The combined number of medications was 9.74 ± 3.37 in HD and 8 ± 3 in PD. Four studies described the various drug classes and their proportions, in general, antihypertensives and phosphate binders were the most commonly used drugs. Five studies mentioned factors associated with medication burden. A total of five studies mentioned medication burden-related outcomes, with one study finding that medication-related burden was associated with increased treatment burden, three studies finding that poor medication adherence was associated with medication burden, and another study finding that medication complexity was not associated with self-reported medication adherence. Limitations: meta-analysis was not possible due to the heterogeneity of studies.

Characterizing and identifying of miRNAs involved in berberine modulating glucose metabolism of Megalobrama amblycephala.

The present study, as one part of a larger project that aimed to investigate the effects of dietary berberine (BBR) on fish growth and glucose regulation, mainly focused on whether miRNAs involve in BBR's modulation of glucose metabolism in fish. Blunt snout bream Megalobrama amblycephala (average weight of 20.36 ± 1.44 g) were exposed to the control diet (NCD, 30% carbohydrate), the high-carbohydrate diet (HCD, 43% carbohydrate) and the berberine diet (HCB, HCD supplemented with 50 mg/kg BBR). After 10 weeks' feeding trial, intraperitoneal injection of glucose was conducted, and then, the plasma and liver were sampled at 0 h, 1 h, 2 h, 6 h, and 12 h. The results showed the plasma glucose levels in all groups rose sharply and peaked at 1 h after glucose injection. Unlike the NCD and HCB groups, the plasma glucose in the HCD group did not decrease after 1 h, while remained high level until at 2 h. The NCD group significantly increased liver glycogen content at times 0-2 h compared to the other two groups and then liver glycogen decreased sharply until at times 6-12 h. To investigate the role of BBR that may cause the changes in plasma glucose and liver glycogen, miRNA high-throughput sequencing was performed on three groups of liver tissues at 2 h time point. Eventually, 20 and 12 differentially expressed miRNAs (DEMs) were obtained in HCD vs NCD and HCB vs HCD, respectively. Through function analyzing, we found that HCD may affect liver metabolism under glucose loading through the NF-κB pathway; and miRNAs regulated by BBR mainly play roles in adipocyte lipolysis, niacin and nicotinamide metabolism, and amino acid transmembrane transport. In the functional exploration of newly discovered novel:Chr12_18892, we found its target gene, adenylate cyclase 3 (adcy3), was widely involved in lipid decomposition, amino acid metabolism, and other pathways. Furthermore, a targeting relationship of novel:Chr12_18892 and adcy3 was confirmed by double luciferase assay. Thus, BBR may promote novel:Chr12_18892 to regulate the expression of adcy3 and participate in glucose metabolism.

[Applicability of H2FPEF and HFA-PEFF Scores in Chinese Patients Suffering From Heart Failure With Preserved Ejection Fraction and Heart Failure With Preserved Ejection Fraction Complicated With Atrial Fibrillation].

Objective To analyze the diagnostic values of H2FPEF and HFA-PEFF scores for heart failure with preserved ejection fraction (HFpEF) and HFpEF complicated with atrial fibrillation (HFpEF-AF) in Chinese patients and explore the related factors. Methods A cross-sectional study was conducted.A total of 835 consecutive HFpEF patients treated in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from 2009 to 2020 were selected and assigned to a HFpEF-AF group (n=267) and a HFpEF group (n=568) according to the presence of AF or not.HFA-PEFF and H2FPEF scores were used for retrospective diagnosis and the diagnostic consistency of the two scores was assessed.One hundred and thirty-six healthy volunteers with age and sex matching the patients during the same period were selected as healthy controls.The receiver operating characteristic (ROC) curves were established for H2FPEF and HFA-PEFF scores in diagnosing HFpEF-AF and HFpEF,on the basis of which the diagnostic performance of the two scores was evaluated. Results There was no difference in the HFA-PEFF score between the two groups (P=0.070).However,the HFpEF-AF group had higher mean H2FPEF score and higher proportion of patients with the score no less than 6 than the HFpEF group (P<0.001).According to the ROC curves,HFA-PEFF and H2FPEF scores demonstrated high performance in diagnosing all HFpEF patients,with the area under the curve (AUC) of 0.892 and 0.922 and the optimal cut-offs of 4 and 4,respectively.The HFA-PEFF score showed similar performance in diagnosing HFpEF and HFpEF-AF,with the AUC of 0.899 and 0.911,respectively.The H2FPEF score had higher performance in diagnosing HFpEF-AF (AUC of approximately 1.000) and low performance in diagnosing HFpEF (AUC of 0.885). Conclusions The HFA-PEFF score is applicable in the diagnosis of both HFpEF and HFpEF-AF.The H2FPEF score may underestimate HFpEF in Chinese patients,and its applicability in the Chinese patients with HFpEF alone remains to be investigated.

Pd-Bi Bimetallic Nanochains for Electroreduction of CO2 to Syngas in Ionic Liquid-Based Electrolytes.

The electroreduction of carbon dioxide (CO2 ) is a sustainable method for generating valuable chemicals; however, avoiding unwanted hydrogen (H2 ) production during the electrolysis is a major challenge. Coproduction of carbon monoxide (CO) and H2 to produce syngas is an effective strategy for solving this problem, and syngas with a desired CO/H2 ratio can be employed to produce methanol or other valuable chemicals. Herein, a series of palladium-bismuth (Pd-Bi) bimetallic nanochains with different Pd/Bi atomic ratios were prepared and used in the electroreduction of CO2 to syngas in ionic liquid-based electrolytes. The ratio of CO/H2 in syngas was regulated in a wide range from 1 : 7 to 9 : 1 by controlling the applied potentials, Pd/Bi atomic ratios and composition of the electrolytes. In particular, the current density reached 19.3 mA cm-2 on Pd3 Bi bimetallic nanochains at an applied potential of -2.3 V versus Ag/Ag+ when the CO/H2 ratio was approximately 1 : 1. Moreover, the maximum CO Faradaic efficiency was 87.7 % for these electrocatalysts at an applied potential of -2.0 V versus Ag/Ag+ . The synergistic effect of Pd and Bi in the ionic liquid-based electrolyte was the primary reason for the distinct electrocatalytic efficiency of the Pd3 Bi bimetallic nanochains. The incorporation of moderate amounts of Bi into the Pd lattice resulted in a stronger CO2 adsorption capacity, more active sites and faster electron transfer rate, which are conducive to improving the electrocatalytic activity.

Cd/Cd(OH)2 Nanosheets Enhancing the Electrocatalytic Activity of CO2 Reduction to CO.

Electric-driven conversion of carbon dioxide (CO2 ) to carbon monoxide (CO) under mild reaction conditions offers a promising approach to mitigate the greenhouse effect and the energy crisis. Surface engineering is believed to be one of the prospective methods for enhancing the electrocatalytic activity of CO2 reduction. Herein, hydroxyl (OH) groups were successfully introduced to cadmium nanosheets to form cadmium and cadmium hydroxide nanocomposites (i. e. Cd/Cd(OH)2 nanosheets) via a facile two-step method. The as-prepared Cd/Cd(OH)2 /CP (CP indicates carbon paper) electrode displays excellent electrocatalytic activity for CO2 reduction to produce CO. The Faradaic efficiency of CO reaches 98.3 % and the current density achieves 23.8 mA cm-2 at -2.0 V vs. Ag/Ag+ in a CO2 -saturated 30 wt% 1-butyl-3-methylimidazole hexafluorophosphate ([Bmim]PF6 )-65 wt% acetonitrile (CH3 CN)-5 wt% water (H2 O) electrolyte. And the CO partial current density can reach up to 71.6 mA cm-2 with the CO Faradaic efficiency of more than 85 % at -2.3 V vs. Ag/Ag+ , which stands out against Cd/CP, Cd(OH)2 /CP, and Cd/CdO/CP electrodes. The excellent electrocatalytic performance of the Cd/Cd(OH)2 /CP electrode can be attributed to its unique structural properties, suitable OH groups, perfect interaction with electrolyte, abundant active sites and fast electron transfer rate.

Serum 25-Hydroxyvitamin D Level Is Negatively Associated with Fatigue in Elderly Maintenance Hemodialysis Patients.

INTRODUCTION: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is frequently observed in maintenance hemodialysis (MHD) patients and is associated with fracture, muscle weakness, malnutrition, etc.; however, relationships of CKD-MBD markers and fatigue are not well established. METHODS: This was a cross-sectional study including 244 MHD patients (89 elders) from July to September 2021 in the First Affiliated Hospital of Shandong First Medical University. CKD-MBD markers and other clinical data were collected from medical records. Fatigue in the past week was measured by Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) fatigue measure; fatigue at the end of hemodialysis was measured by numeric rating scale (NRS). Spearman correlation, linear regression, and robust linear regression were. RESULTS: In all MHD patients, lg[25(OH)D] (nmol/L) was negatively correlated with SONG-HD score (ß = -1.503, 95% CI: -2.826 to 0.18, p = 0.026) and NRS score (ß = -1.532, p = 0.04) in multiple regression models adjusting for sex, age, and all CKD-MBD characters; but no correlations were found on univariate regression or in other multiple regression models. Interaction effects between age ≥65 years and lg(25[OH]D [nmol/L]) in terms of fatigue scores were significant based on multiple linear regressions (SONG-HD score ß = -3.613, p for interaction = 0.006; NRS score ß = -3.943, p for interaction = 0.008). Compared with non-elderly patients, elderly patients were with higher ACCI scores (7 [6, 8] vs. 4 [3, 5], p < 0.001), higher SONG-HD scores (3 [2, 6] vs. 2 [1, 3], p < 0.001), higher NRS score (4 [2, 7] vs. 3 [1, 5], p < 0.001), lower serum phosphate levels (1.65 [1.29, 2.10] vs. 1.87 [1.55, 2.26] mmol/L, p = 0.002), and lower serum iPTH levels (160.6 [90.46, 306.45] vs. 282.2 [139, 445.7] pg/mL, p < 0.001). There were no differences in serum calcium, alkaline serum, or 25(OH)D levels between the two groups. In elderly patients, lg[25(OH)D] was negatively correlated with SONG-HD score (ß = -3.323, p = 0.010) and NRS score (ß = -3.521, p = 0.006) on univariate linear regressions. Following adjustment for sex, age, and all CKD-MBD characters, lg[25(OH)D] was negatively correlated with SONG-HD scores (multiple linear regression ß = -4.012, p = 0.004; multiple robust regression ß = -4.012, p = 0.003) or NRS scores (multiple linear regression ß = -4.104, p = 0.002; multiple robust regression ß = -4.104, p = 0.001). There were no significant correlations between fatigue scores and other CKD-MBD markers (calcium, phosphate, lgiPTH, alkaline phosphatase) in elderly MHD patients, on either univariate linear regressions or multiple regressions. CONCLUSION: Serum 25(OH)D level is negatively associated with fatigue in elderly MHD patients.

Update of dialysis initiation timing in end stage kidney disease patients: is it a resolved question? A systematic literature review.

BACKGROUND: The exact optimal timing of dialysis for ESKD patients remains unknown. This study systematically reviewed the available evidence with regard to the optimal initiation of maintenance dialysis in ESKD patients. METHODS: An electronic search was performed in Embase, PubMed and the Cochrane Library in order to find studies investigating associations between variables reference to "start of dialysis" and outcomes. Quality assessment and bias assessment were performed by the Newcastle-Ottawa scale and the ROBINSI tool. Due to the heterogeneity of studies, a meta-analysis could not be performed. RESULTS: Thirteen studies were included; four studies included only haemodialysis patients, three peritoneal dialysis, six both; study outcomes included mortality, cardiovascular events, technique failure, quality of life and others. Nine studies mainly focused on the optimal GFR of maintenance dialysis initiation; five studies showed none association between GFR and mortality or other adverse outcomes, two studies showed dialysis initiation at higher GFR levels were with poor prognosis, and 2 studies showed higher GFR levels with better prognosis. Three studies paid attention to comprehensive assessment of uremic signs and/or symptoms for optimal dialysis initiation; uremic burden based on 7 uremic indicators (hemoglobin, serum albumin, blood urea nitrogen, serum creatinine, potassium, phosphorus, and bicarbonate) were not associated with mortality; another equation (combination of sex, age, serum creatinine, blood urea nitrogen, serum albumin, haemoglobin, serum phosphorus, diabetes mellitus, and heart failure) based on fuzzy mathematics to assess the timing of haemodialysis initiation was accuracy to prognose 3-year survival; the third study found that volume overload or hypertension was associated with the highest risk for subsequent mortality. Two studies compared urgent or optimal start in dialysis, a study reported increased survival in optimal start patients, another reported no differences between Urgent-Start-PD and Early-Start-PD regarding 6-month outcomes. LIMITATIONS: Heterogeneity among the studies was quite high, with differences in sample size, variable and group characteristics; no RCT studies were included, which weakened the strength of evidences. CONCLUSIONS: The criteria for dialysis initiation were varied. Most studies proved that GFR at dialysis initiation was not associated with mortality, timing of dialysis initiation should not be based on GFR, assessments of volume load and patient's tolerance to volume overload are prospective approaches.

[Cardiac Structural and Functional Features in Patients With Type 2 Diabetes Mellitus and Heart Failure With Preserved Ejection Fraction:A Study Based on Propensity Score Matching].

Objective To investigate the cardiac structural and functional characteristics in the patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM),and predict the factors influencing the characteristics. Methods A total of 783 HFpEF patients diagnosed in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from April 2009 to December 2020 were enrolled in this study.Echocardiography and tissue Doppler technique were employed to evaluate cardiac structure and function.According to the occurrence of T2DM,the patients were assigned into a HFpEF+T2DM group (n=332) and a HFpEF group (n=451).Propensity score matching (PSM)(in a 1∶1 ratio) was adopted to minimize confounding effect.According to urinary albumin excretion rate (UAER),the HFpEF+T2DM group was further divided into three subgroups with UAER<20 µg/min,of 20-200 µg/min,and>200 µg/min,respectively.The comorbidities,symptoms and signs,and cardiac structure and function were compared among the groups to clarify the features of diabetes related HFpEF.Multivariate linear regression was conducted to probe the relationship of systolic blood pressure,blood glucose,glycosylated hemoglobin,and UARE with cardiac structural and functional impairment. Results The HFpEF+T2DM group had higher prevalence of hypertension (P=0.001) and coronary heart disease (P=0.036),younger age (P=0.020),and larger body mass index (P=0.005) than the HFpEF group,with the median diabetic course of 10 (3,17) years.After PSM,the prevalence of hypertension and coronary heart disease,body mass index,and age had no significant differences between the two groups(all P>0.05).In addition,the HFpEF+T2DM group had higher interventricular septal thickness (P=0.015),left ventricular posterior wall thickness (P=0.040),and left ventricular mass (P=0.012) and lower early diastole velocity of mitral annular septum (P=0.030) and lateral wall (P=0.011) than the HFpEF group.Compared with the HFpEF group,the HFpEF+T2DM group showed increased ratio of early diastolic mitral filling velocity to early diastolic mitral annular velocity (E/e') (P=0.036).Glycosylated hemoglobin was correlated with left ventricular mass (P=0.011),and the natural logarithm of UAER with interventricular septal thickness (P=0.004),left ventricular posterior wall thickness (P=0.006),left ventricular mass (P<0.001),and E/e' ratio (P=0.049). Conclusion The patients with both T2DM and HFpEF have thicker left ventricular wall,larger left ventricular mass,more advanced left ventricular remodeling,severer impaired left ventricular diastolic function,and higher left ventricular filling pressure than the HFpEF patients without T2DM.Elevated blood glucose and diabetic microvascular diseases might play a role in the development of the detrimental structural and functional changes of the heart.

Neural Fingerprints Underlying Individual Language Learning Profiles.

Human language learning differs significantly across individuals in the process and ultimate attainment. Although decades of research exploring the neural substrates of language learning have identified distinct and overlapping neural networks subserving learning of different components, the neural mechanisms that drive the large interindividual differences are still far from being understood. Here we examine to what extent the neural dynamics of multiple brain networks in men and women across sessions of training contribute to explaining individual differences in learning multiple linguistic components (i.e., vocabulary, morphology, and phrase and sentence structures) of an artificial language in a 7 d training and imaging paradigm with functional MRI. With machine-learning and predictive modeling, neural activation patterns across training sessions were highly predictive of individual learning success profiles derived from the four components. We identified four neural learning networks (i.e., the Perisylvian, frontoparietal, salience, and default-mode networks) and examined their dynamic contributions to the learning success prediction. Moreover, the robustness of the predictions systematically changes across networks depending on specific training phases and the learning components. We further demonstrate that a subset of network nodes in the inferior frontal, insular, and frontoparietal regions increasingly represent newly acquired language knowledge, while the multivariate connectivity between these representation regions is enhanced during learning for more successful learners. These findings allow us to understand why learners differ and are the first to attribute not only the degree of success but also patterns of language learning across components, to neural fingerprints summarized from multiple neural network dynamics.SIGNIFICANCE STATEMENT Individual differences in learning a language are widely observed not only within the same component of language but also across components. This study demonstrates that the dynamics of multiple brain networks across four imaging sessions of a 7 d artificial language training contribute to individual differences in learning-outcome profiles derived from four language components. With machine-learning predictive modeling, we identified four neural learning networks, including the Perisylvian, frontoparietal, salience, and default-mode networks, that contribute to predicting individual learning-outcome profiles and revealed language-component-general and component-specific prediction patterns across training sessions. These findings provide significant insights in understanding training-dependent neural dynamics underlying individual differences in learning success across language components.

Predictors of Kidney Outcomes of Anti-Glomerular Basement Membrane Disease in a Large Chinese Cohort.

INTRODUCTION: Anti-glomerular basement membrane (GBM) disease is a rare but the most aggressive form of glomerulonephritis. To dissect the prognostic factors, we retrospectively analyzed the clinical features of a large cohort and compared the clinical features and prognosis during decades. METHODS: Data on clinical manifestation, treatment, and prognosis were collected. Cox models and receiver operating characteristic (ROC) curve were used to investigate the predictors for outcomes. The Kaplan-Meier curve and log-rank test were used to compare kidney and patient survival. RESULTS: A total of 448 patients were enrolled. Patient survival and kidney survival at 1 year was 69.4% and 37.7%, respectively. During the past 3 decades, mortality at 3 months and 1 year significantly dropped from 37.5% and 57.1% in 1991-2000 to 2.8% and 6.9% in 2011-2020 (p < 0.001), respectively; kidney prognosis showed a tendency of improvement as well. Serum creatinine (Scr) on diagnosis (HR, 1.16; 95% CI, 1.05-1.29) and crescent percentage (HR, 1.73; 95% CI, 1.34-2.24) were independent predictors for end-stage kidney disease. ROC curve showed that the optimal cutoff point of Scr on diagnosis for prediction of dialysis dependency at 1 year was 536.4 µmol/L (sensitivity 88.3% and specificity 80.8%). Antineutrophil cytoplasmic antibodies (ANCAs) positivity (HR, 4.43; 95% CI, 1.72-11.38) was a predictor for mortality. Plasma exchange was associated with a better patient prognosis (HR, 0.40; 95% CI 0.16-0.95). CONCLUSION: Scr on diagnosis and percentage of crescents were predictors for kidney outcomes. Positive ANCA was a predictor for mortality. Overall patient prognosis of anti-GBM disease was improved during the past 3 decades.

Optimal Value for Serum Anti-PLA2R Antibody in Primary Membranous Nephropathy: A Multicenter Observational Study.

INTRODUCTION: Anti-phospholipase A2 receptor antibody (PLA2R-Ab) is highly specific for primary membranous nephropathy (PMN). Here, we compare the diagnostic value of different circulating PLA2R-Ab cutoff titers in multicenter cohorts, with particular focus on determining the optimal cutoff value for Chinese patients. METHODS: In total, 288 patients with PMN and 301 with other nephropathies were recruited retrospectively from five hospitals in China between September 2011 and October 2018. PLA2R-Ab in serum obtained at renal biopsy was determined by enzyme-linked immunosorbent assay. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic (ROC) curve of PLA2R-Ab in diagnosing PMN were assessed. Diagnostic efficiency was evaluated by internal validation. RESULTS: The sensitivity, specificity, PPV, NPV, and Youden index for PMN diagnosis were 71%, 90%, 88%, 75%, and 0.61 at the cutoff of 3.8 RU/mL; 74%, 86%, 84%, 76%, and 0.60 at 2.7 RU/mL; 68%, 92%, 90%, 73%, and 0.60 at 5.2 RU/mL; 64%, 95%, 93%, 72%, and 0.59 at 9.0 RU/mL; 57%, 96%, 94%, 68%, and 0.54 at 14.0 RU/mL; 51%, 97%, 95%, 66%, and 0.49 at 20.0 RU/mL; 47%, 98%, 96%, 64%, and 0.45 at 40.0 RU/mL, respectively. The area under the ROC curve was 0.83. CONCLUSION: By comprehensively considering specificity and sensitivity, we show that 3.8 RU/mL is the optimal cutoff of PLA2R-Ab in Chinese PMN patients, with a sensitivity of 71% and a specificity of 90%. The cutoff values were 5.2 RU/mL and 9.0 RU/mL when the diagnostic specificity was increased to 92% and 95%, respectively.

Blockade of chloride channel-3 enhances cisplatin sensitivity of cholangiocarcinoma cells though inhibiting autophagy.

Chemotherapy is one of the most important strategies in the treatment of cancer; however, chemoresistance restricts the effect of chemotherapy. Growing reports suggest that chloride channel-3 (ClC-3) is involved in regulating the sensitivity of multiple chemotherapeutic agents in the chemotherapy of various tumours, while its role in the chemotherapy of cholangiocarcinoma (CCA) is still poorly understood. Herein, we observed that ClC-3 was highly expressed in CCA chemoresistant tissues and CCA cisplatin-resistant cells QBC939/DDP, and the sensitivities of QBC939 and QBC939/DDP cells to cisplatin were all increased after inhibition of ClC-3. Further mechanism exploration revealed that ClC-3 knockdown reduced the level of autophagy. Furthermore, in both QBC939 and QBC939/DDP cells, the autophagy agonist rapamycin eliminated the increased cisplatin sensitivity of ClC-3 knockdown without affecting ClC-3 expression. Collectively, all the findings demonstrate that ClC-3 knockdown increases cisplatin-induced cell death in CCA cells though inhibiting autophagy, regardless of the occurrence of cisplatin resistance. In addition, our results also suggest that targeted inhibition of ClC-3 may be a potential strategy for chemosensitization in CCA chemotherapy.

Association of plasma neutrophil gelatinase-associated lipocalin and thoracic aorta calcification in maintenance hemodialysis patients with and without diabetes.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is not only a bone-derived factor involved in metabolism, but also a biomarker of kidney disease and cardiovascular pathophysiology. We conducted this cross-sectional observational study to explore relationships between plasma NGAL and thoracic aorta calcification (TAC) in maintenance hemodialysis (MHD) patients with and without diabetes. METHODS: Plasma NGAL was measured by ELISA, TAC was evaluated via computed tomography scan using a 3D quantification method or chest radiography aortic arch calcification score. Spearman correlation, Logistic regression and Partial correlation analysis were used to describe the correlations between NGAL and TAC. RESULTS: Plasma NGAL levels were lower in MHD patients with diabetes compared to those without diabetes (49.33(42.37, 55.48) vs 56.78(44.37, 674.13) ng/mL, P = 0.026). In MHD patients without diabetes, lg (NGAL) was positively correlated with ARC value(R = 0.612, P = 0.003) analyzed by Spearman correlation; for partial correlation analysis, lg (NGAL) was positively correlated with ARC value, after adjusting for age and sex (R = 0.550, P = 0.015), adjusting for age, sex and CHD (R = 0.565, P = 0.015), adjusting for age, sex, CHD and Alb (R = 0.536, P = 0.027), or adjusting for age, sex, CHD, Alb, and dialyzer membrane (polysulfone) (R = 0.590, P = 0.016); however, when adjusting for age, sex, CHD, Alb and Ca, the correlation between lg (NGAL) and ARC value disappeared. Positive correlation were found between NGAL and Ca (R = 0.644, P < 0.001), Ca and ACR (R = 0.534, P = 0.013) in Spearman coefficient analysis. CONCLUSION: There were positive correlations among plasma NGAL, serum Ca and ARC in MHD patients without diabetes; which suggests that NGAL is possibly a participant in cardiovascular calcification, in non-diabetic MHD.

Neuroimaging-based brain-age prediction of first-episode schizophrenia and the alteration of brain age after early medication.

BACKGROUND: Neuroimaging- and machine-learning-based brain-age prediction of schizophrenia is well established. However, the diagnostic significance and the effect of early medication on first-episode schizophrenia remains unclear. AIMS: To explore whether predicted brain age can be used as a biomarker for schizophrenia diagnosis, and the relationship between clinical characteristics and brain-predicted age difference (PAD), and the effects of early medication on predicted brain age. METHOD: The predicted model was built on 523 diffusion tensor imaging magnetic resonance imaging scans from healthy controls. First, the brain-PAD of 60 patients with first-episode schizophrenia, 60 healthy controls and 21 follow-up patients from the principal data-set and 40 pairs of individuals in the replication data-set were calculated. Next, the brain-PAD between groups were compared and the correlations between brain-PAD and clinical measurements were analysed. RESULTS: The patients showed a significant increase in brain-PAD compared with healthy controls. After early medication, the brain-PAD of patients decreased significantly compared with baseline (P < 0.001). The fractional anisotropy value of 31/33 white matter tract features, which related to the brain-PAD scores, had significantly statistical differences before and after measurements (P < 0.05, false discovery rate corrected). Correlation analysis showed that the age gap was negatively associated with the positive score on the Positive and Negative Syndrome Scale in the principal data-set (r = -0.326, P = 0.014). CONCLUSIONS: The brain age of patients with first-episode schizophrenia may be older than their chronological age. Early medication holds promise for improving the patient's brain ageing. Neuroimaging-based brain-age prediction can provide novel insights into the understanding of schizophrenia.

Association of plasma neutrophil gelatinase-associated lipocalin with parameters of CKD-MBD in maintenance hemodialysis patients.

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is not only a biomarker of kidney injury but also a bone-derived factor involved in metabolism. We aimed to explore relationships between plasma NGAL and chronic kidney disease-mineral bone disorder (CKD-MBD) parameters in maintenance hemodialysis (MHD) patients. MATERIALS AND METHODS: First, a cross sectional observational study, including 105 MHD patients, was conducted to explore relationships between plasma NGAL levels and CKD-MBD parameters. Second, impact of parathyroidectomy and auto-transplantation (PTX + AT) on plasma NGAL was investigated in 12 MHD patients with severe secondary hyperparathyroidism (SHPT). RESULTS: According to Spearman correlation analysis, plasma NGAL levels were positively correlated with female (r = 0.243, P = 0.012), vintage (r = 0.290, P = 0.003), Klotho (r = 0.234, P = 0.016), calcium(Ca) (r = 0.332, P = 0.001), alkaline phosphatase (ALP) (r = 0.401, P < 0.001) and intact parathyroid hormone (iPTH) (r = 0.256, P = 0.008); while inversely correlated with albumin(Alb) (r = - 0.201, P = 0.039). After adjusting for age, sex, vintage, Alb and all parameters of CKD-MBD(Ca, P, lg(ALP), lg(iPTH), Klotho and fibroblast growth factor 23(FGF23)), lg(NGAL) were positively correlated with Ca (r = 0.481, P < 0.001), P (r = 0.336, P = 0.037), lg(ALP) (r = 0.646, P < 0.001) in Partial correlation analysis; further multiple linear regression analysis showed same positive associations between lg(NGAL) and Ca (ß = 0.330, P = 0.002), P (ß = 0.218, P = 0.037), lg(ALP) (ß = 0.671, P < 0.001). During the 4-7 days after PTX + AT, plasma NGAL decreased from 715.84 (578.73, 988.14) to 688.42 (660.00, 760.26) ng/mL (P = 0.071), Klotho increased from 496.45 (341.73, 848.30) to 1138.25 (593.87, 2009.27) pg/mL (P = 0.099). CONCLUSION: Plasma NGAL levels were positively associated with ALP in MHD patients; and downtrends were shown after PTX + AT in patients with severe SHPT. These findings suggest that NGAL is a participant in CKD-MBD under MHD condition.