Early Anuria in Incident Peritoneal Dialysis Patients: Incidence, Risk Factors, and Associated Clinical Outcomes.

Rationale & Objective: The development of anuria has been linked to worse clinical outcomes in patients undergoing peritoneal dialysis (PD). Our objective was to investigate the incidence, risk factors, and associated clinical outcomes of anuria within the first year after starting PD. Study Design: Retrospective cohort study. Setting & Participants: Patients who started continuous ambulatory peritoneal dialysis at our center between 2006 and 2020 were included and followed up until January 31, 2023. Exposure: Age, sex, diabetes, temporary hemodialysis, angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs), diuretics, baseline urine volume, serum albumin, daily glucose exposure, peritonitis, and incremental PD. Outcomes: The primary outcome was early anuria, defined as 24-hour urine volume ≤100 mL within the first year of PD initiation. Secondary outcomes included all-cause mortality, cardiovascular disease mortality, technique failure, and peritonitis. Analytical Approach: Cox proportional hazards model. Results: A total of 2,592 patients undergoing continuous ambulatory peritoneal dialysis aged 46.7 ± 14.9 years were recruited. Among them, 58.9% were male, and 24.0% had diabetes. Within the first year of PD therapy, 159 (6.13%) patients developed anuria, with a median duration of 7.53 (interquartile range, 3.93-10.0) months. Higher baseline urine volume (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.90-0.97), higher serum albumin (HR, 0.92; 95% CI, 0.88-0.95), having diabetes before PD (HR, 0.57; 95% CI, 0.35-0.92), and prescribed incremental PD (HR, 0.27; 95% CI, 0.14-0.51) were associated with a reduced risk for early anuria, whereas a higher level of daily glucose exposure (HR, 1.01; 95% CI, 1.00-1.01) was identified as a risk factor for early anuria. Subgroup analyses showed that using ACEis or ARBs was linked to a lower risk of early anuria (HR, 0.25; 95% CI, 0.09-0.69) in diabetic patients. Treating early anuria as a time-dependent covariate, early anuria was associated with a higher risk for all-cause mortality (HR, 1.69; 95% CI, 1.23-2.32) and technique failure (HR, 1.43; 95% CI, 1.00-2.04) after adjusting for confounding factors. Limitations: Single-center and observational study. Conclusions: Among PD patients at a single center in China, early anuria was relatively uncommon but associated with an increased risk of mortality and PD technique failure. Incremental PD, higher baseline urine output and serum albumin, and lower daily glucose exposure were associated with a lower risk of early anuria. Clinical trials are needed to evaluate the optimal PD techniques to preserve residual kidney function and maximaze outcomes.

The development of anuria has been linked to worse clinical outcomes in patients undergoing peritoneal dialysis (PD). However, does the development of early anuria, which is defined as 24-hour urine volume ≤100 mL, within the first year after PD initiation influence the clinical outcomes of these patients? What are the predictors of early anuria? We conducted a single-center retrospective cohort study and found lower baseline urine volume, lower serum albumin, full-dose PD start, absence of diabetes mellitus, higher daily glucose exposure, and in patients with diabetes mellitus, non-use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers were associated with early anuria. Early anuria was related to a higher risk for all-cause mortality and technique failure. The results provide information for optimizing patient care and improving the prognosis of patients undergoing PD.

Tumor enhancement and shrinkage pattern in dynamic contrast-enhanced magnetic resonance imaging for predicting pathologic complete response after human epidermal growth factor receptor 2 (HER2)-targeted therapy in breast cancer.

Background: Targeted therapy with neoadjuvant chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has increased the rates of pathological complete response (pCR) and breast preservation surgery and improved the overall disease-free survival rate. This study aimed to determine whether tumor enhancement and shrinkage patterns in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can predict the efficacy of targeted therapy in patients with HER2-positive breast cancer and differentiate pCR from non-pCR. Methods: The data of 64 patients with HER2-positive breast cancer who received targeted therapy prior to surgery were retrospectively collected. All patients had complete postoperative pathological data. The pretreatment evaluation of the tumor enhancement pattern and the shrinkage pattern after two treatment cycles were assessed. The difference in the enhancement and shrinkage patterns between the pCR and non-pCR groups was evaluated via the χ2 test. Logistic regression analysis was used to assess the value of enhancement and shrinkage patterns for predicting pCR in patients with HER2-positive breast cancer. Results: There were statistically significant differences in tumor size, estrogen receptor (ER) status, lymph node metastasis, enhancement pattern, and shrinkage pattern between the pCR and non-pCR cases. Patients with a tumor size ≤20 mm were likely to achieve pCR. ER status, lymph node metastasis, and enhancement and shrinkage patterns each had good precision for predicting pCR, and the combination of enhancement and shrinkage patterns had the highest prediction accuracy. Multivariate logistic regression analysis indicated that only enhancement pattern had a significant predictive value. Conclusions: Among patients with HER2-positive breast cancer, those with tumor size ≤20 mm, ER-negative status, no lymph node metastases, and mass enhancement and concentric shrinkage patterns are more likely to achieve pCR. Mass enhancement combined with concentric shrinkage had the highest accuracy in predicting pCR, indicating that preoperative imaging may be useful for guiding clinical decisions regarding targeted treatments.

Identification and Prediction of Differentially Expressed MicroRNAs Associated with Detoxification Pathways in Larvae of Spodoptera frugiperda.

Spodoptera frugiperda poses a severe threat to crops, causing substantial economic losses. The increased use of chemical pesticides has led to resistance in S. frugiperda populations. Micro ribonucleic acids (MicroRNAs or miRNAs) are pivotal in insect growth and development. This study aims to identify miRNAs across different developmental stages of S. frugiperda to explore differential expression and predict target gene functions. High-throughput sequencing of miRNAs was conducted on eggs, 3rd instar larvae, pupae, and adults. Bioinformatics analyses identified differentially expressed miRNAs specifically in larvae, with candidate miRNAs screened to predict target genes, particularly those involved in detoxification pathways. A total of 184 known miRNAs and 209 novel miRNAs were identified across stages. Comparative analysis revealed 54, 15, and 18 miRNAs differentially expressed in larvae, compared to egg, pupa, and adult stages, respectively. Eight miRNAs showed significant differential expression across stages, validated by quantitative reverse transcription PCR (qRT-PCR). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses predicted target genes' functions, identifying eight differentially expressed miRNAs targeting 10 gene families associated with detoxification metabolism, including P450s, glutathione S-transferase (GSTs), ATP-binding cassette (ABC) transporters, and sodium channels. These findings elucidate the species-specific miRNA profiles and regulatory mechanisms of detoxification-related genes in S. frugiperda larvae, offering insights and strategies for effectively managing this pest.

Effect of a Management Algorithm for Wet Contamination of Peritoneal Dialysis System on the Prevention of Peritonitis: A Prospective Observational Study.

Introduction: Wet contamination was a common problem of peritoneal dialysis (PD) system. We developed a management algorithm for wet contamination of PD system (wet contamination) on the basis of the related research literature and clinical practice experience. The purpose of this study was to observe clinical effect of the management algorithm on the prevention of peritonitis. Methods: Patients treated wet contamination in a single PD center between October 2017 and September 2022 were included. A management algorithm was established to treat wet contamination. It comprised identification of the contamination type, addressing contaminated or aging catheters, prophylactic antibiotics, and retraining. Demographic data and clinical data about wet contamination were collected and compared. Results: One hundred and forty-one cases of wet contamination were included in this study. The mean age was 51.7 ± 14.1 years, and 49.6% were female. The proportion of diabetic nephropathy was 9.9%. The median PD duration was 27.0 (1.7-79.7) months. Eighteen episodes (12.8%) of wet contamination-associated peritonitis developed after wet contamination. The main pathogenic bacteria of peritonitis were Gram-positive bacteria (33.3%) and Gram-negative bacteria (27.8%). The incidence of wet contamination-associated peritonitis in the compliance with the management algorithm group was significantly lower than that in the non-compliance with the management algorithm group (0.9 vs. 48.6%; p < 0.001). Non-compliance with management algorithm (OR = 185.861, p < 0.001) together with advance age (OR = 1.116, p < 0.001) and longer distance from home to hospital (OR = 1.007, p < 0.001) were independent risk factors for wet contamination-associated peritonitis. Conclusion: The management algorithm for wet contamination of PD system could reduce the risk of peritonitis.

Differential diagnostic value of radiomics models in benign versus malignant vertebral compression fractures: A systematic review and meta-analysis.

PURPOSE: Early diagnosis of benign and malignant vertebral compression fractures by analyzing imaging data is crucial to guide treatment and assess prognosis, and the development of radiomics made it an alternative option to biopsy examination. This systematic review and meta-analysis was conducted with the purpose of quantifying the diagnostic efficacy of radiomics models in distinguishing between benign and malignant vertebral compression fractures. METHODS: Searching on PubMed, Embase, Web of Science and Cochrane Library was conducted to identify eligible studies published before September 23, 2023. After evaluating for methodological quality and risk of bias using the Radiomics Quality Score (RQS) and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), we selected studies providing confusion matrix results to be included in random-effects meta-analysis. RESULTS: A total of sixteen articles, involving 1,519 vertebrae with pathological-diagnosed tumor infiltration, were included in our meta-analysis. The combined sensitivity and specificity of the top-performing models were 0.92 (95 % CI: 0.87-0.96) and 0.93 (95 % CI: 0.88-0.96), respectively. Their AUC was 0.97 (95 % CI: 0.96-0.99). By contrast, radiologists' combined sensitivity was 0.90 (95 %CI: 0.75-0.97) and specificity was 0.92 (95 %CI: 0.67-0.98). The AUC was 0.96 (95 %CI: 0.94-0.97). Subsequent subgroup analysis and sensitivity test suggested that part of the heterogeneity might be explained by differences in imaging modality, segmentation, deep learning and cross-validation. CONCLUSION: We found remarkable diagnosis potential in correctly distinguishing vertebral compression fractures in complex clinical contexts. However, the published radiomics models still have a great heterogeneity, and more large-scale clinical trials are essential to validate their generalizability.

Clinical characteristics and antibiotic treatment of peritoneal dialysis-associated peritonitis caused by Pseudomonas species: a review of 15 years' experience from southern China.

Pseudomonas can lead to peritoneal dialysis-associated peritonitis, which is characterized by a poor prognosis, such as a substantial failure rate and a high death rate. This study aimed to provide an overview of Pseudomonas peritonitis's clinical features, the regimens of antibiotic, antibiotic resistance, and outcomes in peritoneal dialysis (PD) patients. This study observed patients with Pseudomonas peritonitis in two large PD centers in South China from January 2008 to December 2022. The demographics, symptomatology, antibiotics regimens, resistance to common antibiotics, and clinical outcomes of all included patients were reviewed. A total of 3,459 PD patients were included, among them 57 cases of peritonitis caused by Pseudomonas, including 48 cases (84.2%) of Pseudomonas aeruginosa. The incidence rate of Pseudomonas peritonitis was 0.0041 episode per patient-year. Of them, 28.1% (16 cases) of the patients were accompanied by exit site infection (ESI), and all had abdominal pain and turbid ascites at the time of onset. The most commonly used antibiotic combination was ceftazidime combined with amikacin. Approximately 89% of Pseudomonas species were sensitive to ceftazidime, and 88% were sensitive to amikacin. The overall primary response rate was 28.1% (16 patients), and the complete cure rate was 40.4% (23 patients). There was no significant difference in the complete cure rate of peritonitis using three and other antibiotic treatment regimens (44.8% vs 46.4%; P = 0.9). The successful treatment group had higher baseline albumin level (35.9 ± 6.2; P = 0.008) and residual urine volume (650.7 ± 375.5; P = 0.04). Although the incidence of peritonitis caused by Pseudomonas was low, the symptoms were serious, and prognosis was very poor. Pseudomonas was still highly susceptible to first-line antibiotics currently in use against Gram-negative bacteria. Patients with successful treatment had higher albumin levels and higher urine output. IMPORTANCE: Although the incidence of peritoneal dialysis-associated peritonitis caused by Pseudomonas is very low, it seriously affects the technique survival of peritoneal dialysis patients. However, there are few studies and reports on Pseudomonas peritonitis in the Chinese mainland area. Therefore, the purpose of this study is to describe the clinical characteristics, the regimens of antibiotic, drug resistance, and outcome of peritoneal dialysis patients in southern China in the past 15 years and summarize the clinical experience in the treatment of Pseudomonas peritonitis.

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.

Broadly neutralizing antibodies to combat influenza virus infection.

The diversified classification and continuous alteration of influenza viruses underscore for antivirals and vaccines that can counter a broad range of influenza subtypes. Hemagglutinin (HA) and neuraminidase (NA) are two principle viral surface targets for broadly neutralizing antibodies. A series of monoclonal antibodies, targeting HA and NA, have been discovered and characterized with a wide range of neutralizing activity against influenza viruses. Clinical studies have demonstrated the safety and efficacy of some HA stem-targeting antibodies against influenza viruses. Broadly neutralizing antibodies (bnAbs) can serve as both prophylactic and therapeutic agents, as well as play a critical role in identifying antigens and epitopes for the development of universal vaccines. In this review, we described and summarized the latest discoveries and advancements of bnAbs against influenza viruses in both pre- and clinical development. Additionally, we assess whether bnAbs can serve as a viable alternative to vaccination against influenza. Finally, we discussed the rationale behind reverse vaccinology, a structure-guided universal vaccine design strategy that efficiently identifies candidate antigens and conserved epitopes that can be targeted by antibodies.

The centre-calculated cutoff value is better for identifying fast peritoneal solute transfer of patients on peritoneal dialysis than the traditional value: a retrospective cohort study.

Background: The mean 4-h dialysate to plasma ratio of creatinine (4-h D/Pcr) is a vital cutoff value for recognizing the fast peritoneal solute transfer rate (PSTR) in patients on peritoneal dialysis (PD); however, it shows a noticeable centre effect. We aimed to investigate our centre-calculated cutoff value (CCV) of 4-h D/Pcr and compare it with the traditional cutoff value (TCV) (0.65). Methods: In this study, we enrolled incident PD patients at our centre from 2008 to 2019, and divided them into fast or non-fast PSTR groups according to baseline 4-h D/Pcr-based CCV or TCV. We compared the efficiency of the fast PSTR recognized by two cutoff values in predicting mortality, ultrafiltration (UF) insufficiency and technical survival. Results: In total, 1905 patients were enrolled, with a mean 4-h D/Pcr of 0.71 ± 0.11. Compared with TCV (0.65), CCV (0.71) showed superiority in predicting mortality of PD patients [hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.02-1.59 vs HR 1.24, 95% CI 0.97-1.59]. The odds ratio (OR) of the fast PSTR in centre classification was slightly higher than traditional classification in predicting UF insufficiency (OR 1.67, 95% CI 1.25-2.24 vs OR 1.60, 95% CI 1.15-2.22). Additionally, the restricted cubic splines 4-h D/Pcr has an S-shaped association with mortality and UF insufficiency, and the inflection points of 4-h D/Pcr were 0.71 (equal to CCV). Conclusions: The CCV of 4-h D/Pcr for identifying fast PSTR was 0.71. It was superior to TCV in predicting mortality and UF insufficiency.

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.

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.

Solar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary-lung axis.

The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar ultraviolet (UV) radiation is not fully understood. Here, we show a possible negative correlation between solar UVB radiation and asthmatic inflammation in humans and mice. UVB exposure to the eyes induces hypothalamus-pituitary activation and α-melanocyte-stimulating hormone (α-MSH) accumulation in the serum to suppress allergic airway inflammation by targeting group 2 innate lymphoid cells (ILC2) through the MC5R receptor in mice. The α-MSH/MC5R interaction limits ILC2 function through attenuation of JAK/STAT and NF-κB signaling. Consistently, we observe that the plasma α-MSH concentration is negatively correlated with the number and function of ILC2s in the peripheral blood mononuclear cells (PBMC) of patients with asthma. We provide insights into how solar UVB radiation-driven neuroendocrine α-MSH restricts ILC2-mediated lung inflammation and offer a possible strategy for controlling allergic diseases.

Remnant cholesterol predicts cardiovascular mortality beyond low-density lipoprotein cholesterol in patients with peritoneal dialysis.

BACKGROUND: Patients undergoing peritoneal dialysis (PD) are prone to dyslipidemia. However, studies concerning remnant cholesterol (RC) in such patients are limited. OBJECTIVE: We aimed to investigate the association between RC and cardiovascular (CV) mortality in patients on PD. METHODS: Patients who initiated PD at our center (2006-2018) were retrospectively enrolled. Adjusted Cox models were used to evaluate the independent association between baseline RC levels and CV mortality. We classified patients into 4 concordant/discordant categories according to their baseline lipid profiles. Cox models were then used to determine the association between different low-density lipoprotein cholesterol (LDL-C) and RC levels and CV mortality risk. RESULTS: The study enrolled 2333 individuals, with a mean RC of 33.4 mg/dL. RC levels were positively associated with CV mortality risk independent of LDL-C in patients on PD (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1. 00-1.10). In the concordant/discordant categories, patients with high LDL-C and RC levels had a higher CV mortality risk (HR: 1.52; 95% CI: 1.01-2.28) than those with low LDL-C and RC levels in the entire cohort. Moreover, in older patients, a higher RC level increased CV mortality risk regardless of the LDL-C level (HR: 2.41, 95% CI: 1.22-4.74; HR: 2.15, 95% CI: 1.12-4.14). CONCLUSIONS: RC levels are elevated in patients on PD and can predict CV mortality beyond LDL-C levels. RC levels should be considered alongside LDL-C levels when assessing prognostic lipid levels in these patients. More attention should be given to RC than to LDL-C in older patients undergoing PD.

The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation.

The Mulibrey (Muscle-liver-brain-eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FINmajor (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.

Incremental peritoneal dialysis and survival outcomes: a propensity-matched cohort study.

BACKGROUND: The advantages of an incremental dialysis start are not fully clear. We aimed to evaluate the association of incremental initiation of peritoneal dialysis with mortality. METHODS: Incident peritoneal dialysis patients with a catheter placed at our hospital between 2008 and 2017 were included. All patients were followed up until December 31, 2019. Patients were categorized into different groups according to the initial daily dialysis exchanges, and were matched at a ratio of 1:2 with propensity score matching. Multiple variables including age, sex, residual kidney function, urine volume, hemoglobin, serum albumin and other important variables were included for the matching. Primary outcomes were all-cause and cardiovascular mortality. RESULTS: A total of 1315 patients with a mean age of 45.9 years were enrolled. The mean glomerular filtration rate was 4.32 ml/min/1.73 m2 at start of dialysis. Two hundred eighty-five patients in the incremental group and 502 in the full dose group were matched for age, sex, residual kidney function, urine volume, hemoglobin, serum albumin and other important variables. Patient survival and cardiovascular event-free survival were similar between the two groups. However, during the first 6 years of peritoneal dialysis, patients in the incremental group had better survival (P = 0.011) and cardiovascular event-free survival (P = 0.044) than the full dose group, while such advantages disappeared when dialysis vintage became longer. Further analysis showed that the incremental group (vs full dose dialysis) had a 39% lower risk (95% CI 0.42-0.90, P = 0.012) of all-cause mortality and a 41% decreased risk (95% CI 0.35-0.99, P = 0.047) of cardiovascular mortality during the first 6 years of dialysis. Additionally, the cumulative hazard for anuria was significantly lower in the incremental group versus the full dose group (P = 0.006). CONCLUSIONS: Our study shows a time-related survival advantage for incremental peritoneal dialysis patients, suggesting that an incremental regimen for starting peritoneal dialysis is feasible and is not associated with worse outcomes. Graphical Abstract presenting schematically the measurements of the solvation response function by processing the relevant streak camera images and the time-correlated photon counting (TCSPC) data and appropriately combining them together.

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.

Vitamin B6 regulates IL-33 homeostasis to alleviate type 2 inflammation.

Interleukin-33 (IL-33) is a crucial nuclear cytokine that induces the type 2 immune response and maintains immune homeostasis. The fine-tuned regulation of IL-33 in tissue cells is critical to control of the type 2 immune response in airway inflammation, but the mechanism is still unclear. Here, we found that healthy individuals had higher phosphate-pyridoxal (PLP, an active form of vitamin B6) concentrations in the serum than asthma patients. Lower serum PLP concentrations in asthma patients were strongly associated with worse lung function and inflammation. In a mouse model of lung inflammation, we revealed that PLP alleviated the type 2 immune response and that this inhibitory effect relied on the activity of IL-33. A mechanistic study showed that in vivo, pyridoxal (PL) needed to be converted into PLP, which inhibited the type 2 response by regulating IL-33 stability. In mice heterozygous for pyridoxal kinase (PDXK), the conversion of PL to PLP was limited, and IL-33 levels were increased in the lungs, aggravating type 2 inflammation. Furthermore, we found that the mouse double minute 2 homolog (MDM2) protein, an E3 ubiquitin-protein ligase, could ubiquitinate the N-terminus of IL-33 and sustain IL-33 stability in epithelial cells. PLP reduced MDM2-mediated IL-33 polyubiquitination and decreased the level of IL-33 through the proteasome pathway. In addition, inhalation of PLP alleviated asthma-related effects in mouse models. In summary, our data indicate that vitamin B6 regulates MDM2-mediated IL-33 stability to constrain the type 2 response, which might help develop a potential preventive and therapeutic agent for allergy-related diseases.

A human antibody potently neutralizes RSV by targeting the conserved hydrophobic region of prefusion F.

Respiratory syncytial virus (RSV) continues to pose serious threats to pediatric populations due to the lack of a vaccine and effective antiviral drugs. RSV fusion (F) glycoprotein mediates viral-host membrane fusion and is a key target for neutralizing antibodies. We generated 23 full-human monoclonal antibodies (hmAbs) against prefusion F protein (pre-F) from a healthy adult with natural RSV infection by single B cell cloning technique. A highly potent RSV-neutralizing hmAb, named as 25-20, is selected, which targets a new site Ø-specific epitope. Site-directed mutagenesis and structural modelling analysis demonstrated that 25-20 mainly targets a highly conserved hydrophobic region located at the a4 helix and a1 helix of pre-F, indicating a site of vulnerability for drug and vaccine design. It is worth noting that 25-20 uses an unreported inferred germline (iGL) that binds very poorly to pre-F, thus high levels of somatic mutations are needed to gain high binding affinity with pre-F. Our observation helps to understand the evolution of RSV antibody during natural infection. Furthermore, by in silico prediction and experimental verification, we optimized 25-20 with KD values as low as picomolar range. Therefore, the optimized 25-20 represents an excellent candidate for passive protection against RSV infection.

The Adaptive Evolution in the Fall Armyworm Spodoptera frugiperda (Lepidoptera: Noctuidae) Revealed by the Diversity of Larval Gut Bacteria.

Insect gut microbes have important roles in host feeding, digestion, immunity, development, and coevolution with pests. The fall armyworm, Spodoptera frugiperda (Smith, 1797), is a major migratory agricultural pest worldwide. The effects of host plant on the pest's gut bacteria remain to be investigated to better understand their coevolution. In this study, differences in the gut bacterial communities were examined for the fifth and sixth instar larvae of S. frugiperda fed on leaves of different host plants (corn, sorghum, highland barley, and citrus). The 16S rDNA full-length amplification and sequencing method was used to determine the abundance and diversity of gut bacteria in larval intestines. The highest richness and diversity of gut bacteria were in corn-fed fifth instar larvae, whereas in sixth instar larvae, the richness and diversity were higher when larvae were fed by other crops. Firmicutes and Proteobacteria were dominant phyla in gut bacterial communities of fifth and sixth instar larvae. According to the LDA Effect Size (LEfSe) analysis, the host plants had important effects on the structure of gut bacterial communities in S. frugiperda. In the PICRUSt2 analysis, most predicted functional categories were associated with metabolism. Thus, the host plant species attacked by S. frugiperda larvae can affect their gut bacterial communities, and such changes are likely important in the adaptive evolution of S. frugiperda to host plants.