Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. RESULTS: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients. CONCLUSIONS: Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).

Development of a time-resolved immunochromatographic test strip for rapid and quantitative determination of retinol-binding protein 4 in urine.

Urine retinol-binding protein 4 (RBP4) has recently been reported as a novel earlier biomarker of chronic kidney disease (CKD) which is a global public health problem with high morbidity and mortality. Accurate and rapid detection of urine RBP4 is essential for early monitor of impaired kidney function and prevention of CKD progression. In the present study, we developed a time-resolved fluorescence immunochromatographic test strip (TRFIS) for the quantitative and rapid detection of urine RBP4. This TRFIS possessed excellent linearity ranging from 0.024 to 12.50 ng/mL for the detection of urine RBP4, and displayed a good linearity (Y = 239,581 × X + 617,238, R2 = 0.9902), with the lowest visual detection limit of 0.049 ng/mL. This TRFIS allows for quantitative detection of urine RBP4 within 15 min and shows high specificity. The intra-batch coefficient of variation (CV) and the inter-batch CV were both < 8%, respectively. Additionally, this TRFIS was applied to detect RBP4 in the urine samples from healthy donors and patients with CKD, and the results of TRFIS could efficiently discern the patients with CKD from the healthy donors. The developed TRFIS has the characteristics of high sensitivity, high accuracy, and a wide linear range, and is suitable for rapid and quantitative determination of urine RBP4.

Differentiation Potential of Hypodifferentiated Subsets of Nephrogenic Rests and Its Relationship to Prognosis in Wilms Tumor.

Background Wilms tumor (WT) is highly curable, although anaplastic histology or relapse imparts a worse prognosis. Nephrogenic rests (NR) associated with a high risk of developing WT are abnormally retained embryonic kidney precursor cells. Methods After pseudo-time analysis using single-cell RNA sequencing (scRNA-seq) data, we generated and validated a WT differentiation-related gene (WTDRG) signature to predict overall survival (OS) in children with a poor OS. Results A differentiation trajectory from NR to WT was identified and showed that hypodifferentiated subsets of NR could differentiate into WT. Classification of WT children with anaplastic histology or relapse based on the expression patterns of WTDRGs suggested that patients with relatively high levels of hypodifferentiated NR presented a poorer prognosis. A WTDRG-based risk model and a clinically applicable nomogram was developed. Conclusions These findings may inform oncogenesis of WT and interventions directed toward poor prognosis in WT children of anaplastic histology or relapse.

Effects of honokiol protects against chronic kidney disease via BNIP3/NIX and FUNDC1-mediated mitophagy and AMPK pathways.

BACKGROUND: Chronic kidney disease (CKD) is a serious health threat worldwide. Defective mitophagy has been reported to induce mitochondrial dysfunction, which is closely associated with CKD pathogenesis. Honokiol (HKL) is a bioactive component of Magnolia officinalis that has multiple efficacies. Our study aimed to investigate the effect of HKL on a CKD rat model and explore the possible mechanisms of mitophagy mediated by Bcl-2 interacting protein 3 and BNIP3-like (NIX) (also known as the BNIP3/NIX pathway) and FUN14 domain-containing 1 (the FUNDC1 pathway) and the role of the AMP-activated protein kinase (AMPK) pathway. METHODS: A CKD rat model was established by feeding the animals dietary adenine (0.75% w/w, 3 weeks). Simultaneously, the treatment group was given HKL (5 mg/kg/day, 4 weeks) by gavage. Renal function was assessed by measuring serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Pathological changes were analyzed by periodic acid-Schiff (PAS) and Masson's trichrome staining. Protein expression was evaluated by Western blotting and immunohistochemistry. RESULTS: HKL treatment ameliorated the decline in renal function and reduced tubular lesions and interstitial fibrosis in CKD rats. Accordingly, the renal fibrosis markers Col-IV and α-SMA were decreased by HKL. Moreover, HKL suppressed the upregulation of the proapoptotic proteins Bad and Bax and Cleaved caspase-3 expression in CKD rats. Furthermore, HKL suppressed BNIP3, NIX and FUNDC1 expression, leading to the reduction of excessive mitophagy in CKD rats. Additionally, AMPK was activated by adenine, and HKL reversed this change and significantly decreased the level of activated AMPK (phosphorylated AMPK, P-AMPK). CONCLUSION: HKL exerted a renoprotective effect on CKD rats, which was possibly associated with BNIP3/NIX and FUNDC1-mediated mitophagy and the AMPK pathway.

Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children.

PURPOSE: Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. METHODS: This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. RESULTS: All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. CONCLUSION: Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

Laparoscopic versus open inguinal hernia repair in children: A systematic review.

PURPOSE: Considerable debates exist regarding the preferable technique to repair a paediatric inguinal hernia (PIH). This systematic review aims to compare the efficacy and safety of laparoscopic herniorrhaphy (LH) and open herniorrhaphy (OH) in PIH. METHODS: The randomised controlled trials (RCTs) that compared the outcomes of LH and OH in PIH without region and language restrictions searched from the following databases: PubMed, Web of Science Database, Cochrane Library, SciELO Citation Index, Russian Science Citation Index, China National Knowledge Infrastructure, WanFang Data and China Science and Technology Journal Database. RESULTS: A total of 13 RCTs that involving 1207 patients included in the review. The LH displayed a shorter operative time for bilateral hernia repair (weighted mean difference = -8.23, 95% confidence interval [CI]: -11.22~-5.23, P < 0.00001), a lower complication rate (odds ratio [OR] = 0.32, 95% CI: 013-0.83, P = 0.02) along with a lower wound infection (OR = 0.14, 95% CI: 0.04-0.55, P = 0.005) and major male-specific post-operative complications (OR = 0.10, 95% CI: 0.04-0.24, P < 0.00001) and a less contralateral metachronous inguinal hernia (CMIH) incidence rate (OR = 0.09, 95% CI: 0.02-0.42, P = 0.002). No significant difference was found for unilateral operative time, time to full recovery, length of hospital stay, recurrence and hydrocele rates between the two techniques. CONCLUSION: The present review reiterates that both the LH and OH techniques for the PIH repair are comparable. However, in some aspects, the LH is superior to the OH in terms of operative time for bilateral hernias, post-operative complications rate and CMIH incidence rate. Rigorously designed RCTs are anticipated to confirm the clinical effects of both LH and OH.

Amyloid-Templated Palladium Nanoparticles for Water Purification by Electroreduction.

Electrocatalysis offers great promise for water purification but is limited by low active area and high uncontrollability of electrocatalysts. To overcome these constraints, we propose hybrid bulk electrodes by synthesizing and binding a Pd nanocatalyst (nano-Pd) to the electrodes via amyloid fibrils (AFs). The AFs template is effective for controlling the nucleation, growth, and assembly of nano-Pd on the electrode. In addition, the three-dimensional hierarchically porous nanostructure of AFs is beneficial for loading high-density nano-Pd with a large active area. The novel hybrid cathodes exhibit superior electroreduction performance for the detoxification of hexavalent chromium (Cr6+ ), 4-chlorophenol, and trichloroacetic acid in wastewater and drinking water. This study provides a proof-of-concept design of an AFs-templated nano-Pd-based hybrid electrode, which constitutes a paradigm shift in electrocatalytic water purification, and broadens the horizon of its potential engineered applications.

Demographic, clinical, and socioeconomic factors associated with delayed diagnosis and management of pediatric testicular torsion in West China: a retrospective study of 301 cases in a single tertiary children's hospital.

BACKGROUND: To investigate the association between geographic, clinical, socioeconomic factors and delayed management of pediatric testicular torsion (TT) in West China. METHODS: A retrospective study was conducted on TT at Children's Hospital of Chongqing Medical University in West China from November 2004 to December 2020. Univariate analysis and logistic regression analysis were conducted to determine the association between these factors and delayed management of TT. RESULTS: A total of 301 cases were included in this study. The misdiagnosis rate of TT in primary, secondary healthcare units and tertiary hospitals was 93.8, 71.1, and 8.9%, respectively. Approximately 26.9% of TT boys received timely surgical management (within 12 h from symptoms inset to surgery). Logistic regression analyses suggested the following factors were associated with delayed repair of TT: age less than 6 years (P = 0.001), with a history of symptoms progress (P = 0.001) or former treatment (P <0.001), absence of other diagnosis (P = 0.011) and those boys living far away from the main city zones (P <0.001). CONCLUSIONS: Delayed surgical management for TT was more likely for boys with age less than 6 years, the absence of other diagnosis, with a history of former treatment or symptoms progress, and those living far away from the main city zone. To maximize the possibility of timely surgical management for TT, it is vital to strengthen the public awareness of TT and conduct continuously re-education and update physicians working at primary and secondary healthcare units.

Administration of a mixture of triterpenoids from yeyachun and phenolic acids from danshen ameliorates carbon tetrachloride-induced liver fibrosis in mice by the regulation of intestinal flora.

yeyachun and danshen exist as Chinese patent medicine, Xuemai Tong, and are clearly effective at alleviating liver fibrosis (LF). Previous studies have indicated that triterpenoids from yeyachun (EFT), and phenolic acids from danshen (SMP) are effective in the treatment of LF. The regulation of intestinal flora is an effective method for treating LF. The aim of this study was to investigate the effect of a mixture of EFT and SMP on carbon tetrachloride (CCl4) induced LF. Our results showed the mixture significantly decreased liver damage and fibrosis index, and maintained liver tissue composition, compared to the model group. Moreover, the imbalance of symptoms of intestinal flora was improved. The mixture also caused changes to metabolites of gut flora. Furthermore, the expression of CD68 in liver tissues from the treated groups was significantly decreased when compared to the model group. However, no significant difference was observed from microstructure of gut tissues and LPS concentrations in the serum between mixture treated mice and model mice. This study suggests that the mixture of EFT and SMP had a significant effect on CCl4 induced LF, and the mechanism of this action, at least in part, involved the regulation of intestinal flora and their metabolites.

Volume reduction and water reclamation of reverse osmosis concentrate from coal chemical industry by forward osmosis with an osmotic backwash strategy.

Coal chemical industry (CCI) generally utilizes reverse osmosis (RO) for water reclamation, which generates a highly concentrated stream containing refractory organic substances and high-concentration total dissolved solids (TDS). To address this issue, the present work focuses on volume reduction of RO concentrate (ROC) produced from CCI by forward osmosis (FO). We investigated the effects of membrane orientation and draw solution (DS) concentration on FO performance. Foulant removal was tested by using chemical cleaning, physical cleaning and osmotic backwash (OB). AL-FS (active layer facing feed solution) mode outcompeted AL-DS (active layer facing draw solution) mode, achieving a flux of 26.4 LMH, 92.5% water reclamation and energy consumption of 0.050 kWh·m-3 with 4 M NaCl as DS. The FO process was able to reject >98% SO4 2-, Mg2+and Ca2+, 92-98% Si and 33-55% total organic carbon (TOC). Ten-cycle (10 × 20 h) accelerated fouling test demonstrated approximately 30% flux decline in association with Si-containing foulants, which could be removed almost completely through OB with 97.1% flux recovery. This study provides a proof-of-concept demonstration of FO for volume reduction and water reclamation of ROC produced from CCI, making the treatment of ROC more efficient and more energy effective.

Estimation of drug effect in radiographic progression for rheumatoid arthritis and psoriatic arthritis.

To demonstrate the treatment effect on structural damage in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), radiographic images of hands and feet are scored according to Sharp scoring systems in randomized clinical trials. However, the quantification of such an effect is challenging because the overall mean progression is lack of clinical interpretation. This article attempts to shed a light on the statistical challenges resulted from its scoring methods and heterogeneity of the study population and proposes a mixture distribution model approach to fit radiographic progression data. With such a model, the drug effect is fully captured by the mean progression of those patients who would progress in the study period under the control treatment. The resulting regression model also lends a tool in examining prognostic factors for radiographic progression. Simulations have been carried out to evaluate the precision of the parameter estimation procedure. Using the data examples from RA and PsA, we will show that the mixture distribution approach provides a better goodness of fit and leads to a casual inference of the study drug, hence a clinically meaningful interpretation.

The regulatory effect of Xiaoyao San on glucocorticoid receptors under the condition of chronic stress.

In modern society, fierce competitions cause yearly increase of depression and anxiety. Xiaoyao San is a traditional Chinese medicine which relieves depression and nourishes liver. The active ingredients contain saikoside A, saikoside C, saikoside D, ferulic acid, ligustilide, Atractylenolide I, Atractylenolide II, Atractylenolide Ⅲ, paeoniflorin, Albiflorin, liquiritin, glycyrrhizic acid and pachymic acid. In stress condition, glucocorticoid receptors participate in the hypothalamus-pituitarium-adrenal gland (HPA) axis to regulate the balance of organism. In response to stress, the HPA axis (hypothalamus-pituitarium-adrenal gland) is activated and the levels of glucocorticoid (GC) and catecholamine (CA) are increased to enhance neuroendocrine reactions. Chronic stress activates HPA axis and sustaining increase of GC, reduces the expression amount of GR and inhibits the mechanism of negative feedback on HPA. The lower negative feedback on HPA could lead to ketonemia. Several active ingredients of Xiaoyao San can raise the expression of GR and recover the negative feedback of HPA axis to relieve depression and illness state. In spite of the poor understanding of the current effective components in Xiaoyao San, this will be the focus of our further research. The study of Xiaoyao San could help us better understand its anti-depression mechanism and cure the patients.

Early MRI measures independently predict 1-year and 2-year radiographic progression in rheumatoid arthritis: secondary analysis from a large clinical trial.

OBJECTIVE: To determine if early MRI measures predict X-ray progression at 1 and 2 years in a large RA trial cohort. DESIGN: This study included 256 methotrexate (MTX)-naïve RA patients from a randomised placebo-controlled trial of golimumab (GO-BEFORE). MRIs of wrist and 2nd-5th metacarpophalangeal joints at 0, 12, 24, 52 and 104 weeks were obtained and scored using the RAMRIS system. Multivariable logistic regression examined if baseline and early change (weeks 12/24) in RAMRIS scores independently predicted progression of the van der Heijde-Sharp (vdHS) score and MRI erosion score at 1 and 2 years of follow-up. RESULTS: High baseline score and poor improvement over the first 24 weeks in synovitis (p=0.003 and p=0.003, respectively) and in bone oedema (p=0.02 and p=0.001, respectively) were independent predictors of X-ray progression at 1 year. Associations were significant or tended towards an association at 2 years. An increase in RAMRIS bone erosion >0.5 at weeks 12 and 24 also predicted X-ray progression (p<0.003). Poor 12-week improvement in bone oedema was associated with X-ray and MRI progression at 1 year (p<0.05). Regression models that incorporated baseline and 12-week and 24-week changes in MRI measures of synovitis (AUC=0.71) and bone oedema (AUC=0.70) improved the prediction of X-ray progression at 1 year above clinical disease activity alone (AUC=0.66, p<0.04). CONCLUSIONS: Baseline and early changes in MRI measures independently predicted X-ray and MRI progression at later time-points. The predictive validity established here supports potential use in shorter-duration studies to determine efficacy of RA therapies in preventing structural damage.

Radiographic benefit and maintenance of clinical benefit with intravenous golimumab therapy in patients with active rheumatoid arthritis despite methotrexate therapy: results up to 1 year of the phase 3, randomised, multicentre, double blind, placebo controlled GO-FURTHER trial.

OBJECTIVE: Report on radiographic effects and maintenance of clinical benefit with intravenous golimumab 2 mg/kg+methotrexate (MTX) for up to week (wk) 52 in active rheumatoid arthritis (RA). METHODS: Patients (n=592) with active RA (≥6/66 swollen, ≥6/68 tender joints, C reactive protein (CRP) ≥1.0 mg/dL and positive for rheumatoid factor and/or anticyclic citrullinated protein antibody at screening) despite MTX ≥3 months (stable dose of 15-25 mg/week for ≥4 weeks) participated in this multicentre, international, randomised, double blind, placebo controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and then every 8 weeks; patients continued their stable MTX regimen. Placebo patients started golimumab 2 mg/kg at wk16 (early escape; <10% improvement in tender and swollen joints) or wk24 (crossover by design). Week 24 and wk52 radiographic (van der Heijde-Sharp (vdH-S) scores), clinical efficacy and safety data up to 1 year are reported here. RESULTS: Significant and rapid clinical improvement was observed up to wk24 of intravenous golimumab therapy. Golimumab+MTX treated patients demonstrated less radiographic progression than placebo treated patients at wk24 (vdH-S score mean change 0.03 vs 1.09; p<0.001) and wk52 (0.13 vs 1.22; p=0.001). Among patients with ≥20% improvement in the American College of Rheumatology response criteria or who achieved a 'good' or 'moderate' response according to the 28 joint Disease Activity Score employing CRP at wk24, approximately 80% maintained this response up until wk52. Through an average of 43.5 weeks of follow-up, 64.6% of patients receiving golimumab+MTX reported adverse events, most commonly non-serious infections. CONCLUSIONS: In patients with active RA despite MTX, intravenous golimumab+MTX yielded significant inhibition of structural damage at wk24 and wk52, and sustained clinical improvement in signs and symptoms with no new safety signals up to 1 year. CLINICALTRIALSGOV: NCT00973479, EudraCT 2008-006 064-11.

Clinical efficacy, radiographic and safety findings through 5†years of subcutaneous golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of a randomised, placebo-controlled trial (the GO-REVEAL study).

OBJECTIVES: Assess golimumab's long-term efficacy/safety in psoriatic arthritis (PsA). METHODS: Adults with active PsA (≥3 swollen and tender joints, active psoriasis) were randomly assigned to subcutaneous placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks (q4wks) through wk20. All patients received golimumab 50 mg or 100 mg q4wks from wk24 forward. Methotrexate was allowed and taken by approximately half the patients. Findings through 5 years are reported herein. Efficacy assessments included ≥20% improvement in American College of Rheumatology (ACR20) response, C-reactive-protein-based, 28-joint-count Disease Activity Score (DAS28-CRP) response, ≥75% improvement in Psoriasis Area and Severity Index (PASI75) scores, and PsA-modified Sharp/van der Heijde scores (SHSs). RESULTS: 126/405 (31%) randomised patients discontinued treatment through wk252. Golimumab was effective in maintaining clinical improvement through year-5 (ACR20: 62.8-69.9%, DAS28-CRP: 75.2-84.9% for randomised patients; PASI75: 60.8-72.2% among randomised patients with ≥3% body surface area involvement) and inhibiting radiographic progression (mean changes in PsA-modified SHS: 0.1-0.3) among patients with radiographic data. While concomitant methotrexate did not affect ACR20/PASI75, it appeared to reduce radiographic progression. No new safety signals were identified. Antibodies-to-golimumab occurred in 1.8%/10.0% of patients with/without methotrexate). CONCLUSIONS: Long-term golimumab safety/efficacy in PsA was demonstrated through 5 years. TRIAL REGISTRATION NUMBER: NCT00265096.

Effect of golimumab on carotid atherosclerotic disease measures and cardiovascular events in inflammatory arthritides.

OBJECTIVE: The objective of this study was to assess the effect of golimumab on carotid ultrasound measures and cardiovascular serious adverse events (SAEs) in patients with inflammatory arthritides. METHODS: An exploratory carotid artery ultrasound substudy was performed in the GO-BEFORE study of methotrexate (MTX)-naive rheumatoid arthritis patients, with ultrasounds performed at weeks 0, 24, and 52 to measure common carotid artery intima-media thickness, distensibility coefficient, interadventitial diameter, and plaque count. Cardiovascular SAEs reported over 2 years of follow-up were assessed in 5 golimumab phase 3 clinical trials of patients with rheumatoid arthritis (GO-BEFORE, GO-FORWARD, and GO-AFTER), psoriatic arthritis (GO-REVEAL), and ankylosing spondylitis (GO-RAISE). In GO-BEFORE and GO-FORWARD, patients received placebo + MTX, golimumab 50 mg + MTX, or golimumab 100 mg +/- MTX at baseline and every 4 weeks; in the other 3 trials, patients received placebo or golimumab 50 or 100 mg. RESULTS: The carotid ultrasound substudy showed inconsistent changes in common carotid artery intima-media thickness in the golimumab + MTX groups over time, and there was large variability in the measurements. Increases in interadventitial diameter were observed in the golimumab 100 mg + placebo group, but not in the golimumab + MTX groups. There were no significant differences in the distensibility coefficient and plaque count between the golimumab and placebo groups. Very few patients overall experienced a cardiovascular SAE, and the incidence of cardiovascular SAEs was not statistically different between the golimumab and placebo groups. CONCLUSIONS: The results of the carotid ultrasound substudy were inconclusive, and no increase or decrease in cardiovascular SAEs was observed following 2 years of treatment with golimumab with or without MTX.

Research on Dynamic Response under the External Impact of Paper Honeycomb Sandwich Board.

The dynamic mechanical behavior and cushioning performance of honeycomb sandwich panels, which are extensively employed in product cushioning packaging due to their exceptional energy absorption capabilities, were examined using a combination of experimental and numerical methods. Several factors, such as maximum acceleration-static stress, cushioning coefficient-static stress, and other curves, were analyzed under various impact conditions. The simulated stress-strain, deformation modes, cushioning coefficients, and other parameters demonstrate consistency with the experimental results. The acceleration, maximum compression, and cushioning coefficient obtained from the experiment and simulation calculation were 30.68 g, 15.44 mm, and 2.65, and 31.96 g, 14.91 mm, and 2.79, respectively. The results indicate that all error values were less than 5%, confirming the precision and reliability of the model. Furthermore, the model was utilized to simulate and predict the cushioning performance of honeycomb sandwich panels with different cell structures and paper thicknesses. These results provide a solid basis for enhancing the design of subsequent honeycomb element structures.

Delineation of renal protein profiles in aristolochic acid I-induced nephrotoxicity in mice by label-free quantitative proteomics.

Introduction: Aristolochic acid nephropathy (AAN) is a kidney injury syndrome caused by aristolochic acids exposure. Our study used label-free quantitative proteomics to delineate renal protein profiles and identify key proteins after exposure to different doses of aristolochic acid I (AAI). Methods: Male C57BL/6 mice received AAI (1.25 mg/kg/d, 2.5 mg/kg/d, or 5 mg/kg/d) or vehicle for 5 days. Results and discussion: The results showed that AAI induced dose-dependent nephrotoxicity. Differences in renal protein profiles between the control and AAI groups increased with AAI dose. Comparing the control with the low-, medium-, and high-dose AAI groups, we found 58, 210, and 271 differentially expressed proteins, respectively. Furthermore, protein-protein interaction network analysis identified acyl-CoA synthetase medium-chain family member 3 (Acsm3), cytochrome P450 family 2 subfamily E member 1 (Cyp2e1), microsomal glutathione S-transferase 1 (Mgst1), and fetuin B (Fetub) as the key proteins. Proteomics revealed that AAI decreased Acsm3 and Cyp2e1 while increasing Mgst1 and Fetub expression in mice kidneys, which was further confirmed by Western blotting. Collectively, in AAI-induced nephrotoxicity, renal protein profiles were dysregulated and exacerbated with increasing AAI dose. Acsm3, Cyp2e1, Mgst1, and Fetub may be the potential therapeutic targets for AAN.

Intravenous golimumab is effective in patients with active rheumatoid arthritis despite methotrexate therapy with responses as early as week 2: results of the phase 3, randomised, multicentre, double-blind, placebo-controlled GO-FURTHER trial.

OBJECTIVES: Evaluate the efficacy of intravenous golimumab 2 mg/kg+methotrexate (MTX) in patients with active rheumatoid arthritis (RA) receiving MTX. METHODS: Patients (n=592) with active disease (≥6/66 swollen, ≥6/68 tender joints, C-reactive protein ≥1.0 mg/dl, rheumatoid factor positive and/or anticyclic citrullinated protein antibody positive at screening) despite MTX (15-25 mg/week) participated in this double-blind, placebo-controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg, or placebo infusions at weeks 0 and 4 and every (q) 8 weeks; patients continued MTX. Placebo patients with <10% improvement in combined swollen/tender joint counts at week 16 could early escape to intravenous golimumab 2 mg/kg. The primary endpoint was week 14 American College of Rheumatology 20% (ACR20) response. Analyses employed non-responder imputation and last-observation-carried-forward. RESULTS: At week 14, significantly (p<0.001) larger proportions of golimumab+MTX than placebo+MTX patients achieved ACR20 response (59% vs 25%, respectively), a disease activity score of good/moderate (EULAR) response (81% vs 40%), and greater median improvement in health assessment questionnaire scores (0.500 vs 0.125). Improvements versus placebo+MTX were observed by week 2. Similar proportions of patients receiving golimumab+MTX and placebo+MTX, respectively, reported adverse events through week 16 (47% and 44%) and week 24 (53% and 49%). Serious adverse events were reported by more golimumab+MTX (4.1%) than placebo+MTX (2%) patients at week 24. CONCLUSION: The addition of intravenous golimumab rapidly and significantly improved signs and symptoms in patients with active RA despite ongoing MTX, in some patients by week 2.

Misdiagnosis of food-borne foreign bodies outside of the digestive tract on magnetic resonance imaging: Two case reports.

BACKGROUND: Patients with foreign bodies in the digestive tract are often encountered, but complete penetration of a foreign body through the gastrointestinal tract is rare, and the choice of imaging method is very important. Improper selection may lead to missed diagnosis or misdiagnosis. CASE SUMMARY: An 81-year-old man was diagnosed as having a liver malignancy after he took magnetic resonance imaging and positron emission tomography/computed tomography (CT) examinations. The pain improved after the patient accepted gamma knife treatment. However, he was admitted to our hospital 2 mo later due to fever and abdominal pain. This time, he received a contrast-enhanced CT scan, which showed fish-boon-like foreign bodies in the liver with peripheral abscess formation, then he went to the superior hospital for surgery. It lasted for more than 2 mo from the onset of the disease to the surgical treatment. A 43-year-old woman with a 1 mo history of a perianal mass with no obvious pain or discomfort was diagnosed as having an anal fistula with the formation of a local small abscess cavity. Clinical perianal abscess surgery was performed, and fish bone foreign body was found in perianal soft tissue during the operation. CONCLUSION: For patients with pain symptoms, the possibility of foreign body perforation should be considered. Magnetic resonance imaging is not comprehensive and that a plain computed tomography scan of the pain area is necessary.