Development of Biomarkers and Prognosis Model of Mortality Risk in Patients with COVID-19.

Background: As of 30 April 2023, the COVID-19 pandemic has resulted in over 6.9 million deaths worldwide. The virus continues to spread and mutate, leading to continuously evolving pathological and physiological processes. It is imperative to reevaluate predictive factors for identifying the risk of early disease progression. Methods: A retrospective study was conducted on a cohort of 1379 COVID-19 patients who were discharged from Xin Hua Hospital affiliated with Shanghai Jiao Tong University School of Medicine between 15 December 2022 and 15 February 2023. Patient symptoms, comorbidities, demographics, vital signs, and laboratory test results were systematically documented. The dataset was split into testing and training sets, and 15 different machine learning algorithms were employed to construct prediction models. These models were assessed for accuracy and area under the receiver operating characteristic curve (AUROC), and the best-performing model was selected for further analysis. Results: AUROC for models generated by 15 machine learning algorithms all exceeded 90%, and the accuracy of 10 of them also surpassed 90%. Light Gradient Boosting model emerged as the optimal choice, with accuracy of 0.928 ± 0.0006 and an AUROC of 0.976 ± 0.0028. Notably, the factors with the greatest impact on in-hospital mortality were growth stimulation expressed gene 2 (ST2,19.3%), interleukin-8 (IL-8,17.2%), interleukin-6 (IL-6,6.4%), age (6.1%), NT-proBNP (5.1%), interleukin-2 receptor (IL-2R, 5%), troponin I (TNI,4.6%), congestive heart failure (3.3%) in Light Gradient Boosting model. Conclusion: ST-2, IL-8, IL-6, NT-proBNP, IL-2R, TNI, age and congestive heart failure were significant predictors of in-hospital mortality among COVID-19 patients.

Copper Deficiency Induces Oxidative Stress in Liver of Mice by Blocking the Nrf2 Pathway.

Copper (Cu) is an essential metal required for many physiological processes and biological reactions. Liver is the main organ of metabolism of Cu and is also the site where synthesis of some metalloproteins. The purpose of this study is to explore the effects of Cu deficiency on the liver and to evaluate the changes in liver oxidative stress levels to reveal its possible impact mechanisms. Mice were feed to a nutritional Cu-deficiency diet from weaning and injected with copper sulfate (CuSO4) intraperitoneally to correct Cu deficiency. Cu deficiency resulted in reduced liver index, liver histological alteration, and oxidative stress; decreased the contents of Cu and ALB; elevated ALT and AST concentrations in serum together with decreased mRNA and protein expressions of Nrf2 pathway related molecules (Nrf2, HO-1, NQO1); and increased mRNA and protein expressions of Keap1. However, the supplement of copper sulfate (CuSO4) significantly ameliorated the changes mentioned above. Our results indicate that Cu deficiency can cause hepatic damage in mice is associated with the activation of oxidative stress and inhibition of Nrf2 pathway.

Longitudinal predictions between executive function and general and specific psychiatric problems in school-age children.

This study examined the longitudinal associations of various executive function components with subsequent psychiatric problems in Chinese school-age children. Data from 1,639 children (44.36% girls) ages 6-13 years were drawn from the Children School Functions and Brain Development project. Executive function components were assessed by the cancellation test, the Corsi test, and the Wisconsin Card Sorting Test. Psychiatric problems were determined by parent report. All assessments were administered twice, separated by a 1-year interval. Cross-lagged panel models showed that cognitive flexibility and general psychiatric problems (general p) mutually predicted each other. Worse inhibitory control at baseline significantly predicted more externalizing problems 1 year later, regardless of age, while externalizing problems did not significantly predict inhibitory control 1 year later. Working memory at baseline did not significantly predict internalizing problems and vice versa. These findings demonstrate that better inhibitory control may help to prevent or reduce externalizing problems in Chinese school-age children and that higher cognitive flexibility may help to mitigate general psychiatric problems. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Activation of kappa opioid receptor (KOR) inhibits estrogen receptor (ER)-positive breast cancer through the KOR-ER-XBP1 pathway.

Opioids are commonly used in patients with breast cancer (BC), both for perioperative analgesia and for the relief of chronic cancer pain. Studies have suggested a potential association of opioid receptors (ORs) with the prognosis of BC patients. However, the exact roles of different ORs remain poorly understood. In this study, we found that κ opioid receptor (KOR) was the only OR (among the four types of ORs) that was significantly decreased in BC tumor tissues compared with peritumoral normal tissues. In addition, decreased expression of KOR correlated with poor clinical outcomes in patients with estrogen receptor (ER)-positive BC. In vitro studies confirmed the anti-tumor effects of KOR agonists in ER-positive MCF-7 and T47D cells by showing that activation of KOR significantly inhibited cellular proliferation and promoted apoptosis. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction network (PPI) analysis, we found that KOR-ER-XBP1 was the potential downstream signaling pathway mediating the anti-tumor effects of KOR agonist. Finally, the role of XBP1 was confirmed as KOR activation-induced increase in the proliferative and monoclonal formation abilities of ER-positive BC cells were both significantly abolished after silencing of XBP1. These findings provide us a better understanding of the roles of different ORs in BC, identifying KOR agonists as better opioids than traditional µ opioid receptor (MOR) agonists for providing analgesia in ER-positive BC patients owing to their association with better prognosis.

Dexmedetomidine ameliorates liver injury and maintains liver function in patients with hepatocellular carcinoma after hepatectomy: a retrospective cohort study with propensity score matching.

Background: Although dexmedetomidine (DEX) is widely used during the perioperative period in patients with hepatocellular carcinoma (HCC), its clinical effects on liver function and postoperative inflammation are unclear. This study aimed to explore effects of DEX on postoperative liver function and inflammation in patients with HCC after hepatectomy. Methods: A retrospective cohort study with propensity score matching was performed. A total of 494 patients who underwent hepatectomy from June 2019 to July 2020 and fulfilled the eligibility criteria were included in this study. Baseline data, liver function indexes and inflammation-related biomarkers were collected and compared between the two groups. Survival analysis was conducted to investigate the effects of DEX on the overall survival (OS) of patients. Propensity score matching (PSM) was used to minimize bias between the two groups. Results: The study cohort comprised 189 patients in the DEX-free group and 305 patients in the DEX group. Patients in the DEX group had lower levels of alanine transaminase (ALT, P = 0.018) and lactate dehydrogenase (LDH, P = 0.046) and higher level of serum albumin (ALB, P < 0.001) than patients in the DEX-free group before discharge. A total of 107 pairs of patients were successfully matched by PSM. Results consistently suggested that ALT and LDH levels were significantly lower (P = 0.044 and P = 0.046, respectively) and ALB levels were significantly higher (P = 0.002) in the DEX group than in the DEX-free group in the early postoperative period. No significant differences of inflammation-related biomarkers were observed between two groups after PSM. Neither the Kaplan-Meier survival analysis nor the multiple Cox regression survival analysis identified DEX as a contributing factor that would affect the OS of patients after PSM. Conclusion: DEX exerts protective effects on liver function while has little effects on inflammation-related biomarkers in the early postoperative period in patients undergoing hepatectomy due to HCC.

µ-opioid receptor agonist facilitates circulating tumor cell formation in bladder cancer via the MOR/AKT/Slug pathway: a comprehensive study including randomized controlled trial.

BACKGROUND: µ-opioid receptor agonists (MORAs) are indispensable for analgesia in bladder cancer (BC) patients, both during surgery and for chronic pain treatment. Whether MORAs affect BC progression and metastasis remains largely unknown. This study focused on the effects of MORAs on the formation of circulating tumor cells (CTCs) in BC and aimed to provide potential therapeutic targets, which would retain the pain-relieving effects of MORAs in BC patients without sacrificing their long-term prognosis. METHODS: Different preclinical models were used to identify the effects of MORAs on the progression of BC. A novel immunocapture microfluidic chip was utilized to analyze whether MORAs affected the number of CTCs in mouse models and clinical BC patients. Bioinformatic analyses, total transcriptome sequencing, and molecular biology methods were then used to investigate the underlying mechanisms in these models and in BC cell lines. RESULTS: Mouse models of hematogenous metastasis and in situ BC demonstrated that tumor metastasis was significantly increased after MORA treatment. A significant increase in the number of mesenchymal and/or epithelial CTCs was detected after MORA treatment in both the mouse models and clinical trial patients. Mechanistically, MORAs facilitated the formation of CTCs by activating the MOR/PI3K/AKT/Slug signaling pathway, hereby promoting the epithelial-mesenchymal transition (EMT) of BC cells, as knockdown of MOR, Slug or blockade of PI3K inhibited the EMT process and CTC formation. CONCLUSION: MORAs promoted BC metastasis by facilitating CTC formation. The EMT-CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumor metastasis or recurrence in BC patients.

Association of different central venous pressure levels with outcome of living-donor liver transplantation in children under 12 years.

BACKGROUND: Pediatric liver transplantation is an important modality for treating biliary atresia. The overall survival (OS) rate of pediatric liver transplantation has significantly improved compared with that of 20 years ago, but it is still unsatisfactory. The anesthesia strategy of maintaining low central venous pressure (CVP) has shown a positive effect on prognosis in adult liver transplantation. However, this relationship remains unclear in pediatric liver transplantation. Thus, this study was conducted to review the data of pediatric living-donor liver transplantation to analyze the associations of different CVP levels with the prognosis of recipients. METHODS: This was a retrospective study and the patients were divided into two groups according to CVP levels after abdominal closure: low CVP (LCVP) (≤ 10 cmH2O, n = 470) and high CVP (HCVP) (> 10 cmH2O, n = 242). The primary outcome measured in the study was the overall survival rate. The secondary outcomes included the duration of mechanical ventilation in the intensive care unit (ICU), length of stay in the ICU, and postoperative stay in the hospital. Patient demographic and perioperative data were collected and compared between the two groups. Kaplan-Meier curves were constructed to determine the associations of different CVP levels with the survival rate. RESULTS: In the study, 712 patients, including 470 in the LCVP group and 242 in the HCVP group, were enrolled. After propensity score matching, 212 pairs remained in the group. The LCVP group showed a higher overall survival rate than the HCVP group in the Kaplan-Meier curves and multivariate Cox regression analyses (P = 0.018), and the HCVP group had a hazard ratio of 2.445 (95% confidence interval, 1.163-5.140). CONCLUSION: This study confirmed that a low-CVP level at the end of surgery is associated with improved overall survival and a shorter length of hospital stay.

Development of functional connectome gradients during childhood and adolescence.

Connectome mapping studies have documented a principal primary-to-transmodal gradient in the adult brain network, capturing a functional spectrum that ranges from perception and action to abstract cognition. However, how this gradient pattern develops and whether its development is linked to cognitive growth, topological reorganization, and gene expression profiles remain largely unknown. Using longitudinal resting-state functional magnetic resonance imaging data from 305 children (aged 6-14 years), we describe substantial changes in the primary-to-transmodal gradient between childhood and adolescence, including emergence as the principal gradient, expansion of global topography, and focal tuning in primary and default-mode regions. These gradient changes are mediated by developmental changes in network integration and segregation, and are associated with abstract processing functions such as working memory and expression levels of calcium ion regulated exocytosis and synaptic transmission-related genes. Our findings have implications for understanding connectome maturation principles in normal development and developmental disorders.

Comprehensive analysis to identify the neurotransmitter receptor-related genes as prognostic and therapeutic biomarkers in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with high morbidity and mortality, which accounts for the fourth most common cause of cancer-related deaths. Reports suggest that the neurotransmitter receptor-related genes (NRGs) may influence the tumor microenvironment and the prognosis of patients with HCC. Methods: The clinical information and RNA-seq data of patients with HCC were acquired from the ICGC-LIRI-JP dataset and the TCGA-LIHC dataset. Effects of 115 NRGs on the prognosis of HCC patients were analyzed in the ICGC-LIRI-JP dataset. The least absolute shrinkage and selection operator (LASSO) regression model was utilized to generate a risk score formula based on the critical NRGs. Next, the risk score effectiveness was validated both in the TCGA-LIHC dataset and in our clinical HCC samples. Based on the risk scores, patients with HCC were divided into two groups. Moreover, differentially expressed genes (DEGs) were screened. The gene ontology (GO) was used to analyze the functional enrichments of DEGs and to identify potential signaling pathways. To test the diagnostic effectiveness of our model, the receiver operator characteristic curve (ROC) analysis and nomogram were used. Finally, potential targeted drug prediction was performed based on DEGs of nine clinical HCC samples. Results: Nine NRGs were correlated significantly with the prognosis of patients with HCC, and eight NRGs were successfully included in the LASSO regression model. The Kaplan-Meier analysis of overall survival (OS) suggested that patients in the high-risk score group had worse prognosis; on the other hand, ROC analysis revealed a high prognostic value of the risk score in HCC. Several critical signaling pathways, such as lipid metabolism, organic acid metabolism, cell migration, cell adhesion, and immune response, were enriched both in public datasets and clinical samples. Nomogram results also suggested that the risk scores correlated well with the patients' prognosis. Potential targeted drugs prediction revealed that tubulin inhibitors might be the promising drugs for patients with HCC who have high risk scores based on the NRGs. Conclusion: We established a prognostic model based on critical NRGs. NRGs show a promising prognostic prediction value in HCC and are potential therapeutic targets for the disease treatment.

A Bayesian group sequential design for randomized biosimilar clinical trials with adaptive information borrowing from historical data.

At the time of developing a biosimilar, the reference product has been on market for years and thus ample data are available on its efficacy and characteristics. We develop a Bayesian adaptive design for randomized biosimilar clinical trials to leverage the rich historical data on the reference product. This design takes a group sequential approach. At each interim, we employ the elastic meta-analytic-predictive (EMAP) prior methodology to adaptively borrow information from the historical data of the reference product to make go/no-go decision based on Bayesian posterior probabilities. In addition, the randomization ratio between the test and reference arms is adaptively adjusted at the interim with the goal to balance the sample size of the two arms at the end of trials. Simulation study shows that the proposed Bayesian adaptive design can substantially reduce the sample size of the reference arm, while achieving comparable power as the traditional randomized clinical trials that ignore the historical data. We apply our design to a biosimilar trial for treating breast cancer patients.

The SACT Template: A Human Brain Diffusion Tensor Template for School-age Children.

School-age children are in a specific development stage corresponding to juvenility, when the white matter of the brain experiences ongoing maturation. Diffusion-weighted magnetic resonance imaging (DWI), especially diffusion tensor imaging (DTI), is extensively used to characterize the maturation by assessing white matter properties in vivo. In the analysis of DWI data, spatial normalization is crucial for conducting inter-subject analyses or linking the individual space with the reference space. Using tensor-based registration with an appropriate diffusion tensor template presents high accuracy regarding spatial normalization. However, there is a lack of a standardized diffusion tensor template dedicated to school-age children with ongoing brain development. Here, we established the school-age children diffusion tensor (SACT) template by optimizing tensor reorientation on high-quality DTI data from a large sample of cognitively normal participants aged 6-12 years. With an age-balanced design, the SACT template represented the entire age range well by showing high similarity to the age-specific templates. Compared with the tensor template of adults, the SACT template revealed significantly higher spatial normalization accuracy and inter-subject coherence upon evaluation of subjects in two different datasets of school-age children. A practical application regarding the age associations with the normalized DTI-derived data was conducted to further compare the SACT template and the adult template. Although similar spatial patterns were found, the SACT template showed significant effects on the distributions of the statistical results, which may be related to the performance of spatial normalization. Looking forward, the SACT template could contribute to future studies of white matter development in both healthy and clinical populations. The SACT template is publicly available now ( https://figshare.com/articles/dataset/SACT_template/14071283 ).

Elastic meta-analytic-predictive prior for dynamically borrowing information from historical data with application to biosimilar clinical trials.

A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an approved reference product. Focusing on two-arm randomized clinical trials that aim to establish the equivalence between a test biosimilar product and the reference product, we propose the elastic meta-analytic-predictive (EMAP) prior method to leverage rich historical data available on the reference product to improve the power of the biosimilar trials. We first extract the prior information from multiple historical studies through meta-analysis, and then we discount the resulting meta-analytic-predictive (MAP) prior adaptively according to the congruence between the historical reference data and the trial reference arm data via an elastic function. The EMAP prior method is information-borrowing consistent in that asymptotically it achieves full information borrowing when trial reference arm data are congruent to historical reference data, and no information borrowing when trial reference arm data are not congruent to historical reference data. As a result, the method asymptotically controls the type I error rate at the nominal value. Extensive simulation studies show that the EMAP prior outperforms the robust MAP prior. The EMAP prior generates comparable or higher power and provides better-controlled type I errors. We illustrate the proposed methodology using two trial examples.

Design and Analysis of a Biosimilar Bridging Study with a Prediction Interval-Based Consistency Test.

The development of biosimilars has substantially increased in recent years. A biosimilar is a biological product which is highly similar to a licensed biological product (reference product), with no clinically meaningful differences between the proposed biosimilar and the reference product. A bridging study is a viable strategy to bring an approved biosimilar product from the original region(s) to new regions or countries. While the bridging concept and the principles of conducting bridging studies for innovative products outlined in ICH E5 guidance are informative for biosimilar development, existing statistical strategies for designing and analyzing a bridging study may not be directly applicable when the biosimilar global study compares the biosimilar product to a reference product as control. In this paper, we present a novel and practical statistical methodology for designing and analyzing a biosimilar bridging study based on a prediction interval-based consistency test for assessing consistency between the bridging study and the biosimilar global study. We prove analytically that the method has the desired statistical properties (i.e., high power when the two studies are perfectly consistent or nearly consistent in efficacy and type I error control when the two studies are clearly inconsistent in efficacy). We present a numerical example to illustrate that the implementation of the method is straightforward in practice. We also discuss the application of the method to various endpoints and metrics.

Lactated Ringer's solution versus normal saline in pediatric living-donor liver transplantation: A matched retrospective cohort study.

BACKGROUND: In pediatric living-donor liver transplantation, lactated Ringer's solution and normal saline are commonly used for intraoperative fluid management, but the comparative clinical outcomes remain uncertain. AIMS: To compare the effect between lactated Ringer's solution and normal saline for intraoperative volume replacement on clinical outcomes among pediatric living-donor liver transplantation patients. METHODS: This single-center, retrospective trial study enrolled children who received either lactated Ringer's solution or normal saline during living-donor liver transplantation between January 2010 and August 2016. The groups with comparable clinical characteristics were balanced by propensity score matching. The primary outcome was 90-day all-cause mortality, and the secondary outcomes included early allograft dysfunction, primary nonfunction, acute renal injury, and hospital-free days (days alive postdischarge within 30 days of liver transplantation). RESULTS: We included 333 pediatric patients who met the entry criteria for analysis. Propensity score matching identified 61 patients in each group. After matching, the lactated Ringer's solution group had a higher 90-day mortality rate than the normal saline group (11.5% vs. 0.0%). Early allograft dysfunction and primary nonfunction incidences were also more frequent in the lactated Ringer's solution group (19.7% and 11.5%, respectively) than in the normal saline group (3.3% and 0.0%, respectively). In the lactated Ringer's solution group, four (6.6%) recipients developed acute renal injury within 7 days postoperatively compared with three (4.9%) recipients in the normal saline group. Hospital-free days did not differ between groups (9 days [1-13] vs. 9 days [0-12]). CONCLUSIONS: For intraoperative fluid management in pediatric living-donor liver transplantation patients, lactated Ringer's solution administration was associated with a higher 90-day mortality rate than normal saline. This finding has important implications for selecting crystalloid in pediatric living-donor liver transplantation. Further randomized clinical trials in larger cohort are necessary to confirm this finding.

Successive treatment with naltrexone induces epithelial-mesenchymal transition and facilitates the malignant biological behaviors of bladder cancer cells.

Naltrexone is widely used for alleviating opioid-related side effects in cancer patients. However, the effects of naltrexone on cancer progression are controversial in the literature. The present study was carried out to investigate the effects of successive treatment with clinically relevant doses of naltrexone on the malignant biological behaviors of bladder cancer cells. The human bladder cancer T24 cells and mouse bladder cancer MB49 cells were treated with naltrexone. Cell proliferation, migration, and invasion abilities were analyzed. Morphological changes of the cells were confirmed by F-actin immunofluorescence staining. Epithelial-mesenchymal transition (EMT)-related markers and transcriptional factors, as well as activation of the phosphatidylinositol 3 kinase (PI3K)/AKT signaling pathway, were analyzed. Results showed that, compared with the control group, successive treatment with naltrexone significantly promoted the proliferation and decreased the apoptosis of bladder cancer cells, together with increase in cell migration and invasion ability. Continuous treatment with naltrexone also significantly reduced the expression of epithelial markers (E-cadherin and cytokeratin 19), increased the expression of mesenchymal markers (N-cadherin and vimentin) and EMT-inducing transcription factors (Snail and Slug), and further shifted the morphological phenotype of bladder cancer cells to a mesenchymal phenotype. The PI3K/AKT signaling pathway was activated by successive treatment with naltrexone. Notably, incubation with the specific PI3K inhibitor LY294002 together with naltrexone reversed the naltrexone-induced EMT progression. In conclusion, successive treatment with naltrexone may be favorable for the progression of bladder tumors by activating the PI3K/AKT signaling pathway and inducing EMT. Long-term exposure to naltrexone should be used cautiously in patients with bladder cancer.

Baseline neutrophil-lymphocyte ratio is associated with survival for infant living donor liver transplantation for biliary atresia.

Living donor liver transplantation (LDLT) in infants for congenital biliary atresia (BA) poses various challenges nowadays. We aim to investigate independent preoperative risk factors for LDLT in infants. We retrospectively analyzed medical records of infant patients who underwent LDLT surgery for BA from 1 July 2014 to 31 December 2016. Cox regression was used to explore risk factors. The Kaplan-Meier method was used to calculate the recipient and graft survival, and subgroup analysis was then applied according to the risk factors. Independent t test or Mann-Whitney U test was applied for comparison of certain factors between survival patients and death. A total of 345 infant LDLT for BA were included in the analysis. In the multivariate Cox-regression model, 3 factors were determined as independent risk factors for recipient and graft survival, there were neutrophil-lymphocyte ratio (NLR), pediatric end-stage liver disease (PELD), and recipient age. The HR (95% CI) of baseline NLR for recipient and graft survival were 1.25 (1.12-1.38) and 1.25 (1.13-1.39), with all P < .0001. Kaplan-Meier curves for NLR using different cut-offs (1.5; 1, 2) suggested that higher baseline NLR was significantly associated with recipient and graft survival. The subgroup analysis indicated that for infants with elevated NLR, the recipient survival was significantly lower when their age >6 months or PELD >20. Our results indicate that infants with higher baseline NLR value may have lower survival rate 3 years after transplantation. Further investigations about broaden the application of pre- and post-transplant NLR to guide nutrition intervention and immunosuppression therapy are necessary.

Correction to: Efficacy and safety results from a randomized double-blind study comparing proposed biosimilar ABP 798 with rituximab reference product in subjects with moderate-to-severe rheumatoid arthritis.

This article originally published with the family name and given names of all authors transposed.

Impact of Intraoperative Norepinephrine Support on Living Donor Liver Transplantation Outcomes: A Retrospective Cohort Study of 430 Children.

Norepinephrine (NE) is often administered during the perioperative period of liver transplantation to address hemodynamic instability and to improve organ perfusion and oxygen supply. However, its role and safety profile have yet to be evaluated in pediatric living donor liver transplantation (LDLT). We hypothesized that intraoperative NE infusion might affect pediatric LDLT outcomes. A retrospective study of 430 pediatric patients (median [interquartile range] age, 7 [6.10] months; 189 [43.9%] female) receiving LDLT between 2014 and 2016 at Renji Hospital was conducted. We evaluated patient survival among recipients who received intraoperative NE infusion (NE group, 85 recipients) and those that did not (non-NE group, 345 recipients). The number of children aged over 24 months and weighing more than 10 kg in NE group was more than that in non-NE group. And children in NE group had longer operative time, longer anhepatic phase time and more fluid infusion. After multivariate regression analysis and propensity score regression adjusting for confounding factors to determine the influence of intraoperative NE infusion on patient survival, the NE group had a 169% more probability of dying. Although there was no difference in mean arterial pressure changes relative to the baseline between the two groups, we did observe increased heart rates in NE group compared with those of the non-NE group at anhepatic phase (P=0.025), neohepatic phase (P=0.012) and operation end phase (P=0.017) of the operation. In conclusion, intraoperative NE infusion was associated with a poorer prognosis for pediatric LDLT recipients. Therefore, we recommend the application of NE during pediatric LDLT should be carefully re-considered.

Efficacy and safety results from a randomized double-blind study comparing proposed biosimilar ABP 798 with rituximab reference product in subjects with moderate-to-severe rheumatoid arthritis.

BACKGROUND/OBJECTIVES: ABP 798 is a proposed biosimilar to the originator biologic rituximab, an anti-CD20 monoclonal antibody. This comparative clinical study evaluated the pharmacokinetics (PK), safety, and efficacy of ABP 798 versus rituximab reference product (RP) in patients with moderate-to-severe rheumatoid arthritis (RA). METHODS: Adults with moderate-to-severe RA with an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs including 1 or more tumor necrosis factor inhibitor therapies (n = 311) received ABP 798, US-sourced rituximab RP (rituximab US), or EU-sourced rituximab RP (rituximab EU) (1000 mg, 2 weeks apart). At week 24, ABP 798- or rituximab EU-treated subjects received a second dose of the same treatment, while rituximab US-treated subjects transitioned to receive ABP 798. The key efficacy endpoint was DAS28-CRP change from baseline at week 24. Other efficacy endpoints included DAS28-CRP at other time points; ACR20, ACR50, and ACR70 criteria; and hybrid ACR. The rituximab RP groups were pooled for all efficacy endpoints since PK equivalence had been established between rituximab US and rituximab EU. RESULTS: Clinical equivalence between ABP 798 and rituximab RP was established as the 90% confidence interval for DAS28-CRP change from baseline at week 24 fell within the prespecified equivalence margin (- 0.6, 0.6). Safety and immunogenicity profiles of ABP 798 were comparable across treatment groups and not affected by single transition from RP to ABP 798. CONCLUSIONS: Clinical equivalence in terms of efficacy, safety, and immunogenicity was established between ABP 798 and rituximab RP in this comparative clinical trial in patients with moderate-to-severe RA. Key Points • ABP 798 provided similar efficacy as rituximab reference product (RP) in patients with moderate-severe rheumatoid arthritis. • The safety and immunogenicity profiles for ABP 798 were similar to those for the rituximab RP. • The single transition from rituximab RP to ABP 798 did not show differences in efficacy, safety, or immunogenicity.

Living Donor Liver Transplantation in Children: Perioperative Risk Factors and a Nomogram for Prediction of Survival.

BACKGROUND: Living donor liver transplantation (LDLT) in children has achieved promising outcomes during the past few decades. However, it still poses various challenges. This study aimed to analyze perioperative risk factors for postoperative death in pediatric LDLT. METHODS: We retrospectively analyzed medical records of pediatric patients who underwent LDLT surgery from January 1, 2014, to December 31, 2016, in our hospital. Predictors of mortality following LDLT were analyzed in 430 children. Cox regression and Kaplan-Meier curve analysis were used for covariates selection. A nomogram was developed to estimate overall survival probability. The performance of the nomogram was assessed using calibration curve, decision curve analysis, and time-dependent receiver operating characteristic curve. RESULTS: Among the 430 patients in this cohort (median [interquartile range] age, 7 [6.10] mo; 189 [43.9%] female; 391 [90.9%] biliary atresia), the overall survival was 91.4% (95% confidence interval, 89.2-94.4), and most of the death events (36/37) happened within 6 months after the surgery. Multivariate analysis indicated that the Pediatric End-stage Liver Disease score, neutrophil lymphocyte ratio, graft-to-recipient weight ratio, and intraoperative norepinephrine infusion were independent prognostic factors. A novel nomogram was developed based on these prognostic factors. The C index for the final model was 0.764 (95% confidence interval, 0.701-0.819). Decision curve analysis and time-dependent receiver operating characteristic curve suggested that this novel nomogram performed well at predicting mortality of pediatric LDLT. CONCLUSIONS: We identified several perioperative risk factors for mortality of pediatric LDLT. And the newly developed nomogram can be a convenient individualized tool in estimating the prognosis of pediatric LDLT.