Relationship Between Linezolid Exposure and the Typical Clinical Laboratory Safety and Bacterial Clearance in Chinese Pediatric Patients.

Objectives: There have been limited studies concerning the safety and efficacy of linezolid (LZD) in children. This study aimed to evaluate the association between LZD exposure and clinical safety and efficacy in Chinese pediatric patients. Methods: This retrospective cross-sectional study included patients ≤18 years of age who received ≥3 days of LZD treatment between 31 January 2015, and 31 December 2020. Demographic characteristics, medication information, laboratory test information, and bacterial culture results were collected from the Hospital Information System (HIS). Exposure was defined as AUC24 and calculated by the non-linear mixed-effects modeling program (NONMEM), version 7.2, based on two validated population pharmacokinetic models. Binary logistic regression analyses were performed to analyze the associations between AUC24 and laboratory adverse events, and receiver operating characteristic curves were used to calculate the cut-off values. Efficacy was evaluated by bacterial clearance. Results: A total of 413 paediatric patients were included, with an LZD median (interquartile range) dose, duration, clearance and AUC24 of 30.0 (28.1-31.6) mg/kg/day, 8 (4‒15) days,1.31 (1.29-1.32) L/h and 81.1 (60.6-108.7) mg/L·h, respectively. Adverse events associated with TBil, AST, ALT, PLT, hemoglobin, WBC, and neutrophil count increased during and after LZD treatment when compared with before medication (p < 0.05), and the most common adverse events were thrombocytopaenia (71/399, 17.8%) and low hemoglobin (61/401, 15.2%) during the LZD treatment. Patients with AUC24 higher than 120.69 mg/L h might be associated with low hemoglobin 1-7 days after the end of the LZD treatment, and those with an AUC24 higher than 92.88 mg/L∙h might be associated with thrombocytopaenia 8-15 days after the end of the LZD treatment. A total of 136 patients underwent bacterial culture both before and after LZD treatment, and the infection was cleared in 92.6% (126/136) of the patients, of whom 69.8% (88/126) had AUC24/MIC values greater than 80. Conclusion: Hematological indicators should be carefully monitored during LZD treatment, especially thrombocytopaenia and low hemoglobin, and a continuous period of monitoring after LZD withdrawal is also necessary. Since the AUC24 cut-off values for laboratory adverse events were relatively low, a trade-off is necessary between the level of drug exposure required for treatment and safety, and the exposure target (AUC24/MIC) in pediatric patients should be further studied, especially for patients with complications and concomitant medications.

A Risk-Factor Model for Antineoplastic Drug-Induced Serious Adverse Events in Cancer Inpatients: A Retrospective Study Based on the Global Trigger Tool and Machine Learning.

The objective of this study was to apply a machine learning method to evaluate the risk factors associated with serious adverse events (SAEs) and predict the occurrence of SAEs in cancer inpatients using antineoplastic drugs. A retrospective review of the medical records of 499 patients diagnosed with cancer admitted between January 1 and December 31, 2017, was performed. First, the Global Trigger Tool (GTT) was used to actively monitor adverse drug events (ADEs) and SAEs caused by antineoplastic drugs and take the number of positive triggers as an intermediate variable. Subsequently, risk factors with statistical significance were selected by univariate analysis and least absolute shrinkage and selection operator (LASSO) analysis. Finally, using the risk factors after the LASSO analysis as covariates, a nomogram based on a logistic model, extreme gradient boosting (XGBoost), categorical boosting (CatBoost), adaptive boosting (AdaBoost), light-gradient-boosting machine (LightGBM), random forest (RF), gradient-boosting decision tree (GBDT), decision tree (DT), and ensemble model based on seven algorithms were used to establish the prediction models. A series of indicators such as the area under the ROC curve (AUROC) and the area under the PR curve (AUPR) was used to evaluate the model performance. A total of 94 SAE patients were identified in our samples. Risk factors of SAEs were the number of triggers, length of stay, age, number of combined drugs, ADEs occurred in previous chemotherapy, and sex. In the test cohort, a nomogram based on the logistic model owns the AUROC of 0.799 and owns the AUPR of 0.527. The GBDT has the best predicting abilities (AUROC = 0.832 and AUPR = 0.557) among the eight machine learning models and was better than the nomogram and was chosen to establish the prediction webpage. This study provides a novel method to accurately predict SAE occurrence in cancer inpatients.

Antifungal Therapy with Azoles Induced the Syndrome of Acquired Apparent Mineralocorticoid Excess: a Literature and Database Analysis.

We aimed to estimate the risk of varied antifungal therapy with azoles causing the syndrome of acquired apparent mineralocorticoid excess (AME) in real-world practice. First, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the signal differences of triazoles-related AME. Second, a systematic review was conducted, and clinical features of AME cases reported in clinical practice were described. In the FAERS database, we identified 27 cases of triazoles-AME, posaconazole [ROR = 865.37; 95%CI (464.14; 1613.45)], and itraconazole [ROR = 556.21; 95% (303.05; 1020.85)] significantly increased the risk of AME events, while fluconazole, voriconazole, and isavuconazole did not affect any of the mineralocorticoid excess targets. Eighteen studies with 39 cases raised evidence of AME following posaconazole and itraconazole treatment, and another 27 cases were identified by analysis of the description of clinical features in the FAERS database. The average age of 66 patients was 55.5 years (6-87 years). AME mainly occurs in patients with posaconazole concentrations above 3 µg/mL (mean = 4.4 µg/mL, range 1.8∼9.5 µg/mL), and is less likely to occur when levels are below 2 µg/mL (6%). The median time to event onset was 11.5 weeks, and 50% of the adverse events occurred within 3 months for posaconazole. The presented study supports very recent findings that posaconazole and itraconazole, but not the other three azole antifungals investigated, are associated with AME and that the effects are dose-dependent, which allows for a dose de-escalation strategy and for substitution with fluconazole, isavuconazole, or voriconazole to resolve the adverse effects.

General characteristics and reasons for the discontinuation of drug clinical trials in mainland China.

BACKGROUND: Although discontinuation is common in clinical trials, no study has been conducted to analyse the current situation and reasons for the suspension or discontinuation of drug clinical trials in China. This study aims to analyse the general characteristics and reasons for the discontinuation of registered clinical trials in mainland China and to identify the associated factors. METHODS: We conducted a cross-sectional observational study of discontinued trials registered in the Drug Trial Registration and Information Publication Platform before March 31, 2020. All trials with a status of terminated or stopped recorded in the platform were classified as discontinued trials and included in the analysis. The basic characteristics of the discontinued trials were recorded, reasons for trial discontinuation were recorded and divided into 4 categories as drug development strategy, trial planning, trial conduct and studied drug. Pearson's chi-square test and fisher's exact test were used to compare the differences in reasons for discontinuation between neoplasm trials and non-neoplasm trials, and to examine the associations of trial characteristics with different reasons related to trials discontinuation. RESULTS: Three hundred twelve discontinued trials were included in this study. The studied drugs were mainly chemical drugs [229 (73.4%)], and indications of the studied drugs were mainly neoplasms [77 (24.7%)]. Geographical location of the discontinued trials were mostly in northern [114 (36.5%)] and eastern [96 (30.8%)] China. Study type of the included trials was mainly bioequivalence studies [97 (31.1%)]. The most common reason for trial discontinuation was commercial or strategic decision [84 (26.9%)], followed by futility/lack of efficacy [70 (22.4%)]. The number of trial centers, sample size and whether participants had been enrolled were significantly associated with trial discontinuation (P <  0.05). Multiple center trials showed a higher rate of trial discontinuation due to trial conduct related reasons than single center trials (P <  0.05), trials with sample size > 500 showed a higher rate of trial discontinuation due to studied drug related reasons (P < 0.05), and trials enrolled participants showed a lower rate of trial discontinuation due to commercial or strategic decision and a higher rate of trial discontinuation due to studied drug related reasons than trials without enrolled participants (P < 0.05). Besides, neoplasm trials showed a higher rate of trial discontinuation due to poor recruitment and safety comparing with non-neoplasm trials (P < 0.05). CONCLUSIONS: Trial discontinuation in China mainly occurred because of commercial or strategic decision and futility/lack of efficacy of the studied drug. Clinical trials with multiple centers and a large sample size may more likely be discontinued due to trial conduct related reasons such as good clinical practice. Discontinuation due to drug safety and lack of efficacy in multiple center trials with a large sample size deserves more attention to avoid resources wastes. Full communication with regulatory authorities such as Center for Drug Evaluation and research institutes to develop a feasible protocol is important for sponsors to avoid trial discontinuation due to protocol issues.

Human papillomavirus vaccine-associated premature ovarian insufficiency and related adverse events: data mining of Vaccine Adverse Event Reporting System.

We detected disproportionate reports of premature ovarian insufficiency (POI) and related events, including amenorrhea, menstruation irregular, FSH increased, and premature menopause, following human papillomavirus (HPV) vaccine from FDA Vaccine Adverse Event Reporting System (VAERS). The signal was detected by the methods of Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS). When both methods detected a positive result, a signal was generated. Besides, time-scan map is drawn based on the IC value and 95%CI of BCPNN, if the IC curve showed a steady upward trend and the 95%CI narrowed, the signal was stable and strong association.The results showed that there were not POI reports of HPV vaccine, but VAERS received a total of 2, 389, 27 POI related events for HPV2, HPV4, HPV9 respectively from the year of marketed to 2018. No signal was detected for HPV2. HPV4-POI ralated events were all detected as signals by two methods. There was only one signal of menstruation irregular for HPV9. Time scan of HPV4-POI ralated events showed those signals were stability and strong association, but not for HPV9. Our results only represent statistical association between HPV vaccine and POI related events, causal relationship needs further investigation.

Drug-Induced Liver Injury: Clinical and Etiologic Features at a Large Tertiary Teaching Hospital in China.

BACKGROUND Since the epidemiological profile of drug-induced liver injury (DILI) in China, especially the western of China, it has rarely been studied. The aim of this study was to analyze the characteristics of DILI patients in a large tertiary teaching hospital at Chongqing, a municipality in western China. MATERIAL AND METHODS The medical records of hospitalized patients which diagnosed with DILI between January 2011 and December 2016 were searched retrospectively, and demographic, clinical data, and laboratory data were retrieved for analysis. RESULTS A total of 1811 patients had been diagnosed with DILI, accounting for 0.248% of the total admissions during the same period. Among the 1096 patients included in our analysis, DILI was caused by "medications" in 462 cases (42.15%), "herbs" in 391 cases (35.68%), and combined medications in 189 cases (17.24%). The profiles for each etiology were distinctive for age, sex, clinical features, laboratory features, and types and severity of DILI. CONCLUSIONS Our study provides a systematic etiological profile of DILI in Chinese patients, which can represent references for prevention, diagnosis and treatment, supporting and promoting efforts to ease the burden of this liver disease in China.

Adverse Event Profiles of Anti-CTLA-4 and Anti-PD-1 Monoclonal Antibodies Alone or in Combination: Analysis of Spontaneous Reports Submitted to FAERS.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs)-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1) monoclonal antibodies (mAbs)-either as single agents or in combination have become the standard of care for an increasing number of indications. Understanding both the ICI-associated adverse events (AEs) and the possible rank-order of these drugs in terms of susceptibility is essential if we are to improve the curative effect and reduce toxicity. METHODS: We detected signals of the AEs of ICIs by data mining using the US Food and Drug Administration (FDA) AEs Reporting System (FAERS) database. The definition relied on the preferred terms (PTs) and the standardized MedDRA Queries (SMQs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analysis was performed by calculating the reporting odds ratios (ROR) with 95% confidence intervals (CIs). RESULTS: Adverse effects of CTLA-4 and PD-1 mAbs were most commonly observed in the skin, gastrointestinal tract, endocrine systems, liver, and lung, and they included rash, diarrhea, colitis, and thyroid dysfunction. Thyroid dysfunction, type 1 diabetes mellitus, and pneumonitis were more closely associated with the use of anti-PD-1, whereas colitis, diarrhea, hypophysitis, and adrenal insufficiency were more closely associated with anti-CTLA-4; rash and hepatitis occurred similarly in both. Disproportionality signals for less common AEs in other organ systems, including the renal, neurological, cardiac, ocular, musculoskeletal, and hematologic systems, were also detected. Nivolumab and pembrolizumab have very similar safety profiles, but the signal strength of AEs increased when combined with ipilimumab. CONCLUSIONS: The results of this study are in agreement with clinical observations, suggesting the usefulness of pharmacovigilance in "real-world" safety monitoring.

Adverse drug events in Chinese pediatric inpatients and associated risk factors: a retrospective review using the Global Trigger Tool.

Understanding the epidemiology and risk factors of adverse drug events (ADEs) in pediatric inpatient is essential if we are to prevent, reduce or ameliorate the harm experienced. The Global Trigger Tool (GTT) is a method of retrospective medical record review that measures harm in hospitalized children. We employed a three-stage retrospective chart review of random samples of 1800 pediatric inpatients discharged from January 2013 to December 2015. 31 kinds of pediatric-specific triggers were made based on the previous trigger tool studies developed for use in adult or pediatric. Positive predictive value (PPV) of individual triggers, as well as ADEs detection rates were calculated. Stepwise logistic regression was performed to investigate risk factors associated with ADEs. Of 1746 patients, detected in 221 patients (12.7%) with 247 ADEs. The PPV of the trigger tool was 13.3%. Of the 247 ADEs, 82.6% were identified as category E, 11.7% category F and 5.7% category H. The pediatric-focused trigger tool is a feasible and useful tool for detecting pediatric ADEs. Especially for patients who have had more drugs, more doses or more admissions which needs to be closely monitored as triggers to improve the safety.

A population pharmacokinetic model for individualised dosage regimens of vancomycin in Chinese neonates and young infants.

Population pharmacokinetic (PPK) modelling is an easy and impartment method for estimating drug concentration for use inindividualized therapy, especially for young patients and to help protect drug-induced diseases. The purpose of this study was to develop a PPK model for effective dosing of vancomycin in Chinese neonates and young infants. The PPK modelling tool Phoenix® NLME™ was use to assess demographic and routine clinical pharmacokinetic (PK) data retrospectively collected for patients admitted to Children's Hospital of Chongqing Medical University between 2011 and 2016. Data of patients admitted to the hospital between January and June of 2017 were used in validation study, and the final model was also preliminary validated in 2 cases in another hospital. A total of 421 serum samples from 316 patients were included in the initial PPK analysis. A two-compartment PPK model was developed, and exponential-error model was used to describe inter-individual variability of clearance. Residual variability was described by an additive model. The final PPK model was demonstrated as valid by internal and external model evaluation. Of note, the clearance and volume of vancomycin in Chinese neonates and young infants may be greater than in Caucasians. Herein, we describe the establishment of an accurate PPK model of vancomycin for Chinese neonates and young infants, which may be useful as a dosing algorithm for this particular paediatric population.

[Clinical features of acute poisoning in hospitalized children: an analysis of 586 cases].

OBJECTIVE: To investigate the clinical features of acute poisoning in hospitalized children. METHODS: A retrospective analysis was performed on the clinical data of 586 hospitalized children who were diagnosed with poisoning and discharged from the Children's Hospital of Chongqing Medical University between January 2006 and December 2015. RESULTS: The patients included 354 males and 232 females (age: 24 days to 15.8 years). Of the 586 cases, 450 (76.8%) were infants and preschool children; 463 (79.0%) came from rural areas; 551 (94.0%) were hospitalized because of unintentional poisoning. The drug poisoning, pesticide poisoning, and rodenticide poisoning accounted for 221 cases (37.7%), 167 cases (28.5%), and 175 cases (29.9%) respectively. There was a significant difference in the distribution of the poisoning toxins between urban and rural children (P<0.01), and drugs and pesticides were the most common toxins for urban and rural children respectively. There were significant differences in main clinical manifestations between the children with drug poisoning, pesticide poisoning, and rodenticide poisoning (P<0.01), who presented with main clinical symptoms of the nervous system, digestive system, and circulatory system respectively. There was no significant difference in overall response rate between the children poisoned by different toxins. CONCLUSIONS: Acute poisoning is most common in infants and preschool children. The majority of the patients are from rural areas. The majority of acute poisoning is unintentional. Poisoning by drugs is the main type of acute poisoning. There is no significant difference in overall response rate between the children poisoned by different toxins, but their clinical manifestations are different.

[Spectrum diagnosis of enhanced arcjet thruster using hydrazine propellant].

A set of spectrum diagnostic system was established. With this system, spectrum analysis was carried out for the plume signal of enhanced arcjet thrust using catalytic decomposition products of hydrazine as propellant. Excitation plume temperatures for various wavelengths were obtained through measuring spectral radiation intensity. The averaged excitation temperatures were analyzed based on Boltzman diagram. The results show that there is the highest temperature in the axial center of plume and the temperature drops quickly in the radial direction. The intensity of thermodynamic non-equilibrium weakens with a decrease in current and an increase in radial distance. The temperature of the plume rises with an increase in the proportion of ammonia in the catalytic decomposition mixture of hydrazine.

Spherical piecewise constant basis functions for all-frequency precomputed radiance transfer.

This paper presents a novel basis function, called spherical piecewise constant basis function (SPCBF), for precomputed radiance transfer. SPCBFs have several desirable properties: rotatability, ability to represent all-frequency signals, and support for efficient multiple product. By smartly partitioning the illumination sphere into a set of subregions, and associating each subregion with an SPCBF valued 1 inside the region and 0 elsewhere, we precompute the light coefficients using the resulting SPCBFs. Efficient rotation of the light representation in SPCBFs is achieved by rotating the domain of SPCBFs. We run-time approximate the BRDF and visibility coefficients using the set of SPCBFs for light, possibly rotated, through fast lookup of summed-area-table (SAT) and visibility distance table (VDT), respectively. SPCBFs enable new effects such as object rotation in all-frequency rendering of dynamic scenes and on-the-fly BRDF editing under rotating environment lighting. With graphics hardware acceleration, our method achieves real-time frame rates.