A Noncoding A-to-U Kozak Site Change Related to the High Transmissibility of Alpha, Delta, and Omicron VOCs.

Three prevalent SARS-CoV-2 variants of concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked, so traditional population genetic methods, including machine learning-based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two noncoding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the noncoding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S:p.P681H/R, and N:p.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous noncoding and nonsynonymous changes.

Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

Current status of exercise and its impact on quality of life in patients undergoing peritoneal dialysis in the post-COVID-19 period.

OBJECTIVES: The aims of this study were to investigate the current status and the influence factors of exercise, and to explore the impact of exercise on the quality of life (QoL) in peritoneal dialysis (PD) patients in the post-COVID-19 period. MATERIALS AND METHODS: Those PD patients who were followed up between September 2020 and August 2021 were enrolled. The collected data included demographic information, clinical data, exercise data, and QoL. RESULTS: In total, 339 PD patients were included in this cross-sectional study. The mean age was 44.0 ± 13.0 years, with a median PD duration of 6.7 (1.7 - 41.9) months. The primary renal disease was glomerulonephritis (68.4%). 277 (81.7%) PD patients performed exercise, with median exercise time 5.0 (3.5 - 7.8) hours per week. The main type of exercise was slow walking. Pain (odds ratio (OR) = 0.311, p = 0.002) and lower hemoglobin level (OR = 1.016, p = 0.033) were independent risk factors for exercise. Moreover, male sex (B = 2.803, p < 0.001) was an independent protective factor, while advanced age (B = -0.097, p < 0.001), higher body mass index (B = -0.154, p < 0.001), and pain (B = -0.643, p = 0.023) were independent risk factors for exercise intensity. After adjustment for other confounders, exercise (B = 5.787, p = 0.037) was an independent protective factor for total score of QoL in PD patients. CONCLUSION: In the current study, 81.7% of PD patients performed exercise in the post-COVID-19 period. Pain and anemia were independent risk factors for exercise in PD patients. Advanced age, female sex, higher body mass index, and pain were independently associated with lower exercise capacity in PD patients. PD patients undergoing exercise had better QoL.

Triglyceride glucose-body mass index and cardiovascular mortality in patients undergoing peritoneal dialysis: a retrospective cohort study.

BACKGROUND: Recent studies have shown that triglyceride glucose-body mass index (TyG-BMI) is associated with the risk of ischemic stroke and coronary artery disease. However, little attention has been given to the association between TyG-BMI and cardiovascular disease (CVD) mortality in patients undergoing peritoneal dialysis (PD). Therefore, this study aimed to explore the relationship between TyG-BMI and CVD mortality in southern Chinese patients undergoing PD. METHODS: Incident patients receiving PD from January 1, 2006, to December 31, 2018, with baseline serum triglyceride, glucose, and body mass index (BMI) information, were recruited for this single-center retrospective cohort study. TyG-BMI was calculated based on fasting plasma glucose, triglyceride, and BMI values. The association between TyG-BMI, CVD and all-cause mortality was evaluated using a multivariate-adjusted Cox proportional hazard regression model. RESULTS: Of 2,335 patients, the mean age was 46.1 ± 14.8 years; 1,382 (59.2%) were male, and 564 (24.2%) had diabetes. The median TyG-BMI was 183.7 (165.5-209.2). Multivariate linear regression showed that advanced age, male sex, history of CVD, higher levels of albumin and low-density lipoprotein cholesterol, and higher urine output were correlated with a higher TyG-BMI (P < 0.05). During a median follow-up period of 46.6 (22.4-78.0) months, 615 patients died, of whom 297 (48.2%) died as a result of CVD. After adjusting for demographics and comorbidities, TyG-BMI was significantly associated with an increased risk of CVD mortality (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.05-2.17) and all-cause mortality (HR 1.36, 95% CI 1.05-1.75). After full adjustment, the 28% risk of CVD mortality (HR 1.28, 95% CI 1.13-1.45) and 19% risk of all-cause mortality were elevated (HR 1.19, 95% CI 1.09-1.31) when TyG-BMI increased by 1 stand deviation (SD) (34.2). CONCLUSIONS: A higher baseline TyG-BMI was independently associated with an increased risk of CVD and all-cause mortality in patients receiving PD.

Automatic mammographic breast density classification in Chinese women: clinical validation of a deep learning model.

BACKGROUND: High breast density is a strong risk factor for breast cancer. As such, high consistency and accuracy in breast density assessment is necessary. PURPOSE: To validate our proposed deep learning (DL) model and explore its impact on radiologists on density assessments. MATERIAL AND METHODS: A total of 3732 mammographic cases were collected as a validated set: 1686 cases before the implementation of the DL model and 2046 cases after the DL model. Five radiologists were divided into two groups (junior and senior groups) to assess all mammograms using either two- or four-category evaluation. Linear-weighted kappa (K) and intraclass correlation coefficient (ICC) statistics were used to analyze the consistency between radiologists before and after implementation of the DL model. RESULTS: The accuracy and clinical acceptance of the DL model for the junior group were 96.3% and 96.8% for two-category evaluation, and 85.6% and 89.6% for four-category evaluation, respectively. For the senior group, the accuracy and clinical acceptance were 95.5% and 98.0% for two-category evaluation, and 84.3% and 95.3% for four-category evaluation, respectively. The consistency within the junior group, the senior group, and among all radiologists improved with the help of the DL model. For two-category, their K and ICC values improved to 0.81, 0.81, and 0.80 from 0.73, 0.75, and 0.76. And for four-category, their K and ICC values improved to 0.81, 0.82, and 0.82 from 0.73, 0.79, and 0.78, respectively. CONCLUSION: The DL model showed high accuracy and clinical acceptance in breast density categories. It is helpful to improve radiologists' consistency.

Left ventricular strain and myocardial work in short-term peritoneal dialysis patients.

BACKGROUND: Initiation of dialysis encompasses new cardiovascular challenges on patients with end-stage renal disease (ESRD). This study used two-dimensional speckle-tracking echocardiography (2D-STE) to investigate the change of left ventricular (LV) myocardial function undergoing peritoneal dialysis (PD) within 1-3 months. METHODS: A total of 56 patients with ESRD and 27 healthy controls were enrolled in this prospective study. Mean duration of PD was 44.41 ± 16.44 days. We evaluated LV myocardial function of patients with ESRD in baseline and within 1-3 months after PD by 2D-STE with global longitudinal strains (GLS) and myocardial work (MW). Based on the level of serum phosphate before PD, patients were divided into two groups: the group with normal serum phosphate or hyperphosphatemia. RESULTS: Compared with healthy controls, patients with ESRD had impaired GLS (p < .001) and increased global work index (GWI) (p = .034), global constructive work (GCW) (p < .001), global wasted work (GWW) (p < .001), and lower global work efficiency (GWE) (p = .002). After PD therapy, GWI (p = .001), GCW (p < .001), and GWW (p = .023) decreased and closed to healthy subjects (p > .05) and no significant improvement was observed in GLS (p = .387). GLS of basal segments worsened in the hyperphosphatemia group (p = .005) and GWW reduced remarkably in the group with normal serum phosphate after PD treatment (p = .008). The change of left ventricular internal diameter in diastole (LVIDd) was the only parameter influenced GWI in post-dialysis patients (ß = 0.324, p = .013). CONCLUSIONS: Short-term PD treatment improved LV MW in ESRD patients. They benefited more when receiving treatment before the increase of serum phosphorus.

Thrombin cleaves IL-33 and modulates IL-33-activated allergic lung inflammation.

BACKGROUND: Organisms have orchestrated coagulation and immune systems. Although a link between inflammation and haemostasis has been reported in asthma, the interaction mechanism has not been completely elucidated. Here, we investigated the direct link between the mammalian immune and coagulation systems. METHODS: Mice were administered protease or antigens intranasally to induce airway inflammation with or without thrombin inhibitors treatment. The effects of thrombin and its inhibitors on interleukin (IL)-33 were investigated both in vivo and in vitro. Peripheral blood mononuclear cells (PBMCs) and plasma from asthma patients are collected to verify the correlation between thrombin and group 2 innate lymphocytes (ILC2s). RESULTS: Low-molecular-weight heparin (LMWH, an indirect inhibitor of thrombin) restrained both papain- and fungus-induced type 2 immune responses in mice by inhibiting IL-33 cleavage. Upon examining the potential thrombin protease consensus sites, we found that IL-33 was directly cleaved by thrombin at specific amino acids (R48 and R106) to generate a mature form of IL-33 with potent biological activity. In addition, we found that bivalirudin TFA (a direct inhibitor of thrombin) inhibited a variety of type 2 inflammatory responses, such as those in house dust mite (HDM)- and ovalbumin (OVA)-mediated pulmonary inflammation models. We found that plasma thrombin-antithrombin complex (TATc) levels in asthma patients were positively associated with the number and function of IL-33-responder group 2 innate lymphocytes (ILC2s) among peripheral blood mononuclear cells (PBMCs) from asthma patients. CONCLUSION: The data suggested that thrombin inhibitors administration could be effective in treating lung inflammation by regulating ILC2s via IL-33 maturation, indicating that targeting thrombin is a potential way to treat allergic diseases.

The added value of an artificial intelligence system in assisting radiologists on indeterminate BI-RADS 0 mammograms.

OBJECTIVES: To investigate the value of an artificial intelligence (AI) system in assisting radiologists to improve the assessment accuracy of BI-RADS 0 cases in mammograms. METHODS: We included 34,654 consecutive digital mammography studies, collected between January 2011 and January 2019, among which, 1088 cases from 1010 unique patients with initial BI-RADS 0 assessment who were recalled during 2 years of follow-up were used in this study. Two mid-level radiologists retrospectively re-assessed these BI-RADS 0 cases with the assistance of an AI system developed by us previously. In addition, four entry-level radiologists were split into two groups to cross-read 80 cases with and without the AI. Diagnostic performance was evaluated using the follow-up diagnosis or biopsy results as the reference standard. RESULTS: Of the 1088 cases, 626 were actually normal (BI-RADS 1 and no recall required). Assisted by the AI system, 351 (56%) and 362 (58%) normal cases were correctly identified by the two mid-level radiologists hence can be avoided for unnecessary follow-ups. However, they would have missed 12 (10 invasive cancers and 2 ductal carcinoma in situ cancers) and 6 (invasive cancers) malignant lesions respectively as a result. These missed lesions were not highly malignant tumors. The inter-rater reliability of entry-level radiologists increased from 0.20 to 0.30 (p < 0.005) by introducing the AI. CONCLUSION: The AI system can effectively assist mid-level radiologists in reducing unnecessary follow-ups of mammographically indeterminate breast lesions and reducing the benign biopsy rate without missing highly malignant tumors. KEY POINTS: • The artificial intelligence system could assist mid-level radiologists in effectively reducing unnecessary BI-RADS 0 mammogram recalls and the benign biopsy rate without missing highly malignant tumors. • The artificial intelligence system was capable of detecting low suspicion lesions from heterogeneously and extremely dense breasts that radiologists tended to miss. • The use of an artificial intelligence system may improve the inter-rater reliability and sensitivity, and reduce the reading time of entry-level radiologists in assessing potential lesions in BI-RADS 0 mammograms.

Patient-reported gastrointestinal symptoms in patients with peritoneal dialysis: the prevalence, influence factors and association with quality of life.

BACKGROUND: The aims of this study were to investigate the prevalence and the influence factors of gastrointestinal symptoms, and its association with the quality of life (QOL) in peritoneal dialysis (PD) patients. METHODS: Continuous ambulatory PD patients (CAPD) who followed up in our PD center between March 2016 and December 2017 were enrolled in this cross-sectional study. Gastrointestinal symptom rating scale (GSRS) was used to evaluate gastrointestinal symptoms. The related clinical data were also collected. Multiple linear regression analysis was test for the influence factors associated with score of GSRS and QOL. RESULTS: This study included 471 CAPD patients. The mean age was 48.5±13.9 years, 53.9% were male and 15.1% with diabetic nephropathy. The median duration of PD was 37.3 (17.5~66.5) months. The median score of GSRS was 1.2(1.1~1.3) scores. Totally 82.2% (n=387) CAPD patients had at least one gastrointestinal symptom. Higher glycosylated hemoglobin, higher score of depression, lower diastolic blood pressure, urine output, score of instrumental activities of daily living scale and more amount of pills per day were independently associated with higher score of GSRS (all P<0.05). Score of dyspepsia and eating dysfunction were independently associated with worse score of QOL and physical health (all P<0.05). CONCLUSIONS: Gastrointestinal symptoms were common but not serious in CAPD patients. Glycemic control, depression, blood pressure, urine output, activity of daily life and amount of pills were all associated with gastrointestinal symptoms. Moreover, gastrointestinal symptoms were correlated with QOL of PD patients.

Incidence and Risk Factors Associated with Technique Failure in the First Year of Peritoneal Dialysis: A Single Center Retrospective Cohort Study in Southern China.

BACKGROUND: Technique failure is more likely to occur during the first 12 months after peritoneal dialysis (PD) initiation, which is a great challenge encountered in PD patients. The aim of this study was to investigate the incidence and risk factors associated with technique failure within the first year of PD patients in Southern China. METHODS: Incident PD patients who were followed up for at least one year at The First Affiliated Hospital of Sun Yat-sen University from January 1, 2006 to December 31, 2015 were included. Technique failure was defined as transferring to hemodialysis (HD) for more than 30 days or death within the first year after start of PD. A competitive risk regression analysis was used to explore the incidence and risk factors of the technique failure. RESULTS: Overall, 2,290 incident PD patients were included in this study, with a mean age of 48.2 ± 15.7 years, 40.9% female and 25.2% with diabetes. A total of 173 patients (7.5%) had technique failure during the first year of PD. Among them, the patient death account for 62.4% (n = 108) and transferring to HD account for 37.6% (n = 65). The main reasons for death were cardiovascular diseases (n = 32, 29.6%), infection (n = 15, 13.8%) and for conversion to HD were mechanical cause (n = 28, 43.1%), infection cause (n = 22, 33.8%). The risk factors for the technique failure included advanced age (HR 2.78, 95%CI 1.82-4.30), low body mass index (BMI < 18.5 kg/m2: HR 1.77, 95%CI 1.17-2.67), history of congestive heart failure (HR 2.81, 95%CI 1.58-4.98), or time on HD before PD ≤ 3 months (HR 1.49, 95%CI 1.05-2.10), peritonitis (HR 2.02, 95%CI 1.36-3.01);while higher serum albumin (HR 0.93, 95%CI 0.89-0.96) and using employee medical insurance to pay expenses (HR 0.47, 95%CI 0.32-0.69) were associated with reduced risk. CONCLUSIONS: Advanced age, poor nutritional status, history of HD or congestive heart failure, and peritonitis are related factors that increase the risk of technique failure in the first year of PD, while patients' type of medical insurance may also have an influence on early technique failure.

Sexual Effect of Platelet-to-Lymphocyte Ratio in Predicting Cardiovascular Mortality of Peritoneal Dialysis Patients.

BACKGROUND: The study is aimed at exploring the relationship of platelet-to-lymphocyte (PLR), all-cause, and cardiovascular disease (CVD) mortality in peritoneal dialysis (PD) patients based on gender. METHODS: A total of 1438 PD patients from January 1,2007 to December 31, 2014 in PD center at The First Affiliated Hospital, Sun Yat-sen University, were included. Patients were followed up until December 31, 2019. The endpoint was all-cause mortality and CVD mortality. Cox proportional hazards regression models were used to evaluate the association of PLR with all-cause and CVD mortality to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: After a median of 48.9 (interquartile range [IQR]: 23.4-79.3) months of follow-up, 406 (28.2%) patients died based on all-cause death, among which 200 (49.3%) patients died from CVD. In the multivariate Cox regression model, we found that PLR was independently related to an increased risk of CVD mortality only in female PD patients, with HR of 1.003 (95% CI: 1.001-1.006). Interaction test showed that the correlation between PLR level for all-cause and CVD mortality varied with gender (p = 0.042 and p = 0.012, respectively). CONCLUSION: Higher PLR was associated with a higher risk of CVD mortality in female PD patients.

The incidence of pain and its association with quality of life in patients with peritoneal dialysis.

BACKGROUND: The aims of this study were to investigate the incidence of pain in peritoneal dialysis (PD) patients and to analyze the correlation between pain and quality of life. METHODS: PD patients who followed up in our PD center from March 2016 to December 2017 were included. The Short-Form McGill Pain Questionnaire was used to assess pain status. Depression status, sleep quality, quality of life and clinical data were also collected. RESULTS: A total of 463 PD patients were included, of whom 153 patients (33.1%) with pain. The main cause of pain was calcium and phosphorus metabolism disorder (51.6%). About 101 patients (66.0%) had multiple sites of pain, and 28 patients (18.3%) with pain were treated with analgesic drugs. Binary Logistic regression analysis showed that older age (OR = 1.026; p = 0.032) and higher intact parathyroid hormone level (OR = 1.043; p = 0.040) were independent risk factors for pain in PD patients. Multivariate analysis showed that score of pain rating index was an independent risk factor for depressive symptoms (OR = 1.100; p = 0.015), the score of Pittsburgh sleep quality index (B = 0.005; p = 0.044) and the score of physical component scale (B= -0.727; p = 0.016) in PD patients. CONCLUSIONS: The incidence of pain in PD patients was 33.1%. Older age and higher intact parathyroid hormone level were independent risk factors for pain. Pain was independently associated with depressive symptoms, sleep quality and quality of life in PD patients.

Risk Factors and Clinical Outcomes of Cognitive Impairment in Diabetic Patients Undergoing Peritoneal Dialysis.

INTRODUCTION: Cognitive impairment (CI) is common in patients with CKD or diabetes mellitus (DM). However, the relevance between DM and CI in diabetic patients undergoing peritoneal dialysis (PD) has not been clearly established. This study aimed to explore the role of DM in CI, the association of glycemic control with CI, and clinical outcomes of CI in diabetic PD patients. METHODS: Continuous ambulatory PD (CAPD) patients followed up in our PD center between 2014 and 2016 were enrolled. The participants were followed until an endpoint was reached or December 2017. Demographic data and clinical characteristics were collected, and laboratory parameters were measured. The Montreal Cognitive Assessment (MoCA) was used to evaluate global cognitive function, and a score of <26 was considered to indicate CI. A propensity score matching according to age, gender, and mean arterial pressure was conducted between the DM and non-DM groups. RESULTS: A total of 913 CAPD patients were enrolled, of whom 186 (20.4%) had diabetes. After appropriate matching, 175 patients in the DM group and 270 patients in the non-DM group were included. Patients with diabetes had a higher prevalence of CI and lower scores for visuospatial/executive function, naming, language, delayed recall, and orientation. Higher HbA1c (odds ratio [OR], 1.547; 95% confidence interval [95% CI], 1.013-2.362) and cardiovascular disease (CVD; OR, 2.926; 95% CI, 1.139-7.516) significantly correlated with a risk of CI in diabetic patients. During a median of 26.0 (interquartile range 13.5-35.6) months of follow-up, diabetic patients with CI demonstrated a significantly lower survival rate than those without CI, and CI was an independent risk factor for mortality after adjustment (hazard ratio, 7.224; 95% CI, 1.694-30.806). However, they did not show worse technique survival or higher peritonitis rate than patients without CI. CONCLUSIONS: HbA1c and CVD are independent risk factors for CI in diabetic patients undergoing CAPD, and CI is independently associated with a higher risk of mortality.

De novo transcriptome assemblies of Epicauta tibialis provide insights into the sexual dimorphism in the production of cantharidin.

Blister beetles have medicinal uses for their defensive secretion cantharidin, which has curative effects on many cancers and other diseases. It was demonstrated that sexual dimorphism exists in the production of cantharidin between male and female adults. This study performed a de novo assembly of Epicauta tibialis transcriptomes and analyzed the differentially expressed genes (DEGs) between male and female adults to help to find genes and pathways associated with cantharidin biosynthesis. A total of 99,295,624 paired reads were generated, and more than 7 Gb transcriptome data for each sample were obtained after trimming. The clean data were used to de novo assemble and then cluster into 27,355 unigenes, with a mean length of 1442 bp and an N50 of 2725 bp. Of these, 14,314 (52.33%) unigenes were annotated by protein databases. Differential expression analysis identified 284 differentially expressed genes (DEGs) between male and female adults. Nearly 239 DEGs were up-regulated in male adults than in female adults, while 45 DEGs were down-regulated. The Kyoto Encyclopedia of Gene and Genomes pathway enrichment manifested that seven up-regulated DEGs in male adults were assigned to the terpenoid biosynthesis pathway, to which 19 unigenes were annotated. The DEGs in the terpenoid biosynthesis pathway between male and female adults may be responsible for the sexual dimorphism in cantharidin production. The up-regulated genes assigned to the pathway in male adults may play a significant role in cantharidin biosynthesis, and its biosynthesis process is probably via the mevalonate pathway. The results would be helpful to better understand and reveal the complicated mechanism of the cantharidin biosynthesis.

Uric acid to high-density lipoprotein cholesterol ratio predicts cardiovascular mortality in patients on peritoneal dialysis.

BACKGROUND AND AIMS: Serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) disorders are both considered as risk factors of cardiovascular mortality. The predictive value of UA to HDL-C ratio (UHR) has been validated in diabetes. However, association of UHR with cardiovascular (CV) mortality is undetermined in peritoneal dialysis (PD) patients. METHODS AND RESULTS: In this retrospective cohort study, we enrolled 1953 eligible incident patients who commenced PD treatment on our hospital from January 1, 2006 to December 31, 2015, and followed up until December 31, 2019. Of the participants, 14.9% were older than 65 years (mean age 47.3 ± 15.2 years), 24.6% were diabetics, and 59.4% were male. Patients were categorized into quartiles according to baseline UHR level. Multivariate Cox Proportional Regression analysis was applied to explore the association of UHR with mortality. Overall, 567 patients died during a median follow-up period of 61.3 months, of which 274 (48.3%) were attributed to CV death. The mean baseline UHR was 16.4 ± 6.7%. Compared to quartile 2 UHR, hazard ratios (HRs) for the highest quartile UHR were 1.35 (95% confidence interval [CI] 1.06-1.78; P = 0.017) and 1.46 (95% CI 1.00-2.12; P = 0.047) for all-cause and CV mortality, respectively. Subgroup analysis showed that association of UHR with CV mortality was remarkable among PD patients with age ≥65 years, malnutrition (albumin <35 g/L), diabetes, and CVD history. CONCLUSIONS: An elevated UHR predicted increased risk of all-cause and CV mortality in PD patients.

Prevalence, risk factors and impact on outcomes of 30-day unexpected rehospitalization in incident peritoneal dialysis patients.

BACKGROUND: Rehospitalization is a major problem for end stage renal disease (ESRD) populations. However, researches on 30-day unexpected rehospitalzation of incident peritoneal dialysis (PD) patients were limited. This study aimed to investigate the prevalence, risk factors and impact on outcomes of 30-day unexpected rehospitalization in incident PD patients. METHODS: This was a retrospective cohort study. Patients who accepted PD catheter implantation in our centre from Jan 1, 2006 to Dec 31, 2013 and regular follow-up were included. The demographic characteristics, laboratory parameters, and rehospitalization data were collected and analyzed. The primary outcome was all-cause mortality, and the secondary outcomes included cardiovascular disease (CVD) mortality and technical failure. RESULTS: Totally 1632 patients (46.9 ± 15.3 years old, 60.1% male, 25.6% with diabetes) were included. Among them, 149 (9.1%) had a 30-day unexpected rehospitalization after discharge. PD-related peritonitis (n = 48, 32.2%), catheter malfunction (n = 30, 20.1%) and severe fluid overload (n = 19, 12.8%) were the top three causes for the rehospitalization. Multivariate logistic regression analysis showed that length of index hospital stays [Odds ratio (OR) =1.02, 95% confidence interval (CI) 1.00-1.03, P = 0.036) and hyponatremia (OR = 1.85, 95% CI 1.06-3.24, P = 0.031) were independently associated with the rehospitalization. Multivariate Cox regression analysis indicated that 30-day rehospitalization was an independent risk factor for all-cause mortality [Hazard ratio (HR) =1.52, 95% CI 1.07-2.16, P = 0.019) and CVD mortality (HR = 1.73, 95% CI 1.03-2.90, P = 0.038). CONCLUSIONS: The prevalence of 30-day unexpected rehospitalization for incident PD patients in our centre was 9.1%. The top three causes for the rehospitalization were PD-related peritonitis, catheter malfunction and severe fluid overload. Thirty-day unexpected rehospitalization increased the risk of all-cause mortality and CVD mortality for PD patients.

Extracellular matrix protein 1 promotes follicular helper T cell differentiation and antibody production.

T-follicular helper (TFH) cells are a subset of CD4+ helper T cells that help germinal center (GC) B-cell differentiation and high-affinity antibody production during germinal center reactions. Whether important extracellular molecules control TFH differentiation is not fully understood. Here, we demonstrate that a secreted protein extracellular matrix protein 1 (ECM1) is critical for TFH differentiation and antibody response. A lack of ECM1 inhibited TFH cell development and impaired GC B-cell reactions and antigen-specific antibody production in an antigen-immunized mouse model. ECM1 was induced by IL-6 and IL-21 in TFH cells, promoting TFH differentiation by down-regulating the level of STAT5 phosphorylation and up-regulating Bcl6 expression. Furthermore, injection of recombinant ECM1 protein into mice infected with PR8 influenza virus promoted protective immune responses effectively, by enhancing TFH differentiation and neutralizing antibody production. Collectively, our data identify ECM1 as a soluble protein to promote TFH cell differentiation and antibody production.

Association of brachial-ankle pulse wave velocity with cognitive impairment in peritoneal dialysis patients.

BACKGROUND: The relationship between cognitive impairment (CI) and arterial stiffness in peritoneal dialysis (PD) patients has not been clearly clarified. The aim of this study was to examine the relationship between CI and arterial stiffness in PD patients. METHODS: This cross-sectional study enrolled PD patients who performed a vascular profiler test at a single PD center in China between January 2014 and June 2016. The cognitive function was evaluated using the Montreal cognitive assessment (MoCA). A noninvasive vascular screening device was used to assess arterial stiffness relevant indicators. RESULTS: A total of 643 PD patients with median age 45 (37-57.4) years and median duration of PD 27.8 (8.7-56.4) months were enrolled. The rate of CI was 49.9%. The mean brachial-ankle pulse wave velocity (baPWV) was 17.2 ± 5.6 m/s. Compared with normal cognitive function group, patients with CI had higher baPWV (18.6 ± 7.0 vs. 15.8 ± 3.2 m/s), systolic blood pressure (150.3 ± 21.5 vs. 144.2 ± 20.2 mmHg), and pulse pressure (59.7 ± 14.7 vs. 52.5 ± 11.6 mmHg), and lower ankle-brachial index (ABI, 1.12 ± 0.12 vs. 1.15 ± 0.09) (all p<.05). Compared with systolic blood pressure, pulse pressure, and ABI in receiver operating characteristic (ROC) analysis, baPWV had better performance in predicting CI (area under curve: 0.68, 95% confidence interval: 0.64-0.72). BaPWV was independently associated with MoCA score (B per SD, -0.42 [95% confidence interval, -0.71 to -0.12]; p = .006) and CI (OR per SD, 1.55 [95% confidence interval, 1.11-2.17]; p = .011) in PD patients after adjustment for confounders. CONCLUSIONS: Higher baPWV was independently associated with CI in PD patients.

ECM1 Prevents Activation of Transforming Growth Factor ß, Hepatic Stellate Cells, and Fibrogenesis in Mice.

BACKGROUND & AIMS: Activation of TGFB (transforming growth factor ß) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

Higher Eosinophils Predict Death-Censored Technique Failure in Peritoneal Dialysis Patients.

INTRODUCTION: Eosinophilia (eosinophil fraction of leukocytes >5%), an indicative parameter for bioincompatibility in various circumstances, is well established in hemodialysis. However, change in eosinophil count (EOC) and its association with death-censored technique failure among peritoneal dialysis (PD) patients remain unclear. METHODS: We compared eosinophils before and after PD initiation among 1,432 eligible continuous ambulatory PD patients regularly followed up in our PD center during 2007-2018. Risk factors of early-stage eosinophilia were examined by the logistic regression test. The relationship of early-stage eosinophilia and EOC with death-censored technique failure was examined using the Cox proportional hazards model for overall patients and for men and women separately. RESULTS: After PD initiation, the EOC and percentage of patients with eosinophilia were significantly increased compared with baseline. Being male (odds ratio [OR]: 2.26; 95% confidence interval [CI]: 1.55-3.31; p < 0.001) and higher EOC at baseline (100 cells/µL increase, OR: 1.62; 95% CI: 1.45-1.82; p < 0.001) were risk factors of early-stage eosinophilia after PD initiation. During follow-up, 204 death-censored technique failures were recorded. In fully adjusted models, each with 100 cells/µL increase in EOC, the adjusted hazard ratios (HRs) of technique failure were 1.11 (95% CI: 1.03-1.20; p = 0.009) in the whole cohort, 1.29 (95% CI: 1.10-1.51; p = 0.002) in women, and 1.07 (95% CI: 0.97-1.17; p = 0.196) in men. Eosinophilia was significantly associated with the risk of technique failure for women (HR: 2.24; 95% CI: 1.07-4.70; p = 0.033), which was especially significant for women aged <55 years (HR: 7.61; 95% CI: 1.88-30.90; p = 0.005). CONCLUSION: EOC was increased significantly after PD initiation, and increased numbers of eosinophils were associated with higher death-censored technique failure in PD patients, especially women.