A Systematic Review and Meta-Analysis of the Impacts of Time-Restricted Eating on Metabolic Homeostasis.

This meta-analysis investigated the effect of time-restricted eating (TRE) as an economical lifestyle intervention for the prevention of metabolic syndrome and improving the related metabolic variables. The Cochrane library, MEDLINE, EMBASE, clinical trials, and other databases were searched for randomized controlled trials (RCTs). We included 22 RCTs (1004 participants, aged 18-75 years, including healthy subjects, prediabetes and overweight patients) designed to evaluate the effect of TRE on metabolic parameters. Body mass index (BMI) (-0.56 kg/m2, 95% CI: -1.00, -0.13, P < .01), fasting blood glucose (-1.74 mmol/L, 95% CI: -3.34, -0.14, P < .01), and body weight (-0.48 kg, 95% CI: -0.74, -0.22, P < .01) in the TRE intervention group were decreased to varying degrees compared with controls. In contrast, high-density lipoprotein cholesterol (HDL-C) levels were significantly increased in the TRE group compared with the control group (P < .01). The change in waist circumference, blood pressure, triglycerides, low-density lipoprotein cholesterol (LDL-C), and total cholesterol did not vary markedly across the groups. In conclusion, this meta-analysis found a significant reduction in BMI, weight, and fasting glucose, as well as a rise in HDL-C level with TRE compared with control. TRE could be used as an adjuvant treatment for metabolic dysfunctions.

Is the Tradeoff between Folic Acid or/and Multivitamin Supplementation against Birth Defects in Early Pregnancy Reconsidered? Evidence Based on a Chinese Birth Cohort Study.

BACKGROUND: Several studies have reported conflicting results on the association between maternal exposure to folic acid (FA) and/or multivitamin (MV) supplements and the risk of birth defects (BDs), especially for different subtypes of BDs. The present study aimed to identify the association between maternal exposure to FA or/and MV and BDs in offspring. METHODS: In the Chinese Birth Cohort Study initiated from 20 November 2017, 120,652 pregnant women completed follow-up until 20 August 2021. The participants were classified into four groups: without exposure to FA and MV, exposure to only FA, exposure to only MV, and exposure to FA and MV. Birth defects were coded by the International Classification of Diseases (ICD)-10. In order to explore the structural relationship between maternal FA or MV supplements and BDs, directed acyclic graphs were drawn. Then, an inverse probability treatment weighting was utilized to reduce the systematic differences in the baseline characteristics among the different groups. Lastly, a two-level mixed-effect log binomial regression analysis was used to estimate the relative risk (RR) value of the different subtypes of BDs under different exposures to FA and/or MV. RESULTS: Compared with the maternal group without exposure to FA and MV, the RR values of nervous system defects, face, ear, and neck defects, limb defects, and CHDs in the maternal group with only FA supplementation were less than 1.0, but they were not statistically significant. The RR values of genitourinary defects, abnormal chromosomes, and oral clefts were more than 1.0, and they were also not statistically significant. However, the risk of genitourinary defects (RR: 3.22, 95% CI: 1.42-7.29) and chromosomal abnormalities (RR: 2.57, 95% CI: 1.16-5.73) in the maternal group with only MV supplementation increased more than those in the maternal group without exposure to FA and MV. In addition, the RR values of all subtypes of BDs in the maternal group with exposure to FA and MV were closer to 1.0 than those in maternal group with exposure to only MV, but they were not statistically significant. CONCLUSIONS: It was indicated that the simultaneous supplementation of FA and MV in early pregnancy may have an interaction for the prevention of BDs and may have inconsistent effects for different subtypes of BDs. At the same time, excessive FA supplementation in pregnant women may increase the risk of BDs in their offspring. Although the mechanism is not clear, this evidence reminded us that more trade-offs are necessary for formulating strategies for the prevention of BDs with FA and/or MV supplementation in early pregnancy.

Comparative effectiveness and safety of bolus vs. continuous infusion of loop diuretics: Results from the MIMIC-III Database.

BACKGROUND: It is unclear whether fluid management goals are best achieved by bolus injection or continuous infusion of loop diuretics. In this study, we compared the effectiveness and safety of a continuous infusion with that of a bolus injection when an increased loop diuretic dosage is required in intensive care unit (ICU) patients. METHODS: We obtained data from the MIMIC-III database for patients who were first-time ICU admissions and required an increased diuretic dosage. Patients were excluded if they had an estimated glomerular filtration rate <15 ml/min/1.73 m2, were receiving renal replacement therapy, had a baseline systolic blood pressure <80 mmHg, or required a furosemide dose <120 mg. The patients were divided into a continuous group and a bolus group. Propensity score matching was used to balance patients' background characteristics. RESULTS: The final dataset included 807 patients (continuous group, n = 409; bolus group, n = 398). After propensity score matching, there were 253 patients in the bolus group and 231 in the continuous group. The 24 h urine output per 40 mg of furosemide was significantly greater in the continuous group than in the bolus group (234.66 ml [95% confidence interval (CI) 152.13-317.18, p < 0.01]). There was no significant between-group difference in the incidence of acute kidney injury (odds ratio 0.96, 95% CI 0.66-1.41, p = 0.85). CONCLUSIONS: Our results indicate that a continuous infusion of loop diuretics may be more effective than a bolus injection and does not increase the risk of acute kidney injury in patients who need an increased diuretic dosage in the ICU.

Phenomapping approach to interpreting coronary dimensions in febrile children.

Importance: Coronary artery dilation may occur in febrile children with and without Kawasaki disease (KD). Objective: We explored the application of unsupervised learning algorithms in the detection of novel patterns of coronary artery phenotypes in febrile children with and without KD. Methods: A total of 239 febrile children (59 non-KD and 180 KD patients), were recruited. Unsupervised hierarchical clustering analysis of phenotypic data including age, hemoglobin, white cell count, platelet count, C-reactive protein, erythrocyte sedimentation rate, albumin, alanine aminotransferase, aspartate aminotransferase, and coronary artery z scores were performed. Results: Using a cutoff z score of 2.5, the specificity was 98.3% and the sensitivity was 22.1% for differentiating non-KD from KD patients. Clustering analysis identified three phenogroups that differed in a clinical, laboratory, and echocardiographic parameters. Compared with phenogroup I, phenogroup III had the highest prevalence of KD (91%), worse inflammatory markers, more deranged liver function, higher coronary artery z scores, and lower hematocrit and albumin levels. Abnormal blood parameters in febrile children with z scores of coronary artery segments <0.5 and 0.5-1.5 was associated with increased risks of having KD to 8.7 (P = 0.003) and 4.4 (P = 0.002), respectively. Interpretation: Phenomapping of febrile children with and without KD identified useful laboratory parameters that aid the diagnosis of KD in febrile children with relatively normal-sized coronary arteries.

Detection of pediatric drug-induced kidney injury signals using a hospital electronic medical record database.

Background: Drug-induced kidney injury (DIKI) is one of the most common complications in clinical practice. Detection signals through post-marketing approaches are of great value in preventing DIKI in pediatric patients. This study aimed to propose a quantitative algorithm to detect DIKI signals in children using an electronic health record (EHR) database. Methods: In this study, 12 years of medical data collected from a constructed data warehouse were analyzed, which contained 575,965 records of inpatients from 1 January 2009 to 31 December 2020. Eligible participants included inpatients aged 28 days to 18 years old. A two-stage procedure was adopted to detect DIKI signals: 1) stage 1: the suspected drugs potentially associated with DIKI were screened by calculating the crude incidence of DIKI events; and 2) stage 2: the associations between suspected drugs and DIKI were identified in the propensity score-matched retrospective cohorts. Unconditional logistic regression was used to analyze the difference in the incidence of DIKI events and to estimate the odds ratio (OR) and 95% confidence interval (CI). Potentially new signals were distinguished from already known associations concerning DIKI by manually reviewing the published literature and drug instructions. Results: Nine suspected drugs were initially screened from a total of 652 drugs. Six drugs, including diazepam (OR = 1.61, 95%CI: 1.43-1.80), omeprazole (OR = 1.35, 95%CI: 1.17-1.54), ondansetron (OR = 1.49, 95%CI: 1.36-1.63), methotrexate (OR = 1.36, 95%CI: 1.25-1.47), creatine phosphate sodium (OR = 1.13, 95%CI: 1.05-1.22), and cytarabine (OR = 1.17, 95%CI: 1.06-1.28), were demonstrated to be associated with DIKI as positive signals. The remaining three drugs, including vitamin K1 (OR = 1.06, 95%CI: 0.89-1.27), cefamandole (OR = 1.07, 95%CI: 0.94-1.21), and ibuprofen (OR = 1.01, 95%CI: 0.94-1.09), were found not to be associated with DIKI. Of these, creatine phosphate sodium was considered to be a possible new DIKI signal as it had not been reported in both adults and children previously. Moreover, three other drugs, namely, diazepam, omeprazole, and ondansetron, were shown to be new potential signals in pediatrics. Conclusion: A two-step quantitative procedure to actively explore DIKI signals using real-world data (RWD) was developed. Our findings highlight the potential of EHRs to complement traditional spontaneous reporting systems (SRS) for drug safety signal detection in a pediatric setting.

Signal Detection of Pediatric Drug-Induced Coagulopathy Using Routine Electronic Health Records.

Background: Drug-induced coagulopathy (DIC) is a severe adverse reaction and has become a significantly increased clinical problem in children. It is crucial to the detection of the DIC safety signal for drug post-marketing scientific supervision purposes. Therefore, this study aimed to detect potential signals for DIC in children using the routine electronic medical record (EMR) data. Methods: This study extracted EMR data from Beijing Children's Hospital between 2009 and 2020. A two-stage modeling method was developed to detect the signal of DIC. We calculated the crude incidence by mining cases of coagulopathy to select the potential suspected drugs; then, propensity score-matched retrospective cohorts of specific screened drugs from the first stage were constructed and estimated the odds ratio (OR) and 95% confidence interval (CI) using conditional logistic regression models. The current literature evidence was used to assess the novelty of the signal. Results:In the study, from a total of 340 drugs, 22 drugs were initially screened as potentially inducing coagulopathy. In total, we identified 19 positive DIC associations. Of these, potential DIC risk of omeprazole (OR: 2.23, 95% CI: 1.88-2.65), chlorpheniramine (OR:3.04, 95% CI:2.56-3.60), and salbutamol sulfate (OR:1.36, 95% CI:1.07-1.73) were three new DIC signals in both children and adults. Twelve associations between coagulopathy and drugs, meropenem (OR: 3.38, 95% CI: 2.72-4.20), cefoperazone sulbactam (OR: 2.80, 95% CI: 2.30-3.41), fluconazole (OR: 2.11, 95% CI: 1.71-2.59), voriconazole (OR: 2.82, 95% CI: 2.20-3.61), ambroxol hydrochloride (OR: 2.12, 95% CI: 1.74-2.58), furosemide (OR: 2.36, 95% CI: 2.08-2.67), iodixanol (OR: 2.21, 95% CI: 1.72-2.85), cefamandole (OR: 1.82, 95% CI: 1.56-2.13), ceftizoxime (OR: 1.95, 95% CI: 1.44-2.63), ceftriaxone (OR: 1.95, 95% CI: 1.44-2.63), latamoxef sodium (OR: 1.76, 95% CI: 1.49-2.07), and sulfamethoxazole (OR: 1.29, 95% CI: 1.01-1.64), were considered as new signals in children. Conclusion: The two-stage algorithm developed in our study to detect safety signals of DIC found nineteen signals of DIC, including twelve new signals in a pediatric population. However, these safety signals of DIC need to be confirmed by further studies based on population study and mechanism research.

Effectiveness of Intravenous Ibuprofen on Emergence Agitation in Children Undergoing Tonsillectomy with Propofol and Remifentanil Anesthesia: A Randomized Controlled Trial.

Background: Emergence agitation (EA) has a negative effect on the recovery from general anesthesia in children. This study aimed to evaluate the effectiveness of intravenous ibuprofen in reducing the incidence of EA in children. Methods: This randomized, double-blind, placebo-controlled, single-center study analyzed data from patients aged 3-9 years undergoing tonsillectomy under general anesthesia with propofol and remifentanil. These patients were randomly assigned to receive either the ibuprofen or the placebo intraoperatively. The primary endpoint was a between-group difference in the incidence of EA at 15 min following extubation. EA was defined as Pediatric Anesthesia Emergence Delirium score ≥10. The secondary endpoint included the associated factors of EA. Results: Eighty-nine patients were included in the study. Ibuprofen decreased the incidence of EA at 15 min following extubation (8.9% in the treatment group vs 34.1% in the control group; odds ratio [OR], 0.261; 95% confidence interval [CI], 0.094-0.724; P=0.004). Compared with the control group, there was a significant reduction in the number of rescue fentanyl doses (P=0.045), and fewer patients experienced moderate to severe pain at 15 min following extubation in the treatment group (P=0.048). Upon logistic regression analysis, high modified Pediatric Anesthesia Behavior and pain scores following surgery were considered the risk factors related to EA (OR, 8.07; 95% CI, 1.12-58.07, P=0.038 and OR, 2.78; 95% CI, 1.60-4.82, P<0.001, respectively). Ibuprofen administration was the protective factor related to EA (OR, 0.05; 95% CI, 0.01-0.67, P=0.023). Conclusion: Intraoperative ibuprofen infusion can significantly reduce the incidence of EA following general anesthesia with propofol and remifentanil in children. Trial Registration: The study was registered with the Chinese Clinical Trial Registry on 7 April 2021 (number: ChiCTR2100045128; https://www.chictr.org.cn/edit.aspx?pid=124595&htm=4).

Assessment of evidence on reported non-genetic risk factors of congenital heart defects: the updated umbrella review.

BACKGROUND: Congenital heart defect (CHD) is the leading cause of birth defects globally, which results in a great disease burden. It is still imperative to detect the risk factors of CHD. This umbrella review aimed to comprehensively summarize the evidence and grade the evidence of the associations between non-genetic risk factors and CHD. METHODS: Databases including Medline, Embase, Web of Science, Cochrane Library, and four Chinese databases were searched from inception to 18 Jan 2022. The reference lists of systematic reviews (SR) and meta-analyses (MA) were screened, which aimed to explore the non-genetic risk factors of CHD. Subsequently, titles and abstracts of identified records and full texts of selected SR/MA were screened by two independent reviewers based on predefined eligibility criteria. A priori developed extraction form was used to abstract relative data following the PRISMA 2020 and MOOSE guidelines. The risk of bias was assessed with the AMSTAR2 instrument. Data were synthesized using fixed-effects and random-effects meta-analyses, respectively. Finally, the evidence on the association of non-genetic risk factors and CHD was graded using Ioannidis's five-class evidence grade. RESULTS: A total of 56 SRs, encompassing 369 MAs, were identified. The risk factors included relative factors on air pollution, reproductive-related factors, parental age and BMI, parental life habits, working and dwelling environment, maternal drug exposure, and maternal disease. Based on AMSTAR2 criteria, only 16% (9/56) of SRs were classified as "Moderate". One hundred and two traceable positive association MAs involving 949 component individual studies were included in further analysis and grading of evidence. Family genetic history, number of abortions, maternal obesity, especially moderate or severe obesity, decoration materials, harmful chemicals, noise during pregnancy, folic acid supplementation, SSRIs, SNRIs, any antidepressants in the first trimester, maternal DM (including both PGDM and GDM), and gestational hypertension were convincing and highly suggestive factors for CHD. After sensitivity analyses based on cohort studies, some grades of evidence changed. CONCLUSION: The present umbrella review will provide evidence-based information for women of childbearing age before or during pregnancy to prevent CHD. In addition, sensitivity analysis based on cohort studies showed the changed evidence levels. Therefore, future SR/MA should concern the sensitivity analysis based on prospective birth cohort studies and case-control studies.

Accuracy of equations for predicting 24-h urinary potassium excretion from spot urine samples in Chinese children.

Accurate assessments of potassium intake in children are important for the early prevention of CVD. Currently, there is no simple approach for accurate estimation of potassium intake in children. We aim to evaluate the accuracy of 24-h urinary potassium excretion (24UKV) estimation in children using three common equations: the Kawasaki, Tanaka and Mage formulas, in a hospital-based setting. A total of 151 participants aged 5-18 years were initially enrolled, and spot urine samples were collected in the whole 24-h duration to measure the concentrations of potassium and creatinine. We calculated the mean difference, absolute and relative difference and misclassification rate between measured 24UKV and the predicted ones using Kawasaki, Tanaka and Mage formulas in 129 participants. The mean measured 24UKV was 1193·3 mg/d in our study. Mean differences between estimated and measured 24UKV were 1215·6, -14·9 and 230·3 mg/d by the Kawasaki, Tanaka and Mage formulas, respectively. All estimated 24UKV were significantly different from the measured values in all the time point (all P < 0·05), except for the predicted values from Tanaka formula using morning, afternoon and evening spot urine. The proportions with relative differences over 40 % were 87·2%, 32·5% and 47·3 % for Kawasaki, Tanaka and Mage formulas, respectively. Misclassification rates were 91·5 % for Kawasaki, 44·4 % for Tanaka and 58·9 % for Mage formula at the individual level. Our findings showed that misclassification could occur on the individual level when using Kawasaki, Tanaka and Mage formulas to estimate 24UKV from spot urine in the child population.

Self-controlled case series design in vaccine safety: a systematic review.

BACKGROUND: There is limited comprehensive evaluation of the methodology and reporting quality of observational studies of vaccine safety. METHODS: Databases including Medline, Embase, Web of Science, Scopus, and Chinese databases were searched from inception to 31 May 2021. All observational studies regarding vaccine safety using an SCCS design were selected. Information regarding methodological elements were extracted. In addition, reporting quality was assessed using the REporting of studies Conducted using Observational Routinely collected health Data statement for PharmacoEpidemiology (RECORD-PE). RESULTS: : Of the 105 studies identified, administrative databases were the main data source for vaccination records and adverse events following immunization (AEFI). Twenty-eight articles (27%) used multiple designs to verify the association, and the results obtained with the SCCS design were robust. The top three AEFI studied were intussusception, Guillain-Barré syndrome, and convulsions. Only 21 studies (20%) reported the approach for case validation by chart review. The healthy vaccinee effect was considered by 51 studies (49%), with 16 of them (31%) using extended SCCS models to alleviate this effect. Overall, the reporting quality of included studies could be improved. CONCLUSIONS: Administrative databases were the main data source for vaccination records and adverse events following immunization. Case validation, the validity of assumptions for standard SCCS, and quality of reporting should be given more importance in future research projects.

Detection of Drug-Induced Thrombocytopenia Signals in Children Using Routine Electronic Medical Records.

Background: Drug-induced thrombocytopenia (DITP) is a severe adverse reaction and a significantly under-recognized clinical problem in children. However, for post-marketing pharmacovigilance purposes, detection of DITP signals is crucial. This study aimed to develop a signal detection model for DITP using the pediatric electronic medical records (EMR) data. Methods: This study used the electronic medical records collected at Beijing Children's Hospital between 2009 and 2020. A two-stage modeling method was developed to detect the signal of DITP. In the first stage, we calculated the crude incidence by mining cases of thrombocytopenia to select the potential suspected drugs. In the second stage, we constructed propensity score-matched retrospective cohorts of specific screened drugs from the first stage and estimated the odds ratio (OR) and 95% confidence interval (CI) using conditional logistic regression models. The novelty of the signal was assessed by current evidence. Results: In the study, from a total of 839 drugs, 21 drugs were initially screened as potentially inducing thrombocytopenia. In total, we identified 18 positive DITP associations. Of these, potential DITP risk of nystatin (OR: 1.75, 95% CI: 1.37-2.22) and latamoxef sodium (OR: 1.61, 95% CI: 1.38-1.88) were two new DITP signals in both children and adults. Six associations between thrombocytopenia and drugs including imipenem (OR: 1.69, 95% CI: 1.16-2.45), teicoplanin (OR: 4.75, 95% CI: 3.33-6.78), fusidic acid (OR: 2.81, 95% CI: 2.06-3.86), ceftizoxime sodium (OR: 1.83, 95% CI: 1.36-2.45), ceftazidime (OR: 2.16, 95% CI: 1.58-2.95), and cefepime (OR: 5.06, 95% CI: 3.77-6.78) were considered as new signals in children. Conclusion: This study developed a two-stage algorithm to detect safety signals of DITP and found eighteen positive signals of DITP, including six new signals in a pediatric population. This method is a promising tool for pharmacovigilance based on EMR data.

Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion.

Background: Unexplained recurrent spontaneous abortion (URSA) is a common pregnancy complication and the etiology is unknown. URSA-associated lncRNAs are expected to be potential biomarkers for diagnosis, and might be related to the disease pathogenesis. Objective: To investigate differential lncRNAs in peripheral blood of non-pregnant URSA patients and matched healthy control women and to explore the possible mechanism of differential lncRNAs leading to URSA. Methods: We profiled lncRNAs expression in peripheral blood from 5 non-pregnant URSA patients and 5 matched healthy control women by lncRNA microarray analysis. Functions of URSA-associated lncRNAs were further investigated in vitro. Results: RP11-115N4.1 was identified as the most differentially expressed lncRNA which was highly upregulated in peripheral blood of non-pregnant URSA patients (P = 3.63E-07, Fold change = 2.96), and this dysregulation was further validated in approximately 26.67% additional patients (4/15). RP11-115N4.1 expression was detected in both lymphocytes and monocytes of human peripheral blood, and in vitro overexpression of RP11-115N4.1 decreased cell proliferation in K562 cells significantly. Furthermore, heat-shock HSP70 genes (HSPA1A and HSPA1B) were found to be significantly upregulated upon RP11-115N4.1 overexpression by transcriptome analysis (HSPA1A (P = 4.39E-08, Fold change = 4.17), HSPA1B (P = 2.26E-06, Fold change = 2.99)). RNA pull down and RNA immunoprecipitation assay (RIP) analysis demonstrated that RP11-115N4.1 bound to HNRNPH3 protein directly, which in turn activate heat-shock proteins (HSP70) analyzed by protein-protein interaction and HNRNPH3 knockdown assays. Most importantly, the high expression of HSP70 was also verified in the serum of URSA patients and the supernatant of K562 cells with RP11-115N4.1 activation, and HSP70 in supernatant can exacerbate inflammatory responses in monocytes by inducing IL-6, IL-1ß, and TNF-α and inhibit the migration of trophoblast cells, which might associate with URSA. Conclusion: Our results demonstrated that the activation of RP11-115N4.1 can significantly increase the protein level of HSP70 via binding to HNRNPH3, which may modulate the immune responses and related to URSA. Moreover, RP11-115N4.1 may be a novel etiological biomarker and a new therapeutic target for URSA.

The Role of Serum Calcium Levels in Pediatric Dyslipidemia: Are There Any?

Background: No previous study explored the association between serum calcium levels and dyslipidemia in children. This study aimed to explore this relationship in children, based on a multicenter cross-sectional study population in China. Methods: Cross-sectional data was derived from the Pediatric Reference Intervals in China (PRINCE) study conducted between 2017 and 2018 involving 5,252 males and 5,427 females with a mean age of 10.0 ± 4.6 years. Multivariable logistic regression models were applied to calculate odds ratios (ORs), with 95% confidence intervals (CIs), for dyslipidemia of each serum calcium level and albumin-corrected calcium levels, which were sorted into quartiles. The restricted cubic spline model was fitted for the dose-response analysis. An L-shaped dose-response relation between calcium levels and the probability of dyslipidemia was found after the adjustment for multiple potential confounding factors, p for non-linear < 0.001. Results: Using the middle category of calcium level as the reference, multivariable-adjusted ORs and 95% CIs of the lowest and the highest quartile categories were 0.96 (0.82-1.12) and 1.29 (1.12-1.48), respectively, for total serum calcium levels and 1.06 (0.91-1.23) and 1.39 (1.21-1.60) for albumin-corrected calcium levels. Conclusions: Individuals with higher levels of serum calcium were associated with increased risk of dyslipidemia in a sample of a healthy Chinese pediatric population. The association between serum calcium levels and dyslipidemia needs to be examined prospectively in future studies.

Determination of Cytokines and Oxidative Stress Biomarkers in Cognitive Impairment Induced by Methylmalonic Acidemia.

OBJECTIVE: Methylmalonic acidemia (MMA) is the most common organic acidemia in children. Many patients with MMA suffered from cognitive impairments. The aim of this study was to identify the significance of cytokines and oxidative stress biomarkers in MMA-induced cognitive impairment. METHODS: We enrolled 64 children with combined MMA and homocystinuria and 64 age- and sex-matched healthy volunteers. Participants were subsequently classified as with or without cognitive impairments using a uniform neuropsychological assessment test. Serum samples were collected. The serum levels of cytokines and oxidative stress biomarkers were measured using the ELISA or chemical methods. RESULTS: Compared to control group, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, malondialdehyde (MDA), and nitric oxide (NO) in the MMA patients increased markedly (p < 0.05); glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (p < 0.01). The levels of IL-6, TNF-α, NO, and MDA in the serum were negatively associated with DQ or IQ scores. The levels of GSH and SOD in the serum were positively correlated with DQ or IQ scores. After receiver operating characteristic curve analysis, NO was the most useful individual marker for distinguishing the cognitive dysfunction, corresponding to the area under ROC curve (AUC) of 0.82 (95% CI, 0.74-0.91), sensitivity of 76.60%, and specificity of 80.25%. GSH and MDA were also useful for diagnosis of MMA-induced cognitive dysfunction, corresponding to the AUC of 0.80 (95% CI, 0.70-0.89), and 0.73 (95% CI, 0.63-0.82), respectively. The sensitivity and specificity of GSH were 72.34 and 80.25%, respectively. The sensitivity and specificity of MDA were 85.11 and 51.85%, respectively. CONCLUSIONS: The high-concentration methylmalonic acid in the blood induced immune cells to release pro-inflammatory cytokines such as TNF-α and IL-6. These cytokines and high-concentration methylmalonic acid stimulated the immune cells to produce reactive oxygen species (ROS) and reactive nitrogen species (RNS). The serum methylmalonic acid, cytokines, ROS, and RNS were across the blood-brain barrier and induced cognitive impairment. The small molecule substances such as serum NO, MDA, and GSH participated in the process of neuroinflammation and oxidative stress injury induced by MMA and could be useful for distinguishing the cognitive impairment.

Effect of More Intensive LDL-C-Lowering Therapy on Long-term Cardiovascular Outcomes in Early-Phase Acute Coronary Syndrome: A Systematic Review and Meta-analysis.

PURPOSE: The effect of more intensive LDL-C-lowering therapy (ILLT) on long-term cardiovascular outcomes during the early phase of acute coronary syndromes (ACSs) remains uncertain. We aimed to explore the influence of more intensive LDL-C-lowering therapyduring the early disease phase on long-term cardiovascular events among patients with ACSs. METHODS: Randomized controlled trials that focused on the effect of more ILLT during early-phase ACSs on long-term major adverse cardiac events (MACEs) were searched in electronic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases) from database inception until November 23, 2019. The end points included the incidence of MACEs, myocardial infarction, stroke, revascularization, heart failure, and death events. Study risk of bias was assessed using the Cochrane Collaboration tools. Fixed- or random-effects models and meta-regression were performed to evaluate the association between baseline/proportional reduction of LDL-C levels during early-phase disease and the risk of end points using risk ratios with 95% CIs. FINDINGS: A total of 53,199 participants were involved from 19 studies. The risk of MACEs decreased by 17% (95% CI, 0.76-0.90; P = 0.0012) for more intensive versus control therapy but varied by baseline and proportional reduction of LDL-C levels during early disease phase. The risk reduction of MACEs for more intensive versus control therapy among different subgroups was 26% (95% CI, 0.57-0.95; P = 0.06) with a baseline level >130 mg/dL, 23% (95% CI, 0.63-0.94; P = 0.02) with a baseline level of 100 to 130 mg/dL, and 10% (95% CI, 0.83-0.99; P = 0.07) with a baseline level <100 mg/dL. A significant difference of risk reduction for MACEs existed between patients treated with statin plus ezetimibe versus statin alone in the subgroup with a baseline level >130 mg/dL and proportional reduction >50%. Patients treated with more intensive therapy benefited from reduced risk of myocardial infarction, stroke, revascularization, and heart failure compared with control therapy. IMPLICATIONS: More ILLT during early disease phase could significantly reduce the risk of long-term cardiovascular outcome in patients with ACSs. This benefit was most pronounced in patients with higher baseline and larger reduction of LDL-C levels in MACEs.

The Effects of LIT and MLR-Bf on Immune Biomarkers and Pregnancy Outcomes in Women With Previous Early Recurrent Miscarriage: A Retrospective Study.

Background: Immunological failure during pregnancy is considered one of the etiologies of recurrent miscarriage (RM). The decreased production of mixed lymphocyte reaction-blocking factors (MLR-Bf) may play a major role in this condition. Lymphocyte immunotherapy (LIT), which induces the production of MLR-Bf, has been used in treating RM patients since 1984. However, the effectiveness of LIT is currently being heatedly debated. In addition to that, possible changes to the maternal immune system upon induced MLR-Bf production by LIT remains unclear. Objectives: To explore the possible impacts that MLR-Bf may have on the expression of immune biomarkers and pregnancy outcomes, and deduce whether the prevention of miscarriages is possible with LIT or MLR-Bf in RM patients. Materials and Methods: Women with previous early RM (eRM) were enrolled in this retrospective study after they got pregnant again. LIT was implemented before pregnancy and during the first trimester. MLR-Bf and immune biomarkers were checked as the clinical routine. Patients were followed up until 12 gestational weeks. Levels of immune biomarkers and successful pregnancy rates were compared between MLR-Bf- group and MLR-Bf+ group stratified by LIT. Independent associations between LIT, or MLR-Bf, and miscarriage were estimated. All data management and analysis were conducted using SPSS 20.0. Results: A total of 1,038 patients, 497 MLR-Bf- (49 cases accepted LIT), and 541 MLR-Bf+(463 cases induced by LIT) were included in the study. Percentage of lymphocytes, the ratio of CD4+ T cells/lymphocytes, and levels of some rheumatoid biomarkers (anti-U1-nRNP, anti-SAA-52kd, and anti-CENOP B) were statistically higher in MLR-Bf+ group than in MLR-Bf- group among women without LIT. With LIT treatment the successful pregnancy rate was statistically higher in MLR-Bf+ group than in MLR-Bf- group (66.7% vs. 51.0%, P = 0.028) among women with LIT. Meanwhile, LIT was estimated to have an independent negative association with miscarriage. Conclusion: Upon LIT treament levels of immune biomarkers were different in women with and without MLR-Bf when stratified by whether they received LIT. Not MLR-Bf, but LIT, has an independent protective effect on miscarriage.

Nonselective Compared With Selective α-Blockade Is Associated With Less Intraoperative Hypertension in Patients With Pheochromocytomas and Paragangliomas: A Retrospective Cohort Study With Propensity Score Matching.

BACKGROUND: Both selective and nonselective α-blockade are used for preoperative preparation in patients with pheochromocytomas and paragangliomas (PPGLs). However, the effects of different types of α-blockade on perioperative outcomes remain inconclusive. This study was designed to assess the association between the choice of α-blockade and the amount of intraoperative hypertension in patients undergoing surgery for PPGLs. METHODS: In this propensity-matched retrospective cohort study, data of patients who received either selective or nonselective α-blockade preoperatively and underwent surgery for PPGLs were collected. The primary end point was the time-weighted average above the systolic blood pressure (SBP) of 160 mm Hg (TWA-SBP >160 mm Hg), which was calculated as the total area of the SBP-time curve above the SBP of 160 mm Hg and divided by anesthesia duration. RESULTS: A total of 286 patients were included in analysis; of them, 156 received selective α-blockade and 130 nonselective α-blockade. After propensity score matching, 89 patients remained in each group. Patients who received nonselective α-blockade had a lower TWA-SBP >160 (median 0.472 mm Hg, interquartile range [IQR], 0.081-1.300) versus those who received selective α-blockade (median 1.114 mm Hg, IQR, 0.162-2.853; median difference -0.391, 95% confidence interval [CI], -0.828 to -0.032; P = .016); they also had a lower highest SBP during surgery (193 ± 24 mm Hg versus 205 ± 34 mm Hg; mean difference -12, 95% CI, -20 to -3; P = .008). Postoperative outcomes did not differ significantly between the 2 groups. CONCLUSIONS: For patients undergoing surgery for PPGLs, preoperative nonselective α-blockade was associated with less intraoperative hypertension when compared with selective α-blockade.

Signal Detection of Potentially Drug-Induced Liver Injury in Children Using Electronic Health Records.

Background: This study proposes a quantitative 2-stage procedure to detect potential drug-induced liver injury (DILI) signals in pediatric inpatients using an data warehouse of electronic health records (EHRs). Methods: Eight years of medical data from a constructed database were used. A two-stage procedure was adopted: (i) stage 1: the drugs suspected of inducing DILI were selected and (ii) stage 2: the associations between the drugs and DILI were identified in a retrospective cohort study. Results: 1,196 drugs were filtered initially and 12 drugs were further potentially identified as suspect drugs inducing DILI. Eleven drugs (fluconazole, omeprazole, sulfamethoxazole, vancomycin, granulocyte colony-stimulating factor (G-CSF), acetaminophen, nifedipine, fusidine, oseltamivir, nystatin and meropenem) were showed to be associated with DILI. Of these, two drugs, nystatin [odds ratio[OR]=1.39, 95%CI:1.10-1.75] and G-CSF (OR = 1.91, 95%CI:1.55-2.35), were found to be new potential signals in adults and children. Three drugs [nifedipine [OR = 1.77, 95%CI:1.26-2.46], fusidine [OR = 1.43, 95%CI:1.08-1.86], and oseltamivi r [OR = 1.64, 95%CI:1.23-2.18]] were demonstrated to be new signals in pediatrics. The other drug-DILI associations had been confirmed in previous studies. Conclusions: A quantitative algorithm to detect potential signals of DILI has been described. Our work promotes the application of EHR data in pharmacovigilance and provides candidate drugs for further causality assessment studies.