Growth hormone treatment in pre-pubertal short Chinese children with chronic kidney disease prior to transplantation.

BACKGROUND: The effect of recombinant human GH (rhGH) in Chinese children with chronic kidney disease (CKD) is unclear. METHODS: This was a 52-week, multicenter, randomized, open-label, negative-controlled phase 3 study. Prepubertal subjects were randomized 1:1 to either daily subcutaneous injections of rhGH 0.05 mg/kg/day or no treatment for 52 weeks. RESULTS: A total of 68 subjects with a mean age of 7.8 ± 3.27 years were enrolled. At week 52, the height standard deviation score (HT-SDS) in the treated group increased by 0.75 ± 0.58, which was significantly higher compared with 0.17 ± 0.47 in the untreated group (least squares mean 0.58, 95% confidence interval, 0.32-0.84; P < 0.001). At week 52, significant improvements were observed in other growth parameters (height velocity [P < 0.001]), insulin-like growth factor 1 (IGF-1) SDS [P < 0.001], IFG-1/insulin-like growth factor binding protein-3 molar ratio [P < 0.001], and height [P < 0.001]) compared with the untreated control. Seven patients reported treatment-related adverse events (TRAEs) and most TRAEs were mild in severity. Most subjects recovered without further intervention. CONCLUSIONS: Daily rhGH for 52 weeks in children with CKD-induced growth retardation significantly improved HT-SDS and other growth parameters without compromising safety. IMPACT: The efficacy and safety of growth hormone (GH) therapy in Chinese children with chronic kidney disease (CKD) are unclear. This study found that giving short stature Chinese children with CKD daily recombinant human growth hormone (rhGH) for 52 weeks improved growth parameters without compromising safety. This study's information can give physicians the confidence to treat these patients in their clinical practice.

Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy.

BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children. Exploring the correlation between the phenotype and genotype of NPHP-RC is helpful for early diagnosis and management. We investigated the phenotype and genotype spectra of NPHP-RC in a Chinese multicentre cohort. METHODS: Crosss-ectional and longitudinal data of 60 patients from 57 families with pathogenic NPHP-RC gene mutations distributed in 22 regions of China were collected into a unified, anonymous database. The mean observation time of this cohort was 3.5±3.1 years. RESULTS: Mutations in NPHP1 and NPHP3 were the most common genetic defects. Overall, 45% of patients presented with isolated nephronophthisis (NPH), and 55% exhibited the extrarenal phenotype, which frequently involved the liver (41.7%, n=25), central nervous system (26.7%, n=16), eyes (26.7%, n=16) and skeletal system (11.7%, n=7). Accidental detection of elevated serum creatinine and non-specific symptoms caused by chronic kidney disease occurred in 65% of patients. Patients carrying NPHP1 mutations mainly presented with isolated NPH (90%, 18/20) and progressed to ESRD at a mean age of 12.9±0.5 years. The mean age of ESRD onset in the non-NPHP1 group was lower than that in the NPHP1 group (6.2±1.4 years, p<0.001), especially for patients carrying NPHP3 mutations (3.1±1.2 years), showing a heterogeneous phenotype characterised by Bardet-Biedl syndrome (12.5%, n=5), Joubert syndrome (7.5%, n=3), COACH syndrome (2.5%, n=1), Mainzer-Saldino syndrome (2.5%, n=1), short-rib thoracic dysplasia (2.5%, n=1) and unclassified symptoms (32.5%, n=13). CONCLUSIONS: The Chinese Children Genetic Kidney Disease Database registry characterised the spectrum of the phenotype and genotype of NPHP-RC in the Chinese population. NPHP1 and NPHP3 were the most common pathogenic genes. Rapid progression to ESRD and liver involvement were noted in patients with NPHP3 mutations.

Genetic spectrum of CAKUT and risk factors for kidney failure: a pediatric multicenter cohort study.

BACKGROUND: Congenital anomalies of the kidney and urinary tracts (CAKUT) are the leading cause of kidney failure in children with phenotypic and genotypic heterogeneity. Our objective was to describe the genetic spectrum and identify the risk factors for kidney failure in children with CAKUT. METHODS: Clinical and genetic data were derived from a multicenter network (Chinese Children Genetic Kidney Disease Database, CCGKDD) and the Chigene database. A total of 925 children with CAKUT who underwent genetic testing from 2014 to 2020 across China were studied. Data for a total of 584 children wereobtained from the CCGKDD, including longitudinal data regarding kidney function. The risk factors for kidney failure were determined by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: A genetic diagnosis was established in 96 out of 925 (10.3%) children, including 72 (8%) with monogenic variants, 20 (2%) with copy number variants (CNVs), and 4 (0.4%)with major chromosomal anomalies. Patients with skeletal abnormalities were more likely to have large CNVs or abnormal karyotypes than monogenic variants. Eighty-two patients from the CCGKDD progressed to kidney failure at a median age of 13.0 (95% confidence interval, 12.4-13.6) years, and twenty-four were genetically diagnosed with variants of PAX2, TNXB, EYA1, HNF1B and GATA3 or the 48, XXYY karyotype. The multivariate analysis indicated that solitary kidney, posterior urethral valves, bilateral hypodysplasia, the presence of certain variants and premature birth were independent prognostic factors. CONCLUSIONS: The genetic spectrum of CAKUT varies among different subphenotypes. The identified factors indicate areas that require special attention.

Production of purple Ma bamboo (Dendrocalamus latiflorus Munro) with enhanced drought and cold stress tolerance by engineering anthocyanin biosynthesis.

MAIN CONCLUSION: Overexpression of the leaf color (Lc) gene in Ma bamboo substantially increased the accumulation level of anthocyanin, and improved plant tolerance to cold and drought stresses, probably due to the increased antioxidant capacity. Most bamboos, including Ma bamboo (Dendrocalamus latiflorus Munro), are naturally evergreen and sensitive to cold and drought stresses, while it's nearly impossible to make improvements through conventual breeding due to their long and irregular flowering habit. Moreover, few studies have reported bamboo germplasm innovation through genetic engineering as bamboo genetic transformation remains difficult. In this study, we have upregulated anthocyanin biosynthesis in Ma bamboo, to generate non-green Ma bamboo with increased abiotic stress tolerance. By overexpressing the maize Lc gene, a bHLH transcription activator involved in the anthocyanin biosynthesis in Ma bamboo, we generated purple bamboos with increased anthocyanin levels including cyanidin-3-O-rutinoside, peonidin 3-O-rutinoside, and an unknown cyanidin pentaglycoside derivative. The expression levels of 9 anthocyanin biosynthesis genes were up-regulated. Overexpression of the Lc gene improved the plant tolerance to cold and drought stress, probably due to increased antioxidant capacity. The levels of the cold- and drought-related phytohormone jasmonic acid in the transgenic plants were also enhanced, which may also contribute to the plant stress-tolerant phenotypes. High anthocyanin accumulation level did not affect plant growth. Transcriptomic analysis showed higher expressions of genes involved in the flavonoid pathway in Lc transgenic bamboos compared with those in wild-type ones. The anthocyanin-rich bamboos generated here provide an example of ornamental and multiple agronomic trait improvements by genetic engineering in this important grass species.

Highly sensitive differential fiber-optic SPR sensor in telecom band.

We proposed a differential fiber-optic SPR remote sensor with ultra-high sensitivity in telecom band. The working band of the sensor is designed as the C-band which is the low loss band of optical fiber communication aiming to improve the sensitivity and enable the capability of remote monitoring. The sensor head is a BK7 prism coated with Au/TiO2 films, enabling two channels for differential intensity interrogation. The intensities of the reflected lights through the channels vary oppositely within the measurement range of refractive index. Due to the sharp dip of angular resonant response in the C-band, the differential signal produces a steep slope as the refractive index of the sample varies, thus higher sensitivity is expected in a narrow measurement range. According to the results, the sensitivity is as high as 456 V/RIUs within the narrow measurement range of 1.3×10-2 RIUs and the resolution reaches to 6×10-6 RIUs. The measurement range can be tuned conveniently by adjusting the thickness of TiO2 film and can be expanded by increasing the number of sensing channels, which provides great convenience for the application of biosensor requiring high sensitivity.

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system.

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

Gene mutation and clinical analysis of nephronophthisis diagnosed using whole exome sequencing: Experience from China
.

OBJECTIVE: Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease. Its onset is obscure, and its early clinical manifestations and pathological changes lack specificity, which makes clinical diagnosis difficult. At present, as many as 90 genetic alterations can result in NPH, which exhibits significant genetic heterogeneity. Therefore, high-throughput sequencing technology provides an effective method to identify and characterize novel NPH pathogenic genes when compared to Sanger sequencing. This study summarizes the gene mutations and clinical data of whole exome sequencing, which was used to diagnose 5 NPH patients to improve the understanding of the causative genes and clinical phenotypes of NPH. MATERIALS AND METHODS: The clinical manifestations, laboratory examination indexes, and imaging data of 5 patients of NPH were reported. Whole exome sequencing was performed in 5 children, and the causative genes and mutation sites were analyzed by bioinformatics and genetics. The mutation sites were verified in children and their parents using Sanger direct sequencing. RESULTS: Among the 5 patients (3 male and 2 female), 2 patients had infantile NPH, and 3 patients had juvenile NPH. The 2 infantile NPH patients were characterized by the onset of liver dysfunction accompanied by hypertension and left ventricular change, and the renal function progressed to end-stage renal disease (ESRD) after 7 months and 9 months, respectively. The 2 cases of infantile NPH had NPHP3 mutations, with one carrying compound heterozygous mutations (c.1358A>G, c.2369A>G) and the other simultaneously carrying a c.1174C>T IVS26-3A>G cleavage site mutation from the father and a nonsense mutation (p.392R>X, 939) from the mother. The 2 juvenile NPH children had entered ESRD at the onset of the disease, including 1 patient with Joubert syndrome. The 2 patients with juvenile NPH had frameshift mutations (c.1583 to 1596: deletion) and homozygous point mutations (7 c.640G>T) of the NPHP1 gene. In addition, another patient with frequent urination and nocturia resulting in stage CKD3 renal function had a complex heterozygous mutation of the NPHP2 gene (c.2686G>A, c.1943A>G). The urine A1MU/creatinine and urinary transferrin increased in all 5 patients without hematuria. CONCLUSION: Whole exome sequencing identified the causative genes of NPH in 5 children. In NPH children with NPHP3 gene mutations, renal functional damage was characterized by early onset and rapid progression to ESRD, often accompanied by liver dysfunction and hypertension.

Synthesis, structure-activity relationships and preliminary mechanism study of N-benzylideneaniline derivatives as potential TLR2 inhibitors.

Toll-like receptor 2 (TLR2) can recognize pathogen-associated molecular patterns to defense against invading organisms and has been represents an attractive therapeutic target. Until today, none TLR2 small molecule antagonist have been developed in clinical trial. Herein, we designed and synthesized 50 N-benzylideneaniline compounds with the help of CADD. And subsequent in vitro studies leading to the optimized compound SMU-A0B13 with most potent inhibitory activity to TLR2 (IC50=18.21 ±â€¯0.87 µM). Preliminary mechanism studies indicated that this TLR2 inhibitor can work through the NF-κB signaling pathway with high specificity and low toxicity, and can also efficiently downregulate inflammatory cytokines, such as SEAP, TNF-α and NO in HEK-Blue hTLR2, human PBMC and Raw 264.7 cell lines. Additionally, the docking situation also indicate SMU-A0B13 can well bind to the TLR2-TIR (PDB: 1FYW) active domain, which probably explains the bioactivity.

Retracted: Effects of Nano-Hydroxyapatite/Polyetheretherketone-Coated, Sandblasted, Large-Grit, and Acid-Etched Implants on Inflammatory Cytokines and Osseointegration in a Peri-Implantitis Model in Beagle Dogs.

The article is withdrawn by the authors request.

Effect of Choukroun Platelet-Rich Fibrin Combined With Autologous Micro-Morselized Bone on the Repair of Mandibular Defects in Rabbits.

PURPOSE: The aim of this study was to explore the effect of Choukroun platelet-rich fibrin (PRF) combined with autologous micro-morselized bone on the repair of mandibular defects in rabbits. MATERIALS AND METHODS: Thirty-six healthy New Zealand rabbits were selected for the present study. After models of mandibular defects were established, rabbits were randomly divided into Choukroun PRF, autologous micro-morselized bone (autologous), Choukroun PRF combined with autologous bone (combined) and model groups. After the rabbits were sacrificed at 2, 8, and 12 weeks postoperatively, their bone formation was assessed by x-ray and scanning electron microscopy, and the histologic changes of the mandibular defect area were detected by hematoxylin and eosin staining. Cone-beam computed tomography was used to observe the size of the change of the mandibular defect area. Bone mineral density (BMD) was analyzed by dual-energy x-ray absorptiometry. RESULTS: The bone defect in the combined group showed better repair, increased bone mineral content, and denser callus than the other groups, and the defect area was filled with mature trabecular bone. In the Choukroun PRF and autologous groups, the defect area was smaller and filled with osteoporotic trabecular bone. A clear mandibular defect area was still observed in the model group. Compared with the other groups, the combined group showed more bone regeneration, more fibrous tissue regeneration, and greater bone maturity at all time points. The combined group had the highest BMD, there was no relevant difference in BMD between the Choukroun PRF and autologous groups, and the model group had the lowest BMD. BMD in all 4 groups increased with time. CONCLUSION: These findings indicate that Choukroun PRF combined with autologous micro-morselized bone can substantially improve the repair of mandibular defects in rabbits, and the effect is superior to Choukroun PRF or autologous micro-morselized bone alone.

Effects of Nano-Hydroxyapatite/Polyetheretherketone-Coated, Sandblasted, Large-Grit, and Acid-Etched Implants on Inflammatory Cytokines and Osseointegration in a Peri-Implantitis Model in Beagle Dogs.

BACKGROUND This study explored the effects of nano-hydroxyapatite/polyetheretherketone (n-HA/PEEK)- coated sandblasted, large-grit, and acid-etched (SLA) implants on inflammatory cytokines and osseointegration in peri-implantitis model beagle dogs. MATERIAL AND METHODS Peri-implantitis models were established. Eight beagle dogs were randomly and evenly assigned into SLA tied, SLA + n-HA/PEEK tied, SLA untied, or SLA + n-HA/PEEK untied groups. A special periodontal probe was used to detect the plaque index (PLI), probing depth (PD), and modified Sulcus Bleeding Index (mSBI). Gingival crevicular fluid was collected and an ELISA kit was utilized to detect IL-1, IL-6, and IL-17 levels. The colony-forming units were counted and the maximum shear strength of implants was tested using the axial pullout test. HE staining was used to detect the inflammation of peri-implant bone tissues. Osseointegration was observed through toluidine blue staining. Bone-to-implant contact (BIC) was obtained through histological observation and the mineral apposition rate (MAR) was calculated after immune fluorescent double staining. RESULTS The SLA tied group demonstrated higher levels of PLI, PD, mSBI, IL-1, IL-6, and IL-17 and a higher degree of inflammation than the SLA + n-HA/PEEK tied group. The tied groups also displayed similar results over the untied groups at the same time point. The maximum shear strength, BIC, and MAR in the SLA tied group were significantly lower than in the SLA + n-HA/PEEK tied group. CONCLUSIONS Our findings demonstrate that SLA + n-HA/PEEK implants can promote osseointegration and relieve the inflammation response of peri-implantitis in beagle dogs.

Maternal protein restriction reduces perlecan at mid-metanephrogenesis in rats.

AIM: Maternal dietary protein restriction reduces nephron number in offspring and increases the risk of cardiovascular and chronic kidney diseases. Perlecan is the major basement membrane/extracellular matrix heparan sulfate proteoglycan (HSPG) that plays a crucial role in nephron formation. This study was to determine whether maternal dietary protein restriction during pregnancy leads to an abnormal perlecan expression pattern during kidney development and a correlation with aberrant cell proliferation and apoptosis. METHODS: Pregnant Sprague-Dawley rats were divided into two groups, maintained on either a low-protein diet (MLP group) or a normal-protein diet (MNP group). Kidneys were dissected from embryos of different kidney development stages. Real-time PCR and immunohistochemistry were performed to detect the transcript level of rHSPG2, the coding gene of perlecan, and its protein expression pattern. Apoptosis and proliferation cell were detected by TUNEL system and Ki67 marker. RESULTS: Embryonic weights and nephron number were significantly affected by maternal low protein diets. The transcript level of rHSPG2 in the MLP group was significantly lower at embryonic day 18 and the neonatal period. Immunohistochemistry study was consistent with the RT-PCR results. The proliferation level of the MLP group was significantly lower than the MNP group at E18 and more apoptotic cells was detected in MLP newborn. CONCLUSION: Maternal protein restriction reduced the expression of perlecan and lead aberrant cell proliferation and apoptosis during mid-metanephrogenesis in offspring. This data may provide new evidence to understand the mechanism of reduced nephron number due to maternal protein restriction and enlighten solution.

A novel deep generative model for mRNA vaccine development: Designing 5' UTRs with N1-methyl-pseudouridine modification.

Efficient translation mediated by the 5' untranslated region (5' UTR) is essential for the robust efficacy of mRNA vaccines. However, the N1-methyl-pseudouridine (m1Ψ) modification of mRNA can impact the translation efficiency of the 5' UTR. We discovered that the optimal 5' UTR for m1Ψ-modified mRNA (m1Ψ-5' UTR) differs significantly from its unmodified counterpart, highlighting the need for a specialized tool for designing m1Ψ-5' UTRs rather than directly utilizing high-expression endogenous gene 5' UTRs. In response, we developed a novel machine learning-based tool, Smart5UTR, which employs a deep generative model to identify superior m1Ψ-5' UTRs in silico. The tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing models. As a result, Smart5UTR can successfully design superior 5' UTRs, greatly benefiting mRNA vaccine development. Notably, Smart5UTR-designed superior 5' UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2, surpassing the performance of vaccines using high-expression endogenous gene 5' UTRs.

A novel heterologous receptor-binding domain dodecamer universal mRNA vaccine against SARS-CoV-2 variants.

There are currently approximately 4,000 mutations in the SARS-CoV-2 S protein gene and emerging SARS-CoV-2 variants continue to spread rapidly worldwide. Universal vaccines with high efficacy and safety urgently need to be developed to prevent SARS-CoV-2 variants pandemic. Here, we described a novel self-assembling universal mRNA vaccine containing a heterologous receptor-binding domain (HRBD)-based dodecamer (HRBDdodecamer) against SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28.1), Delta (B.1.617.2) and Omicron (B.1.1.529). HRBD containing four heterologous RBD (Delta, Beta, Gamma, and Wild-type) can form a stable dodecameric conformation under T4 trimerization tag (Flodon, FD). The HRBDdodecamer -encoding mRNA was then encapsulated into the newly-constructed LNPs consisting of a novel ionizable lipid (4N4T). The obtained universal mRNA vaccine (4N4T-HRBDdodecamer) presented higher efficiency in mRNA transfection and expression than the approved ALC-0315 LNPs, initiating potent immune protection against the immune escape of SARS-CoV-2 caused by evolutionary mutation. These findings demonstrated the first evidence that structure-based antigen design and mRNA delivery carrier optimization may facilitate the development of effective universal mRNA vaccines to tackle SARS-CoV-2 variants pandemic.

mRNA-based therapeutics: powerful and versatile tools to combat diseases.

The therapeutic use of messenger RNA (mRNA) has fueled great hope to combat a wide range of incurable diseases. Recent rapid advances in biotechnology and molecular medicine have enabled the production of almost any functional protein/peptide in the human body by introducing mRNA as a vaccine or therapeutic agent. This represents a rising precision medicine field with great promise for preventing and treating many intractable or genetic diseases. In addition, in vitro transcribed mRNA has achieved programmed production, which is more effective, faster in design and production, as well as more flexible and cost-effective than conventional approaches that may offer. Based on these extraordinary advantages, mRNA vaccines have the characteristics of the swiftest response to large-scale outbreaks of infectious diseases, such as the currently devastating pandemic COVID-19. It has always been the scientists' desire to improve the stability, immunogenicity, translation efficiency, and delivery system to achieve efficient and safe delivery of mRNA. Excitingly, these scientific dreams have gradually been realized with the rapid, amazing achievements of molecular biology, RNA technology, vaccinology, and nanotechnology. In this review, we comprehensively describe mRNA-based therapeutics, including their principles, manufacture, application, effects, and shortcomings. We also highlight the importance of mRNA optimization and delivery systems in successful mRNA therapeutics and discuss the key challenges and opportunities in developing these tools into powerful and versatile tools to combat many genetic, infectious, cancer, and other refractory diseases.

Protective role of endorepellin in renal developmental programming.

Adverse intrauterine and early postnatal environment cause reduced nephron endowment and subsequent hypertension, chronic kidney disease (CKD). Exploring modifiable approaches is particularly important to alleviate the global burden of CKD. Enhanced glomerular progenitor cell apoptosis is a major contributor to renal developmental programming. The differentially expressed protein perlecan, which we previously identified using proteomics, is an important extracellular matrix glycoprotein, and its domain V (endorepellin) can inhibit apoptosis through a paracrine form. In explanted mice embryonic metanephros, we found that endorepellin can rescue glomeruli-deficit phenotype resulting from malnutrition, and this protective effect was also verified in vivo using a renal developmental programming model which was given a low-protein diet during pregnancy. We further demonstrated that endorepellin significantly inhibited glomerular progenitor cell apoptosis which activates ERK1/2 phosphorylation. Our results show that endorepellin rescues the nephron number reduction in renal developmental programming, possibly through the inhibition of progenitor cell apoptosis via the ERK1/2 pathway.

Ultrafine particles exposure is associated with specific operative procedures in a multi-chair dental clinic.

Air quality in dental clinics is critical, especially in light of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, given that dental professionals and patients are at risk of regular exposure to aerosols and bioaerosols in dental clinics. High levels of ultrafine particles (UFP) may be produced by dental procedures. This study aimed to quantify ultrafine particles (UFP) concentrations in a real multi-chair dental clinic and compare the levels of UFP produced by different dental procedures. The efficiency of a high-volume evacuator (HVE) in reducing the UFP concentrations during dental procedures was also assessed. UFP concentrations were measured both inside and outside of a dental clinic in Shanghai, China during a 12-day period from July to September 2020. Dental activities were recorded during working hours. The mean (±standard deviation) concentrations of indoor and outdoor UFP during the sampling period were 8,209 (±4,407) counts/cm3 and 15,984 (±7,977) counts/cm3, respectively. The indoor UFP concentration was much higher during working hours (10,057 ± 5,725 counts/cm3) than during non-working hours (7,163 ± 2,972 counts/cm3). The UFP concentrations increased significantly during laser periodontal treatment, root canal filling, tooth drilling, and grinding, and were slightly elevated during ultrasonic scaling or tooth extraction by piezo-surgery. The highest UFP concentration (241,136 counts/cm3) was observed during laser periodontal treatment, followed by root canal filling (75,034 counts/cm3), which showed the second highest level. The use of an HVE resulted in lower number concentration of UFP when drilling and grinding teeth with high-speed handpieces, but did not significantly reduce UFP measured during laser periodontal therapy. we found that many dental procedures can generate high concentration of UFP in dental clinics, which may have a great health impact on the dental workers. The use of an HVE may help reduce the exposure to UFP during the use of high-speed handpieces.

Protocol for an open-label, single-arm, multicentre clinical study to evaluate the efficacy and safety of rituximab in the first episode of paediatric idiopathic nephrotic syndrome.

INTRODUCTION: Rituximab (RTX) effectively prevents relapses in patients with complicated steroid-sensitive nephrotic syndrome (SSNS). The 1-year relapse-free survival rate is approximately 30% in children after the first episode of SSNS treated with standardised corticosteroids. Whether the benefits of RTX extend to the first relapse are unknown. The efficacy and safety of RTX in the first episode of paediatric idiopathic nephrotic syndrome (RTXFIRPedINS) trial (NCT04783675) will assess its effect on the risk of subsequent relapse. METHODS AND ANALYSIS: RTXFIRPedINS is an open-label, single-arm, multicentre trial targeting patients aged 1-18 years with a first episode of SSNS. All patients will receive standardised corticosteroid treatment for 12 weeks. A sample size of 44 patients provides 80% power to detect a 20% increase in the 1-year relapse-free rate, assuming a dropout rate of 10%. After obtaining informed consent and screening, eligible patients will be treated with a single intravenous infusion of 375 mg/m2 RTX within 1 week after achieving remission. Trimethoprim-sulfamethoxazole will be administered for 3 months after RTX administration to prevent Pneumocystis carinii infection. The follow-up period will be 1 year. The primary outcome is the 1-year relapse-free survival rate after RTX infusion. The secondary study outcomes are the number of days from the infusion of RTX to the occurrence of the first relapse, 6-month relapse-free survival rate, the B cell recovery time and treatment-related adverse events. Immunological factors will be studied as predictors of response. ETHICS AND DISSEMINATION: This trial was approved by the Ethics Committee of the Children's Hospital of Fudan University and seven local ethics committees. We will publish our study results in peer-reviewed journals and present them at international scientific meetings. TRIAL REGISTRATION NUMBER: NCT04783675.

Duration of initial prednisolone therapy for first episode of childhood nephrotic syndrome based on time to response.

Background: The duration of initial corticosteroid therapy in newly diagnosed Idiopathic nephrotic syndrome (INS) is about 3 months. Our study was designed to test the feasibility of a shorter duration of corticosteroid therapy in newly diagnosed INS who show a quicker response. Methods: Patients who responded within 10 days (Group A) received 8 weeks of corticosteroid therapy as compared to 12-14 weeks of standard therapy in those who responded between >10 days to 28 days (Group B), and follow up for 52 weeks. The primary endpoint is time to first relapse after treatment completion. (NCT03878914, March 18, 2019). Results: A total of 33 children with INS were enrolled and the follow-up data were analyzed. The clinical and laboratory characteristics of patients in both groups were similar. No significant difference was found in time to first relapse [65(14.5, 159) days for Group A vs. 28(17, 61.5) days for Group B, P = 0.371], the incidence of frequently relapsing nephrotic syndrome [6/18 (33.3%) vs. 5/10(50%), P = 0.644] or requirement for alternative immunosuppressant [4/18 (22.2%) vs. 1/10 (10%), P = 0.769]. Group A received similar corticosteroid dose compare with Group B (3511 ± 2421 mg/m2 vs. 4117 ± 2556 mg/m2, P = 0.524). Frequency and severity of corticosteroid-related complications was similar in both groups. Conclusions: The time to first relapse and the number of relapses per patient were comparable between the two groups. However, more patients in Group A relapsed and the mean total dose of prednisolone for the study period was very similar between the two groups.

Risk factors for breakthrough urinary tract infection in children with vesicoureteral reflux receiving continuous antibiotic prophylaxis.

BACKGROUND: To investigate the risk factors for breakthrough urinary tract infection (BT-UTI) in children with vesicoureteral reflux (VUR) receiving continuous antibiotic prophylaxis (CAP). METHODS: This was a single-centre cohort study (January 2016 to December 2019). The clinical data of 256 children with grade I-V VUR receiving CAP were analysed. In this study, exposure variables were sex, younger age at the initial diagnosis of UTI ≤12 months, high-grade VUR, bilateral VUR, aetiology, presence of renal scarring at the initial diagnosis, presence of renal function impairment at the initial diagnosis, ultrasound abnormalities, antibiotic used and bladder and bowel dysfunction (BBD). Outcome was BT-UTI. RESULTS: BT-UTI occurred in 81 out of 256 children with grade I-V VUR who received CAP, an incidence of 31.64%. Univariate analysis showed that younger age at the initial diagnosis of UTI (≤12 months), bilateral VUR, renal scarring on the dimercaptosuccinic acid (DMSA) scan at the initial diagnosis of UTI and BBD were correlated with the occurrence of BT-UTI. Multivariate analysis showed that younger age at the initial diagnosis of UTI (≤12 months) [hazard ratio (HR): 4.629; 95% confidence interval (CI): 1.302-16.462], bilateral VUR (HR: 2.078; 95% CI: 1.084-4.022) and BBD (HR: 3.194; 95% CI: 1.243-8.206) were independent risk factors for the occurrence of BT-UTI. CONCLUSIONS: For VUR children receiving CAP, younger age at the initial diagnosis of UTI (≤12 months), bilateral VUR, and BBD were independent risk factors for the occurrence of BT-UTI.