Association between hemoglobin A1c and abdominal aortic calcification: results from the National Health and Nutrition Examination Survey 2013-2014.

BACKGROUND: Hemoglobin A1c (HbA1c), a "gold standard" for the assessment of glycemic control, was associated with an increased risk of cardiovascular disease and coronary artery calcification. However, its effects on abdominal aortic calcification (AAC) are uncertain. The present study comprehensively investigated the association between HbA1c and AAC in the 2013-2014 National Health and Nutrition Examinations Surveys. METHODS: Among 1,799 participants ≥ 40 years, dual-energy X-ray absorptiometry-derived AAC was quantified using the Kauppila score (AAC-24). Severe AAC was defined as a total AAC-24 > 6. Weighted linear regression models and logistic regression models were used to determine the effects of HbA1c on AAC. The restricted cubic spline model was used for the dose-response analysis. RESULTS: The mean AAC-24 of participants was 1.3, and 6.7% of them suffered from severe AAC. Both AAC-24 and the prevalence of severe AAC increased with the higher tertile of HbA1c (P < 0.001). Elevated HbA1c levels would increase the AAC-24 (ß = 0.73, 95% CI: 0.30-1.16) and the risk of severe AAC (OR = 1.63, 95% CI: 1.29-2.06), resulting in nearly linear dose-response relationships in all participants. However, this positive correlation were not statistically significant when participants with diabetes were excluded. Furthermore, subgroup analysis showed significant interactions effect between HbA1c and hypertension on severe AAC with the OR (95% CI) of 2.35 (1.62-3.40) for normotensives and 1.39 (1.09-1.79) for hypertensives (P for interaction = 0.022). CONCLUSION: Controlling HbA1c could reduce AAC scores and the risk of severe AAC. Glycemic management might be a component of strategies for preventing AAC among all participants, especially normotensives.

Fingerprinting trimeric SARS-CoV-2 RBD by capillary isoelectric focusing with whole-column imaging detection.

Because the spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) is the immunodominant antigen, the S protein and its receptor-binding domain (RBD) are both targets currently to be genetically engineered for designing the broad-spectrum vaccine. In theory, the expressed protein exists as a set of variants that are roughly the same but slightly different, which depends on the protein expression system. The variants can be phenotypically manifested as charge heterogeneity. Here, we attempted to depict the charge heterogeneity of the trimeric SARS-CoV-2 RBD by using capillary isoelectric focusing with whole-column imaging detection (cIEF-WCID). In its nature form, the electropherogram fingerprints of the trimeric RBD were presented under optimized experimental conditions. The peaks of matrix buffers can be fully distinguishable from peaks of trimeric RBD. The isoelectric point (pI) was determined to be within a range of 6.67-9.54 covering the theoretical pI of 9.02. The fingerprints of three batches of trimeric RBDs are completely the same, with the intra-batch and batch-to-batch relative standard deviations (RSDs) of both pI values and area percentage of each peak no more than 1.0%, indicating that the production process is stable and this method can be used to surveillance the batch-to-batch consistency. The fingerprint remained unchanged after incubating at 37 °C for 7 d and oxidizing by 0.015% H2O2. In addition, the fingerprint was destroyed when adjusting the pH value to higher than 10.0 but still stable when the pH was lower than 4.0. In summary, the cIEF-WCID fingerprint can be used for the identification, batch-to-batch consistency evaluation, and stability study of the trimeric SARS-CoV-2 RBD, as part of a quality control strategy during the potential vaccine production.

Optimal exposure to docetaxel in adjuvant chemotherapy for early-stage breast cancer.

WHAT IS KNOWN AND OBJECTIVE: Drug-induced neutropenia is the main reason for the dose limitation of docetaxel in patients with breast cancer. The area under the drug concentration-time curve (AUC) of docetaxel is associated with neutropenia. However, the optimal exposure to docetaxel for receiving postoperative adjuvant chemotherapy remains unclear. Therefore, we aimed to evaluate the relationship between the docetaxel AUC and neutropenia, identify potential influencing factors, and explore the best monitoring target for docetaxel when treating patients with early-stage breast cancer using a population pharmacokinetic (PopPK) model. METHODS: Docetaxel plasma concentration, demographics, clinical data, and related laboratory data were collected. PopPK analyses were performed using a nonlinear mixed-effect modelling program. The docetaxel AUC was determined using the maximum a posteriori Bayesian (MAPB) method. The docetaxel exposure-toxicity threshold measured from the AUC for neutropenia was determined using the receiver operating characteristic (ROC) curve. The correlation between docetaxel exposure and neutropenia was analysed using multivariable logistic regression. RESULTS: Among the 70 participants, 47 (67.1%) developed severe neutropenia. The PopPK analysis showed that the typical drug clearance (CL) rate was 37.4 L/h. Age was a significant covariate of CL rate, and aspartate aminotransferase and albumin levels were covariables of the volume of distribution. The multivariable regression analysis showed that AUC >3.0 mg.h/L (odds ratio [OR], 5.940; 95% confidence interval [CI], 1.693-20.843; P = 0.005), platinum use (OR, 0.156; 95% CI, 0.043-0.562; P = 0.005) and baseline haemoglobin level (OR, 0.938; 95% CI, 0.887-0.993; P = 0.027) were significant factors influencing the occurrence of grade 3/4 neutropenia. The AUC of first cycle may not predict the occurrence rates of grade 3/4 neutropenia in later cycles. WHAT IS NEW AND CONCLUSION: We developed a docetaxel PopPK model for patients with early-stage breast cancer. Age and AST and ALB levels were significant covariates. AUC estimated using the MAPB method can predict the toxicity of docetaxel in patients with breast cancer. Docetaxel AUC >3.0 mg.h/L, absence of platinum use and low baseline haemoglobin level were risk factors for docetaxel-induced grade 3/4 neutropenia. STUDY REGISTRATION: Chinese Clinical Trial Center Registry (ChiCTR2200056460).

Safety profile of methotrexate used off-label in ectopic pregnancy: an active monitoring study based on a Chinese hospital pharmacovigilance system.

OBJECTIVE: Methotrexate (MTX) is characterized as first-line therapy although its indication of ectopic pregnancy is off-label use. We aimed to conduct a retrospective cohort study to investigate the incidence, characteristics of adverse drug reactions (ADRs) of MTX, provide valuable insights for medical workers. METHODS: Basing on China Hospital Pharmacovigilance System (CHPS), a retrospective analysis was performed to evaluate the safety of MTX (n = 672). An active monitoring model was set to detect ADR signals from the hospital information system. Frequency, Common Terminology Criteria for Adverse Events (CTCAE) grade proportion and association of dose exposure with ADRs were presented as outcomes. RESULTS: The total incidence of ADRs was 54.0%. Anaemia (37.6%) was the most frequent ADR, followed by hepatic function abnormal (11.3%), hyperuricemia (6.1%), neutropenia (4.6%), leukopenia (4.0%), and dyslipidaemia (2.5%). For the composition of all ADRs, CTCAE grade one, two and three dominated for 86.3%, 12.1% and 1.6%, respectively. The severity of hepatic function abnormal was more serious in the two-dose exposed group (p = .021), while other types of ADRs had no statistical or clinical differences. Logistic regression analysis showed the incidence of any ADRs (OR 1.87 [1.31-2.64]; p = .001), hepatic function abnormal (OR 2.75 [1.69-4.48]; p < .001), dyslipidaemia (OR 5.15 [1.87-14.13]; p = .001) were significantly higher in the two-dose exposed group. After adjusted, the positive associations were still maintained. CONCLUSIONS: MTX is quite safe in ectopic pregnancy, despite its mild to moderate hematotoxicity, hepatotoxicity and nephrotoxicity. Taking CHPS can present the accurate denominator of the incidence of adverse drug reactions into account, our study advocates that it may have great potential to be used as an active monitoring tool for off-label drug use risk management.

Dried Blood Spots Sampling and Population Pharmacokinetic Modeling for Dosing Optimization of Piperacillin in Chinese Neonates.

Piperacillin is commonly used off-label in neonates for the treatment of bacterial infections. This study aimed to assess a dried blood spots (DBS)-based microsampling strategy for supporting population pharmacokinetics and treatment optimization of piperacillin in Chinese neonates. DBS samples from neonatal patients were collected at predefined intervals. Drug blood concentrations were quantified using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling approach. The pharmacokinetic/pharmacodynamics (PK/PD) target was 75% of the time with the unbound drug plasma concentration above the minimum inhibitory concentration (fT>MIC), with a toxicity threshold of unbound drug plasma trough concentration above 64 mg/L. A total of 45 piperacillin samples from 24 neonates were collected. The pharmacokinetics of piperacillin was described using a one-compartment model with postmenstrual age (PMA) as the most significant covariate on clearance. Simulations showed that dosing regimens achieving >90% PK/PD target attainment with <10% risk of possible toxicity were: PMA 33-35 weeks (50 mg/kg q12h), 35-37 weeks (50 mg/kg q8h), and 37-41 weeks (50 mg/kg q6h). In conclusion, Using DBS sampling, we developed a population pharmacokinetic model of piperacillin in Chinese neonates, incorporating PMA to determine optimal dosing regimens.

Effect of OPRM1/COMT gene polymorphisms on sufentanil labor analgesia: a cohort study based on propensity score matching.

Background: This study investigated the use of COMT G1947A and OPRM1 A118G polymorphisms as predictive markers for sufentanil epidural analgesia. Methods: The visual analogue scale (VAS) score, and sufentanil consumption of 136 pairs of parturients using sufentanil with lidocaine and ropivacaine for epidural analgesia were used for analysis. Results: OPRM1 AG/GG had lower VAS score difference between fifth and 0 min (1.55 vs 1.87; p = 0.012) and higher consumption (19.65 µg vs 17.11 µg; p = 0.049) than AA carriers. COMT GA/AA had higher VAS score difference than GG carriers (1.86 vs 1.55; p = 0.021). Conclusion: Sufentanil may provide better epidural labor analgesia in OPRM1 AA and COMT GA/AA carriers compared with OPRM1 AG/GG and COMT GG carriers. Clinical Trial Registration: ChiCTR1900026897 (Chinese Clinical Trial Center Registry).

Development and implementation of medication-related clinical rules for obstetrics, gynaecology, and paediatric outpatients.

OBJECTIVES: Prescription errors can cause serious adverse drug events. Clinical decision support systems prevent prescription errors; however, real-time clinical rules in obstetrics, gynaecology, and paediatric outpatients remain unexplored. We evaluated the effects of localised, real-time clinical rules on alert rates and acceptance rates compared with manual prescription review. METHODS: We developed real-time clinical rules that incorporate information systems to obtain characteristic information and laboratory values. We conducted a retrospective cohort study to compare the alert and recommendation acceptance rates of all prescription error types before and after clinical rule implementation in obstetrics, gynaecology, and paediatrics. Clinical rules, prescription error types, and alerts were determined by a prescribing review committee comprising physicians, pharmacists, nurses, and administrators. The difference in alert and acceptance rates between the groups was analysed using relative risk. RESULTS: The number of alerts increased after clinical rules implementation; the number of on-duty pharmacists for review decreased from 10 to 2. Compared with those with manual review, the alert rates for paediatrics and obstetrics and gynaecology increased with the clinical rules by 3.97- and 11.26-fold, respectively, and the alert rates for drug-drug interactions (DDIs) and combined medication errors in obstetrics and gynaecology increased with the clinical rules by 26.10- and 26.54-fold, respectively. In paediatrics, the alert rate for all prescription error types was higher with the clinical rules review than with the manual review; the alert rates for DDI, dosage, and combination medication errors were significantly different between the clinical rules and the manual review. However, there was no difference in the recommendation acceptance rate between the manual review and the clinical rules. CONCLUSIONS: Clinical rules can identify prescription errors that manual review cannot detect and ensure real-time review efficiency in high-volume outpatient prescription settings. The high acceptance rate and modification of prescriptions may be relevant to highly customised and localised clinical rules.

Optimal exposure targets for vancomycin in the treatment of neonatal coagulase-negative Staphylococcus infection: A retrospective study based on electronic medical records.

BACKGROUND: The currently advocated ratio of area under the curve (AUC) over 24 h to minimum inhibitory concentration (AUC/MIC) > 400 and AUC < 600 mg h/L as the therapeutic drug monitoring (TDM) target of vancomycin is based on data from multiple observational studies in adult patients with methicillin-resistant Staphylococcus aureus (MRSA) infection. It may not be applicable to newborns with coagulase-negative Staphylococcus (CoNS) infection. We conducted a retrospective study to identify the optimal exposure targets for vancomycin in the treatment of neonatal CoNS infection. METHODS: Based on the inclusion and exclusion criteria, serum vancomycin concentration, demographics, clinical data, and related laboratory data of newborns who received vancomycin intravenous infusion from June 1, 2016 to February 1, 2021 were collected retrospectively. The AUC was calculated using the maximum a posteriori Bayesian (MAPB) method. The vancomycin exposure threshold of AUC/MIC for efficacy and AUC for toxicity (acute kidney injury, AKI) were determined based on receiver operating characteristic (ROC) curve analysis. The correlation between vancomycin exposure and both clinical effect and nephrotoxicity was analyzed using logistic multivariate regression. RESULTS: In total, 153 patients and 245 vancomycin concentrations (160 trough and 85 peak concentrations) were included. The ROC curve analysis showed that the exposure thresholds of AUC/MIC for clinical efficacy and AUC for nephrotoxicity were 281 and 602 mg h/L, respectively. The multivariate regression analysis showed that AUC/MIC > 280 was a predictor of efficacy (OR: 13.960, 95% CI: 1.891-103.078, P < 0.05) and AUC > 600 mg h/L was associated with AKI (OR: 9.008, 95% CI: 2.706-29.983, P < 0.05). The vancomycin AUC/MIC threshold for treating neonatal CoNS infection with vancomycin is lower than the currently advocated AUC/MIC >400. CONCLUSION: The optimal exposure targets for vancomycin in neonatal CoNS infection were AUC/MIC > 280 and AUC < 600 mg h/L.

Prognostic Value of Two Polymorphisms, rs1045642 and rs1128503, in ABCB1 Following Taxane-based Chemotherapy: A Meta-Analysis.

OBJECTIVE: Genetic polymorphisms can influence the chemotherapeutic response; however, previous studies have produced conflicting results, and have failed to identify the most relevant polymorphisms for predicting the response to treatment in patients with cancer. The present meta-analysis was conducted to determine the correlation between two polymorphisms (rs1045642 and rs1128503) in ATP-binding cassette transporter B subfamily member 1 (ABCB1), which is associated with multidrug resistance, and the survival of patients treated with taxane-containing chemotherapy. METHODS: Several databases, including PubMed and Embase, were used to retrieve articles evaluating the association between the ABCB1 rs1045642 and rs1128503 polymorphisms and survival, published prior to August 2019. The meta-analysis was conducted using R software to determine the pooled hazard ratio (HR) and 95% confidence intervals (95% CIs). RESULTS: Fifteen studies involving 3320 patients were included in the meta-analysis. The effect of the rs1128503 polymorphism on progression-free survival remained significant in the heterozygote (HR 0.81; 95% CI: 0.67-0.98) and homozygote (HR 0.71; 95% CI: 0.58-0.88) models. The TT genotype rs1128503 was associated with better overall survival (HR 0.72; 95% CI: 0.53-0.97). CONCLUSION: Carriers of the rs1128503 T allele of ABCB1 showed a survival benefit after taxane-containing chemotherapy.

Terlipressin in the treatment of neonatal refractory hypotension caused by septic shock: a case report.

BACKGROUND: While the clinical benefits of terlipressin (TP) have been reported in adults and children with refractory hypotension, data in neonates are limited. CASE: Herein, we report a case of off-label rescue TP therapy in a neonate with septic shock and persistent hypotension. The patient`s blood pressure was normalized, and tissue perfusion improved without serious adverse reactions. However, genetic testing revealed mitochondrial gene defects in the patient, and the parents subsequently elected to stop treatment after 25 doses of TP (20 µg/kg/min every 4 h for 100 h). CONCLUSION: While TP treatment appeared to help control hypotension and may prolong the survival time, there are no conclusive data regarding the safety and efficacy of TP in neonates.

Vancomycin-induced severe thrombocytopenia in a young infant.

Vancomycin is a first-line drug for treating methicillin-resistant Staphylococcus aureus. Thrombocytopenia is a rare adverse reaction to vancomycin treatment, and there are no reports of vancomycin-induced thrombocytopenia (VIT) in infants. We describe the case of a 3-month-old girl who was diagnosed with purulent meningitis. After 13 days of treatment with vancomycin, her platelet count reduced to 8 × 109/L. Vancomycin was discontinued, and intravenous methylprednisolone was administered. The platelet count returned to normal after 4 days. Patients, especially young children, receiving vancomycin for a long clinical course should undergo careful monitoring of laboratory indicators and blood tests.

Vancomycin-induced severe thrombocytopenia in a young infant

Abstract Vancomycin is a first-line drug for treating methicillin-resistant Staphylococcus aureus. Thrombocytopenia is a rare adverse reaction to vancomycin treatment, and there are no reports of vancomycin-induced thrombocytopenia (VIT) in infants. We describe the case of a 3-month-old girl who was diagnosed with purulent meningitis. After 13 days of treatment with vancomycin, her platelet count reduced to 8 × 109/L. Vancomycin was discontinued, and intravenous methylprednisolone was administered. The platelet count returned to normal after 4 days. Patients, especially young children, receiving vancomycin for a long clinical course should undergo careful monitoring of laboratory indicators and blood tests.