Population pharmacokinetics and dose optimization of levofloxacin in elderly patients with pneumonia.

AIMS: Levofloxacin is a quinolone antibiotic with a broad antibacterial spectrum. It is frequently used in elderly patients with pneumonia. The pharmacokinetic profile of elderly patients changes with age, but data on the pharmacokinetics of levofloxacin in these patients are limited. The aim of this study was to establish a population pharmacokinetic model of levofloxacin in elderly patients with pneumonia and to optimize individualized dosing regimens based on this newly developed model. METHODS: This is a prospective, open-label pharmacokinetic study in elderly patients with pneumonia. Blood samples were collected using an opportunistic approach. The plasma concentrations of levofloxacin were determined by high-performance liquid chromatography. A population pharmacokinetic model was established using nonlinear mixed-effect model software. Monte Carlo simulations were used for dose simulation and dose optimization. RESULTS: Data from 51 elderly patients with pneumonia were used for the population pharmacokinetic analysis. A one-compartment model with first-order elimination was most suitable for describing the data, and the estimated glomerular filtration rate was the only covariate that had a significant impact on the model. The final model estimated that the mean clearance of levofloxacin in elderly patients with pneumonia was 5.26 L/h. Monte Carlo simulation results showed that the optimal dosing regimen for levofloxacin was 750 mg once a day in elderly patients with pneumonia, with a minimum inhibitory concentration of 2 mg/L. CONCLUSIONS: The population pharmacokinetic model of levofloxacin in elderly patients with pneumonia was established, and the dose optimization of levofloxacin was completed through Monte Carlo simulation.

A novel approach to exploit Small-Molecule glucagon-like Peptide-1 receptor agonists with high potency.

Small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonists are recognized as promising therapeutics for type 2 diabetes mellitus (T2DM) and obesity. Danuglipron, an investigational small-molecule agonist, has demonstrated high efficacy in clinical trials. However, further development of danuglipron is challenged by a high rate of gastrointestinal adverse events. While these effects may be target-related, it is plausible that the carboxylic acid group present in danuglipron may also play a role in these outcomes by affecting the pharmacokinetic properties and dosing regimen of danuglipron, as well as by exerting direct gastrointestinal irritation. Therefore, this study aims to replace the problematic carboxylic acid group by exploring the internal binding cavity of danuglipron bound to GLP-1R using a water molecule displacement strategy. A series of novel triazole-containing compounds have been designed and synthesized during the structure-activity relationship (SAR) study. These efforts resulted in the discovery of compound 2j with high potency (EC50 = 0.065 nM). Moreover, docking simulations revealed that compound 2j directly interacts with the residue Glu387 within the internal cavity of GLP-1R, effectively displacing the structural water previously bound to Glu387. Subsequent in vitro and in vivo experiments demonstrated that compound 2j had comparable efficacy to danuglipron in enhancing insulin secretion and improving glycemic control. Collectively, this study offers a practicable approach for the discovery of novel small-molecule GLP-1R agonists based on danuglipron, and compound 2j may serve as a lead compound to further exploit the unoccupied internal cavity of danuglipron's binding pocket.

Discovery of betulinic acid derivatives as gut-restricted TGR5 agonists: Balancing the potency and physicochemical properties.

The pleiotropic effects of TGR5 make it an appealing target for intervention of metabolic and inflammatory disorders, but systemic activation of TGR5 faces challenges of on-target side effects, especially gallbladder filling. Gut-restricted agonists were proved to be sufficient to circumvent these side effects, but extremely low systemic exposure may not be effective in activating TGR5 since it is located on the basolateral membrane. Herein, to balance potency and physicochemical properties, a series of gut-restricted TGR5 agonists with diversified kinetophores had been designed and synthesized. Compound 22-Na exhibited significant antidiabetic effect, and showed favorable gallbladder safety after 7 days of oral administration in humanized TGR5H88Y mice, confirming that gut-restricted agonism of TGR5 is a viable strategy to alleviate systemic target-related effects.

Topoisomerase Inhibitors and PIM1 Kinase Inhibitors Improve Gene Editing Efficiency Mediated by CRISPR-Cas9 and Homology-Directed Repair.

The CRISPR-Cas9 system has emerged as the most prevalent gene editing technology due to its simplicity, high efficiency, and low cost. However, the homology-directed repair (HDR)-mediated gene knock-in in this system suffers from low efficiency, which limits its application in animal model preparation, gene therapy, and agricultural genetic improvement. Here, we report the design and optimization of a simple and efficient reporter-based assay to visualize and quantify HDR efficiency. Through random screening of a small molecule compound library, two groups of compounds, including the topoisomerase inhibitors and PIM1 kinase inhibitors, have been identified to promote HDR. Two representative compounds, etoposide and quercetagetin, also significantly enhance the efficiency of CRISPR-Cas9 and HDR-mediated gene knock-in in mouse embryos. Our study not only provides an assay to screen compounds that may facilitate HDR but also identifies useful tool compounds to facilitate the construction of genetically modified animal models with the CRISPR-Cas9 system.

Evaluation of guidelines for the diagnosis and treatment of achalasia.

Due to the unclear quality of the current guidelines, users may be confused about how to diagnose and treat achalasia. The objective of this work is to systematically evaluate the methodological quality of the current guidelines for diagnosing and treating achalasia and to determine the heterogeneity among recommendations. We systematically searched literature databases to retrieve relevant guidelines for the diagnosis and treatment of achalasia. The Appraisal of Guidelines for Research and Evaluation II tool was used to evaluate the quality of the included guidelines. Key recommendations in the guidelines were extracted, and the reasons for the heterogeneity of the key recommendations between different guidelines were further analyzed. Seven guidelines on the diagnosis and treatment of achalasia are included in this study. The overall score of three guidelines exceeded 60%. The average score in domain 5 was the lowest, at 41.8%. The average scores in domain 2, domain 3, and domain 6 were also low, at 45.4%, 57.1% and 56.9%, respectively. The main recommendations and quality of evidence for different guidelines vary greatly, mainly due to the different emphases among different guidelines, the lack of systematic retrieval, or the unfairness of evidence use in some guidelines. There are considerable differences in the methodological quality of diagnosis and treatment guidelines for achalasia. Additionally, the differences in the main recommendations and evidence support among guidelines are also obvious. Guideline developers should improve the above related factors to decrease the heterogeneity, and they should further formulate or update the guidelines for the diagnosis and treatment of achalasia.

Electrochemical skin conductance and heart rate variability in patients with non-dialysis chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is very common now and associates with high overall and cardiovascular mortality. Numerous studies have reported that Heart rate variability (HRV) could also be used to detect cardiovascular autonomic dysfunction (CAD). We investigated the association of electrochemical skin conductance (ESC) of EZSCAN results with HRV in non-dialysis CKD patients. METHODS: In a cross-sectional study, we enrolled 248 prevalent non-dialysis CKD patients. Patients underwent a 24-h Holter (CB-2302-A, Bio Instrument, China). A time domain analysis of HRV was performed, and the following parameters were obtained: SDNN, SDANN, rMSSD, pNN50. EZSCAN device (Impeto Medical, Paris, France) measures ESC values of each participants. Mean global skin conductance computed as 0.5 * (reflecting (right + left hand)/2 + (right and left foot)/2). Log transforms data into a normal distribution for statistical analysis. RESULTS: There were 142 males and 106 females included in the present study. Patients' age was 56.6±17.08 years. Logarithm(Log) (global ESC) was independently predicted by age (P<0.01), hypertension history, estimated Glomerular filtration rate (eGFR) and log SDNN (P<0.05). While log SDANN, rMSSD and pNN50 were not independent predictors for log (global ESC). CONCLUSION: Increased global ESC significantly associated with elevated HRV, specifically SDNN in non-dialysis CKD patients. This suggested that global ESC may appear to be an important predictor of CAD, and even could be used as a cardiovascular risk factor in non-dialysis CKD patients.

Molecular epidemiology and change trend of methicillin-resistant Staphylococcus aureus from invasive infections of a hospital in Hangzhou from 2012 to 2018.

The disease caused by methicillin-resistant Staphylococcus aureus (MRSA) is a global public health challenge that threatens society and patients seriously. Therefore, the molecular epidemiology and change trend of MRSA is essential for the control and treatment of diseases caused by the pathogen in their regions. To explore molecular epidemiology of MRSA in Hangzhou, we collected 162 MRSA isolates from 2012 to 2018, conducted the antimicrobial susceptibility and used polymerase chain reaction(PCR) to test the molecular typing including multilocus sequence typing (MLST), staphylococcal chromosome cassette mec (SCCmec), staphylococcal protein A (spa A) and Panton-Valentine leucocidin (PVL). All the strains was divided into community-associated MRSA (CA-MRSA) or hospital-associated MRSA (HA-MRSA). 162 MRSA isolates were divided into 16 STs and 30 spa types. The major ST type was ST5 (96/162, 59.3%) and the predominant spa type was t311 (83/162, 51.2%). Five SCCmec types were found and the most common SCCmec type was type II (101/162, 61.7%). ST5-II-t311 was the predominant MRSA clone. And the prevalence of ST5 MRSA gradually declined from 2014 to 2018 but the prevalence of ST59 MRSA significantly increased. At the same time, livestock-associated methicillin-resistant Staphylococcus aureus(LA-MRSA) ST398 and ST9 were detected. Twenty-eight isolates were PVL gene positive (28/162, 17.3%). The most prevalent PVL-positive clone was ST59-IVa-t437. Comparing with HA-MRSA, CA-MRSA had a lower probability of ST5 (9.1% vs 67.1%, P=0.000) but a higher probability of ST59 (63.6% vs 11.4%, P=0.000), not only that, it was more likely to carrying PVL-positive gene (36.4% vs 14.3%, P=0.028). In summary, the molecular types of MRSA were getting complex over time. ST5-II-t311 was the predominant clone of MRSA isolate with a downward incidence from 2014 to 2018. ST59 MRSA strains, which is thought community related strain are spreading into hospitals and has an upward incidence from 2014 to 2018.

Recent progress in assays for GPCR drug discovery.

G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors, are the largest family of cell surface receptors in eukaryotes. There are ∼800 GPCRs in human, regulating diverse physiological processes. The GPCRs are the most intensively studied drug targets. Drugs that target GPCRs account for about a quarter of the global market share of therapeutic drugs. Therefore, to develop physiologically relevant and robust assays to search new GPCR ligands or modulators remain the major focus of drug discovery research worldwide. Early functional GPCR assays mainly depend on the measurement of G-protein-mediated second messenger generation. Recent developments in GPCR biology indicate that the signaling of these receptors is much more complex than the oversimplified classical view. The GPCRs have been found to activate multiple G proteins simultaneously and induce ß-arrestin-mediated signaling. They have also been found to interact with other cytosolic scaffolding proteins and form dimer or heteromer with GPCRs or other transmembrane proteins. Here, we mainly discuss technologies focused on detecting protein-protein interactions, such as fluorescence resonance energy transfer/bioluminescence resonance energy transfer (FRET/BRET), NanoLuc binary technology (NanoBiT), Tango, etc., and their applications in measuring GPCRs interacting with various signaling partners. In the final part, we also discuss the species differences in GPCRs when using animal models to study the in vivo functions of GPCR ligands, and possible ways to solve this problem with modern genetic tools.

Solasonine induces apoptosis of the SGC-7901 human gastric cancer cell line in vitro via the mitochondria-mediated pathway.

Solasonine, a steroidal glycoalkaloid isolated from the herbal plant Solanum nigrum Linn., has shown active against multiple human cancers; however, there is little knowledge on the activity of solasonine against gastric cancer until now. This study aimed to examine the effect of solasonine on the biological behaviours of human gastric cancer SGC-7901 cells. The results showed that solasonine suppressed SGC-7901 cell proliferation in a dose-dependent manner. Solasonine treatment mainly induced the cell cycle arrest at G2 phase in SGC-7901 cells. Treatment with solasonine resulted in significant down-regulation of Bcl-2 and Caspase-3 protein expression and reduced Bax and Bcl-xL protein expression in SGC-7901 cells. Solasonine shows a comparable inhibitory effect on the proliferation of human gastric cancer SGC-7901 cells with cisplatin, and solasonine induces of SGC-7901 cell apoptosis through triggering the endoplasmic reticulum stress pathway and the mitochondrial pathway. Our data indicate that solasonine may be a promising agent for the treatment of gastric cancer.

Anncaliia algerae Microsporidiosis Diagnosed by Metagenomic Next-Generation Sequencing, China.

We report a case of Anncaliia algerae microsporidia infection in an immunosuppressed kidney transplant recipient in China. Light microscopy and transmission electron microscopy initially failed to identify A. algerae, which eventually was detected by metagenomic next-generation sequencing. Our case highlights the supporting role of metagenomic sequencing in early identification of uncommon pathogens.

Proteomic profiling of kidney samples in patients with pure membranous and proliferative lupus nephritis.

Renal injury in lupus nephritis (LN) does not manifest as one uniform entity. The clinical presentation, management, and prognosis of membranous LN (MLN) differ from that of the proliferative LN (PLN). Differentiating the molecular mechanisms involved in MLN and PLN and discovering the reliable biomarkers for early diagnosis and target therapy are important. We compared the kidney protein expression patterns of 11 pure MLN and 12 pure PLN patients on formalin-fixed paraffin-embedded (FFPE) kidney tissues using label-free liquid chromatography-mass spectrometry (LC-MS) for quantitative proteomics analysis. FunRich software was used to identify proteins in differentially expressed pathways. Quantitative comparisons of differentially expressed proteins in each patient were further analyzed based on protein intensity levels determined by LC-MS. The protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was established through Search Tool for the Retrieval of Interacting Genes database (STRING) website, visualized by Cytoscape. A total of 5112 proteins were identified. In total, 12 significantly upregulated (fold change ≥2, p < 0.05) proteins were identified in the MLN group and 220 proteins (fold change ≥2, p < 0.05) were upregulated in the PLN group. Further analysis showed that the most significant upregulated pathway involved in MLN was histone deacetylase (HDAC) class I pathway, and the three most significant upregulated pathways in PLN were interferon signaling, interferon gamma signaling, and the immune system. Next, we selected sirtuin-2 (SIRT2) in MLN, and vascular cell adhesion protein 1 (VCAM1) and Bcl-xl in PLN for further mass spectrometry (MS) intensity and PPI analysis. SIRT2 expression was significantly increased in the MLN group compared with the PLN group, and VCAM1, Bcl-xl expression was significantly increased in the PLN group compared with the MLN group, based on MS intensity. These results may help to improve our understanding of the underlying molecular mechanisms of MLN and PLN and provide potential targets for the diagnosis and treatment of different subclasses of LN.

Significance of Mannan Binding Lectin-Associated Serine Protease 2 in Urinary Extracellular Vesicles in IgA Nephropathy.

PURPOSE: Immunoglobulin A (IgA) nephropathy (IgAN) is a common chronic glomerulonephritis and the main cause of end-stage renal diseases. Recent evidence suggests that mannan binding lectin associated serine proteases 2 (MASP2) is related to IgAN; therefore, we investigated the expression and significance of MASP2 in serum and urinary extracellular vesicles (UEVs) in patients with IgAN. METHODS: Thirty-eight patients with IgAN and 17 healthy controls were enrolled in this study. UEVs were extracted by ultracentrifugation. The separation by ultra-high-speed centrifuge was verified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Candidate internal references (TSG101, CD9, flotillin, ß-actin and GAPDH) were identified by western blotting in the control group, and the expression of MASP2 in the UEVs was compared. The levels of MASP2 in the serum and UEVs in the IgAN and control groups were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: TEM and NTA results demonstrated that UEVs were successfully extracted. Western blotting results confirmed that TSG101 was suitable as an internal reference for this study. Compared with the control group, the IgAN group showed positive expression of MASP2. MASP2 levels in the UEVs, determined by ELISA, showed significant differences between IgAN and control groups, which were significantly positively correlated with the level of urinary microalbumin. CONCLUSIONS: The level of MASP2 in UEVs was related to IgAN and shows promise as a biomarker for evaluating the severity of renal injury and prognosis of IgAN, thereby helping to elucidate the role of MASP2 in the mannan-binding lectin pathway.

The development of empathy in the healthcare setting: a qualitative approach.

BACKGROUND: Healthcare professionals' empathetic behaviors have been known to lead to higher satisfaction levels and produce better health outcomes for patients. However, empathy could decrease over time especially during training and clinical practice. This study explored factors that contributed to the development of empathy in the healthcare setting. Findings could be used to improve the effectiveness and sustainability of empathy training. METHOD: A qualitative approach, informed by aspects of grounded theory, was utilized to identify factors that enabled the development of empathy from the perspectives of doctors, nurses, allied healthcare workers and students. Twelve sessions of focus group discussions were conducted with 60 participants from two hospitals, a medical school, and a nursing school. Data was analyzed independently by three investigators who later corroborated to refine the codes, subthemes, and themes. Factors which influence the development of empathy were identified and categorized. This formed the basis of the creation of a tentative theory of empathy development for the healthcare setting. RESULTS: The authors identified various personal (e.g. inherent characteristics, physiological and mental states, professional identity) and external (e.g. work environment, life experience, situational stressors) factors that affected the development of empathy. These could be further categorized into three groups based on the stability of their impact on the individuals' empathy state, contributed by high, medium, or low stability factors. Findings suggest empathy is more trait-like and stable in nature but is also susceptible to fluctuation depending on the circumstances faced by healthcare professionals. Interventions targeting medium and low stability factors could potentially promote the development of empathy in the clinical setting. CONCLUSIONS: Understanding factors that impact the development of empathy allows us to develop measures that could be implemented during training or at the workplace leading to improve the quality of care and higher clinical work satisfaction.

Learning Curve of Upper Aerodigestive Tract Foreign Body Management for Otorhinolaryngology Residents.

INTRODUCTION: Foreign body ingestion is the most common reason for otolaryngology specialist consultations in emergency departments. Among the different types of foreign bodies, fish bones are the most common, particularly in Asian populations. In Taiwan, upper aerodigestive tract foreign bodies (UADT-FBs) are mostly managed by residents in the otorhinolaryngology (ORL) department. Considering the learning curve required for all procedures, different management types between residents, and possible resulting safety issues, this study explored the outcomes of UADT-FB management by residents in different years of ORL training. MATERIALS AND METHODS: The medical records of 2,283 patients who visited Kaohsiung Veterans General Hospital's Emergency Department for UADT-FB during June 2013-August 2019 were retrospectively reviewed. The reviewed data included the demographic data of enrolled patients, outcomes of foreign body management, and follow-up chart records of the patients. RESULTS: Among the 2,283 patients, 1,324 (58%) were found to be negative for foreign bodies, and foreign bodies in 951 (41.7%) were removed immediately. In the negative finding (NF) group, 2 (4.9%) patients were later found to be positive for foreign bodies during follow-up in the outpatient department. One (2.4%) patient developed a deep neck infection and esophageal perforation. The percentage of NFs decreased from 62.58% in residents in the first half of their first year (R1a) to 54% for third-year residents (R3). Comparing R1a with R3, the number needed to harm for retained UADT-FBs after patients visited the emergency department was 12.2. DISCUSSION/CONCLUSION: This study provides data from 1 referral center regarding the management of UADT-FBs. With increasing resident training, the percentage of NFs declined from 62.58 to 54%. Young residents, especially those in the first 6 months of their training, should have senior residents perform a second examination if UADT-FBs are not found in suspected cases.

Systematic appraisal of the guidelines for the diagnosis and treatment of Hirschsprung's disease.

BACKGROUND: Some guidelines for management of Hirschsprung's disease (HSCR, HD) have been developed, but their quality is vague. This study will systematically assess the quality of guidelines and analyze the key recommendations and the best evidence for guidelines. METHODS: Applicable guidelines were retrieved using a systematic search of databases. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool was used to assess the quality of the guidelines. Then, the recommendations and evidence for the included guidelines were extracted and compared. RESULTS: A total of nine guidelines were included in this study, and only one had an overall standardized score of more than 60%, indicating that it is worthy of recommendation. The problems identified included ambiguous and low-quality evidence; obvious distributional heterogeneity among the recommendations; a lack of in-depth discussion on the interpretation of staging, diagnostic methods, conservative treatment, and surgical staging of disease. CONCLUSION: The quality of guidelines varies widely, and there is a lack of high-quality professional opinions and supporting evidence for the main recommendations. At present, only comprehensive guidelines can be considered high-quality and there is still room for improvement.

[Polymorphisms of 35 Insertion/deletion Loci and Genetic Structure of the Han Population in Shaanxi Province].

Objective To evaluate the genetic polymorphisms and forensic efficiencies of 35 deletion/insertion polymorphism(DIP)loci and explore the genetic structure of the Han population in Shaanxi province.Methods Blood samples of 305 unrelated healthy individuals of the Han population in Shaanxi province were collected.And the allelic frequencies and forensic parameters of 35 DIP loci were calculated and analyzed based on their genotyping results by a self-developed amplification system.The genetic relationship of the Han population in Shaanxi province with the reference populations was explored by molecular variance analyses,phylogenetic tree reconstruction,multidimensional scale analyses,principal component analyses,and STRUCTURE analyses.Results The combined power of discrimination and probability of exclusion of the 35 DIP loci in the Han population in Shaanxi province were 0.999 999 999 999 991 119 and 0.9991,respectively.Population genetic analyses indicated that the Han population in Shaanxi province shared relatively closer genetic relationships with those in other regions of China.Conclusions The 35 DIP loci possessed high polymorphisms and could be used as an effective tool for forensic identification of individuals of the Han population in Shaanxi province.Furthermore,the 35 DIP loci could provide basic data for the genetic analysis of the Han population in Shaanxi province.

[Biosynthetic pathways of triterpenes in medicinal plants and key enzyme genes: a review].

Triterpenes, with high diversity and a wide range of sources, can be found in many medicinal plants. They have been found free or as glycosides/esters by combining with sugars. Most of them act as signaling molecules and function in stress response. They are also the material basis for the therapeutic effect of various medicinal plants. Modern pharmacological research has shown that they have the anti-inflammatory, antibacterial, antiviral, anti-tumor, fertility-regulating, and immunomodulatory effects. They top plant natural products in both quantity and diversity, and among them, tetrachyclic triterpenes and pentachyclic triterpenes are most abundant. The first step of the structural diversification is the cyclization 2,3-oxidosqualene, which is catalyzed by oxidosqualene cyclases(OSCs). Numerous OSCs exist, each with a specific cyclization mechanism, and thus over 100 different cyclic triterpene skeletons have been found in nature. This study reviewed the research on the biosynthetic pathways of triterpenes in medicinal plants, regulatory mechanisms of the pathways, and the key enzymes, and analyzed the expression regulation and structural characteristics of key enzyme genes involved in the synthetic pathways. This study is expected to serve as a reference for further research on triterpenes, such as the directional regulation of metabolic flow and heterologous biosynthesis and lay a basis for the regulation of triterpene synthesis and the selection of high-quality germplasm. This study also provides basic materials for further research and development of triterpenes from medicinal plants.

Kidney Transplantation From Hepatitis B Surface Antigen (HBsAg)-Positive Living Donors to HBsAg-Negative Recipients: Clinical Outcomes at a High-Volume Center in China.

BACKGROUND: Data on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg)-positive (HBsAg+) donors to HBsAg-negative (HBsAg-) recipients [D(HBsAg+)/R(HBsAg-)] are limited. We aimed to report the outcomes of D(HBsAg+)/R(HBsAg-) KTx in recipients with or without hepatitis B surface antibody (HBsAb). METHODS: Eighty-three D(HBsAg+)/R(HBsAg-) living KTx cases were retrospectively identified. The 384 cases of KTx from hepatitis B core antibody-positive (HBcAb+) living donors to HBcAb-negative (HBcAb-) recipients [D(HBcAb+)/R(HBcAb-)] were used as the control group. The primary endpoint was posttransplant HBsAg status change from negative to postive (-- →+). RESULTS: Before KTx, 24 donors (28.9%) in the D(HBsAg+)/R(HBsAg-) group were hepatitis B virus (HBV) DNA positive, and 20 recipients were HBsAb-. All 83 D(HBsAg+)/R(HBsAg-) recipients received HBV prophylaxis, while no D(HBcAb+)/R(HBcAb-) recipients received prophylaxis. After a median follow-up of 36 months (range, 6-106) and 36 months (range, 4-107) for the D(HBsAg+)/R(HBsAg-) and D(HBcAb+)/R(HBcAb-) groups, respectively, 2 of 83 (2.41%) D(HBsAg+)/R(HBsAg-) recipients and 1 of 384 (0.26%) D(HBcAb+)/R(HBcAb-) became HBsAg+, accompanied by HBV DNA-positive (P = .083). The 3 recipients with HBsAg-→+ were exclusively HBsAb-/HBcAb- before KTx. Recipient deaths were more frequent in the D(HBsAg+)/R(HBsAg-) group (6.02% vs 1.04%, P = .011), while liver and graft function, rejection, infection, and graft loss were not significantly different. In univariate analyses, pretransplant HBsAb-/HBcAb- combination in the D(HBsAg+)/R(HBsAg-) recipients carried a significantly higher risk of HBsAg-→+, HBV DNA-→+, and death. CONCLUSIONS: Living D(HBsAg+)/R(HBsAg-) KTx in HBsAb+ recipients provides excellent graft and patient survivals without HBV transmission. HBV transmission risks should be more balanced with respect to benefits of D(HBsAg+)/R(HBsAg-) KTx in HBsAb-/HBcAb- candidates.

von Willebrand factor variants in C3 glomerulopathy: A Chinese cohort study.

C3 glomerulopathy (C3G) is a rare renal disease characterized by predominant glomerular C3 staining. Complement alternative pathway dysregulation due to inherited complement defects is associated with C3G. To identify novel C3G-related genes, we screened 86 genes in the complement, coagulation and endothelial systems in 35 C3G patients by targeted genomic enrichment and massively parallel sequencing. Surprisingly, the most frequently mutated gene was VWF. Patients with VWF variants had significantly higher proteinuria levels, higher crescent formation and lower factor H (FH) levels. We further selected two VWF variants to transiently express the von Willebrand factor (vWF) protein, we found that vWF expression from the c.1519A > G variant was significantly reduced. In vitro results further indicated that vWF could regulate complement activation, as it could bind to FH and C3b, act as a cofactor for factor I-mediated cleavage of C3b. Thus, we speculated that vWF might be involved in the pathogenesis of C3G.

Pre-transplant donor HBV DNA+ and male recipient are independent risk factors for treatment failure in HBsAg+ donors to HBsAg- kidney transplant recipients.

BACKGROUND: In order to reduce the burden on organ shortage around the world, using potential infectious donor might be an option. However, scarce evidences have been published on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg) + donors to HBsAg- recipients [D (HBsAg+)/R(HBsAg-)] without hepatitis B virus (HBV) immunity. Here, we reported the results of D(HBsAg+/HBV DNA- or +)/R(HBsAg-) living KTx recipients with or without HBV immunity. METHODS: We retrospectively identified 83 D(HBsAg+)/R(HBsAg-) living KTx recipients, and 83 hepatitis B core antibody (HBcAb) + living donors to HBcAb- recipients [D(HBcAb+)/R(HBcAb-)] were used as control group by reviewing medical archives and propensity score matching. Treatment failure (defined as any HBV serology conversion, liver injury, graft loss, or recipient death) is the primary endpoint. RESULTS: Twenty-four donors (28.9%) were HBV DNA+, and 20 recipients had no HBV immunity in the D(HBsAg+)/R(HBsAg-) group pre-transplantation. HBV prophylaxis was applied in all D(HBsAg+)/R(HBsAg-) recipients, while none was applied in the D(HBcAb+)/R(HBcAb-) group. We observed a significant higher treatment failure in D(HBsAg+)/R(HBsAg-) than D(HBcAb+)/R(HBcAb-) group (21.7% vs. 10.8%, P < 0.001). Interestingly, no significant difference was found between groups on HBV seroconversion, liver and graft function, rejection, infection, graft loss, or death. However, 2/20 recipients without HBV immunity in the D(HBsAg+)/R(HBsAg-) group developed HBV DNA+ or HBsAg+, while none observed in the D(HBcAb+)/R(HBcAb-) group. HBV DNA+ donor and male recipient were significant risk factors for treatment failure. CONCLUSION: D(HBsAg+)/R(HBsAg-) should be considered for living kidney transplantation, but with extra caution on donors with HBV DNA+ and male candidates.