Developing and validating a clinlabomics-based machine-learning model for early detection of retinal detachment in patients with high myopia.

BACKGROUND: Retinal detachment (RD) is a vision-threatening disorder of significant severity. Individuals with high myopia (HM) face a 2 to 6 times higher risk of developing RD compared to non-myopes. The timely identification of high myopia-related retinal detachment (HMRD) is crucial for effective treatment and prevention of additional vision impairment. Consequently, our objective was to streamline and validate a machine-learning model based on clinical laboratory omics (clinlabomics) for the early detection of RD in HM patients. METHODS: We extracted clinlabomics data from the electronic health records for 24,440 HM and 5607 HMRD between 2015 and 2022. Lasso regression analysis assessed fifty-nine variables, excluding collinear variables (variance inflation factor > 10). Four models based on random forest, gradient boosting machine (GBM), generalized linear model, and Deep Learning Model were trained for HMRD diagnosis and employed for internal validation. An external test of the models was done. Three random data sets were further processed to validate the performance of the diagnostic model. The primary outcomes were the area under the receiver operating characteristic curve (AUC) and the area under the precision-recall curve (AUCPR) to diagnose HMRD. RESULTS: Nine variables were selected by all models. Given the AUC and AUCPR values across the different sets, the GBM model was chosen as the final diagnostic model. The GBM model had an AUC of 0.8550 (95%CI = 0.8322-0.8967) and an AUCPR of 0.5584 (95%CI = 0.5250-0.5879) in the training set. The AUC and AUCPR in the internal validation were 0.8405 (95%CI = 0.8060-0.8966) and 0.5355 (95%CI = 0.4988-0.5732). During the external test evaluation, it reached an AUC of 0.7579 (95%CI = 0.7340-0.7840) and an AUCPR of 0.5587 (95%CI = 0.5345-0.5880). A similar discriminative capacity was observed in the three random data sets. The GBM model was well-calibrated across all the sets. The GBM-RD model was implemented into a web application that provides risk prediction for HM individuals. CONCLUSION: GBM algorithms based on nine features successfully predicted the diagnosis of RD in patients with HM, which will help ophthalmologists to establish a preliminary diagnosis and to improve diagnostic accuracy in the clinic.

Metabolomics identifies and validates serum androstenedione as novel biomarker for diagnosing primary angle closure glaucoma and predicting the visual field progression.

Background: Primary angle closure glaucoma (PACG) is the leading cause of irreversible blindness in Asia, and no reliable, effective diagnostic, and predictive biomarkers are used in clinical routines. A growing body of evidence shows metabolic alterations in patients with glaucoma. We aimed to develop and validate potential metabolite biomarkers to diagnose and predict the visual field progression of PACG. Methods: Here, we used a five-phase (discovery phase, validation phase 1, validation phase 2, supplementary phase, and cohort phase) multicenter (EENT hospital, Shanghai Xuhui Central Hospital), cross-sectional, prospective cohort study designed to perform widely targeted metabolomics and chemiluminescence immunoassay to determine candidate biomarkers. Five machine learning (random forest, support vector machine, lasso, K-nearest neighbor, and GaussianNaive Bayes [NB]) approaches were used to identify an optimal algorithm. The discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC). Calibration was assessed by Hosmer-Lemeshow tests and calibration plots. Results: Studied serum samples were collected from 616 participants, and 1464 metabolites were identified. Machine learning algorithm determines that androstenedione exhibited excellent discrimination and acceptable calibration in discriminating PACG across the discovery phase (discovery set 1, AUCs=1.0 [95% CI, 1.00-1.00]; discovery set 2, AUCs = 0.85 [95% CI, 0.80-0.90]) and validation phases (internal validation, AUCs = 0.86 [95% CI, 0.81-0.91]; external validation, AUCs = 0.87 [95% CI, 0.80-0.95]). Androstenedione also exhibited a higher AUC (0.92-0.98) to discriminate the severity of PACG. In the supplemental phase, serum androstenedione levels were consistent with those in aqueous humor (r=0.82, p=0.038) and significantly (p=0.021) decreased after treatment. Further, cohort phase demonstrates that higher baseline androstenedione levels (hazard ratio = 2.71 [95% CI: 1.199-6.104], p=0.017) were associated with faster visual field progression. Conclusions: Our study identifies serum androstenedione as a potential biomarker for diagnosing PACG and indicating visual field progression. Funding: This work was supported by Youth Medical Talents - Clinical Laboratory Practitioner Program (2022-65), the National Natural Science Foundation of China (82302582), Shanghai Municipal Health Commission Project (20224Y0317), and Higher Education Industry-Academic-Research Innovation Fund of China (2023JQ006).

The Zhu-Lu formula: a machine learning-based intraocular lens power calculation formula for highly myopic eyes.

BACKGROUND: To develop a novel machine learning-based intraocular lens (IOL) power calculation formula for highly myopic eyes. METHODS: A total of 1828 eyes (from 1828 highly myopic patients) undergoing cataract surgery in our hospital were used as the internal dataset, and 151 eyes from 151 highly myopic patients from two other hospitals were used as external test dataset. The Zhu-Lu formula was developed based on the eXtreme Gradient Boosting and the support vector regression algorithms. Its accuracy was compared in the internal and external test datasets with the Barrett Universal II (BUII), Emmetropia Verifying Optical (EVO) 2.0, Kane, Pearl-DGS and Radial Basis Function (RBF) 3.0 formulas. RESULTS: In the internal test dataset, the Zhu-Lu, RBF 3.0 and BUII ranked top three from low to high taking into account standard deviations (SDs) of prediction errors (PEs). The Zhu-Lu and RBF 3.0 showed significantly lower median absolute errors (MedAEs) than the other formulas (all P < 0.05). In the external test dataset, the Zhu-Lu, Kane and EVO 2.0 ranked top three from low to high considering SDs of PEs. The Zhu-Lu formula showed a comparable MedAE with BUII and EVO 2.0 but significantly lower than Kane, Pearl-DGS and RBF 3.0 (all P < 0.05). The Zhu-Lu formula ranked first regarding the percentages of eyes within ± 0.50 D of the PE in both test datasets (internal: 80.61%; external: 72.85%). In the axial length subgroup analysis, the PE of the Zhu-Lu stayed stably close to zero in all subgroups. CONCLUSIONS: The novel IOL power calculation formula for highly myopic eyes demonstrated improved and stable predictive accuracy compared with other artificial intelligence-based formulas.

Association between red blood cell distribution width and ischemic stroke recurrence in patients with acute ischemic stroke: a 10-years retrospective cohort analysis.

Numerous studies have reported that a higher red blood cell distribution width (RDW) level was associated with adverse outcomes in patients with the first stroke. However, no studies have examined the association between RDW and recurrent ischemic stroke. We performed a population-based cohort data analysis from 2007 to 2017. Baseline RDW was measured in 6402 first ischemic stroke participants, who were followed for about five years on average. During 62 months of median follow-up, 205 participants (3.20%) reported a recurrence (self-reported). RDW showed a nonlinear relationship with the risk of ischemic stroke recurrence. When RDW was assessed as quartiles (quartile 1, RDW<12.4; quartile 2, 12.4 to 12.8; quartile 3,12.8 to 13.3, quartile4, RDW>13.3), compared with the reference group (quartile 1), the hazard ratios (HRs) of ischemic stroke recurrence were 1.372 (95% confidence interval [CI]=0.671-2.805, P=0.386) in quartile 2, 1.835 (95% CI=1.222-2.755, P=0.003) in quartile 3, and 1.732 (95% CI=1.114-2.561, P<0.001) in quartile 4. The trend test was significant (P<0.001). When quartiles 3 and 4 were combined, the adjusted HR of ischemic stroke recurrence was 1.439 (95% CI=1.330-1.556, P<0.001) compared with the combined quartiles 1 and 2 subgroups. This study demonstrated that elevated RDW levels were positively associated with an increased risk of recurrent ischemic stroke. RDW can provide a new perspective for initial risk assessment and identify high-risk patients early. Further research is required to confirm our results.

Association Between Pre-Treatment and Post-Treatment 3-Month Red Cell Distribution Width with Three-Year Prognosis of Prostate Cancer.

PURPOSE: Red cell distribution width (RDW), an inflammation biomarker, has been linked to poor outcomes in patients with different types of cancers. The present study aimed to investigate the relationship between pre-/post-treatment 3-month RDW levels and changes in RDW with 3-year prognosis of prostate cancer. PATIENTS AND METHODS: A total of 348 patients with prostate cancer were recruited between June 1, 2012 and June 1, 2017 and were followed up for at least 3 years. RDW was measured with the Mindray BC-6800Plus automatic blood counting system at pre- and post-treatment 3-month. Demographic and clinical information of the participants were also collected. The overall survival (OS) and cancer-specific survival (CSS) were analyzed using the Kaplan-Meier method. Cox regression and competing risk regression analyses were performed. RESULTS: During the follow-up period, 51 (14.66%) deaths occurred. The levels of pre- and post-treatment RDW levels were significantly higher in the death group than in the survival group (p<0.001). In the death group, the level of RDW continued to rise in most subjects, and the mean level of RDW was significantly higher at post-treatment than pre-treatment, contrary to the results observed in the survival group. Multivariate Cox regression analysis revealed that high pre-treatment RDW, high post-treatment RDW, and persistently higher RDW were independently associated with OS and CSS (p<0.001). Similar results were observed in the competing risk regression analysis. Kaplan-Meier analysis revealed that patients with higher pre-treatment RDW levels, higher post-treatment RDW levels, and persistently higher RDW levels had poorer 3-year OS and CSS rates (p<0.05). CONCLUSION: The levels of and changes in RDW before and after treatment were associated with the 3-year prognosis of prostate cancer, suggesting that RDW might be an efficient prognostic predictor in patients with prostate cancer.

An Optical Coherence Tomography-Based Deep Learning Algorithm for Visual Acuity Prediction of Highly Myopic Eyes After Cataract Surgery.

BACKGROUND: Due to complicated and variable fundus status of highly myopic eyes, their visual benefit from cataract surgery remains hard to be determined preoperatively. We therefore aimed to develop an optical coherence tomography (OCT)-based deep learning algorithms to predict the postoperative visual acuity of highly myopic eyes after cataract surgery. MATERIALS AND METHODS: The internal dataset consisted of 1,415 highly myopic eyes having cataract surgeries in our hospital. Another external dataset consisted of 161 highly myopic eyes from Heping Eye Hospital. Preoperative macular OCT images were set as the only feature. The best corrected visual acuity (BCVA) at 4 weeks after surgery was set as the ground truth. Five different deep learning algorithms, namely ResNet-18, ResNet-34, ResNet-50, ResNet-101, and Inception-v3, were used to develop the model aiming at predicting the postoperative BCVA, and an ensemble learning was further developed. The model was further evaluated in the internal and external test datasets. RESULTS: The ensemble learning showed the lowest mean absolute error (MAE) of 0.1566 logMAR and the lowest root mean square error (RMSE) of 0.2433 logMAR in the validation dataset. Promising outcomes in the internal and external test datasets were revealed with MAEs of 0.1524 and 0.1602 logMAR and RMSEs of 0.2612 and 0.2020 logMAR, respectively. Considerable sensitivity and precision were achieved in the BCVA < 0.30 logMAR group, with 90.32 and 75.34% in the internal test dataset and 81.75 and 89.60% in the external test dataset, respectively. The percentages of the prediction errors within ± 0.30 logMAR were 89.01% in the internal and 88.82% in the external test dataset. CONCLUSION: Promising prediction outcomes of postoperative BCVA were achieved by the novel OCT-trained deep learning model, which will be helpful for the surgical planning of highly myopic cataract patients.

Association Between Sex Hormones and Visual Field Progression in Women With Primary Open Angle Glaucoma: A Cross-Sectional and Prospective Cohort Study.

Purpose: We evaluated the level of sex hormones in female patients with primary open angle glaucoma (POAG) to determine whether they are associated with the onset and/or progression of POAG. Methods: The cross-sectional study enrolled 63 women with POAG and 56 healthy women as normal control subjects. Furthermore, 57 women with POAG were included and followed-up for at least 2 years in the cohort study. All subjects were evaluated for serum concentration of sex hormones [prolactin (PRL), luteinizing hormone (LH), testosterone (TESTO), follicle-stimulating hormone (FSH), progesterone (PROG), and estrogen (E2)] and underwent visual field (VF) examination. In the cross-sectional study, Spearman analysis, linear regression analysis, and logistic regression analysis were performed to assess risk factors for POAG in women. In the cohort study, Cox regression analyses and Kaplan-Meier survival analysis were performed to identify factors associated with VF progression in women with POAG. Results: In the cross-sectional study, the level of E2 was significantly lower in the POAG group than in the normal group (p < 0.05). Multiple logistic regression showed that the decreased level of E2 was a risk factor of POAG (OR = 0.27, 95% CI = 0.09-0.78, p < 0.05), especially in premenopausal subjects. In the cohort study, there were 29 non-progression subjects and 28 progression subjects. Patients in the progression group had significantly lower levels of E2 than those in the no progression group (p < 0.01). The decreased level of E2 at baseline was associated with POAG progression (HR = 0.08, 95% CI = 0.02-0.46, p < 0.05), especially in premenopausal subjects. Patients with POAG and with lower baseline E2 levels had significantly lower VF non-progression rates than patients with higher E2 levels (log-rank test p < 0.001), especially premenopausal subjects (log-rank test p < 0.05). Additionally, logistic regression analyses, Cox regression analyses, and Kaplan-Meier survival analysis showed that PROG, LH, FSH, and TESTO were risk factors of POAG and/or significantly associated with POAG progression. Conclusion: A decreased E2 level is a POAG risk factor and is associated with VF progression in women with POAG, especially in premenopausal subjects. Additionally, other sex hormones (PROG, LH, FSH, and TESTO) might also play a role in POAG pathogenesis.

17-ß-Estradiol and Progesterone as Efficient Predictors of Survival in Older Women Undergoing Hip Fracture Surgery.

Objective: Sex hormones have been linked to fractures in older women. The purpose of this present study was to investigate the prognostic impact of preoperative sex hormone levels on 30-day mortality in older women undergoing hip fracture surgery. Patients and Methods: A total of 157 female subjects with hip fractures were eligible for the study conducted from January 2010 to December 2019. The serum levels of sex hormones [follicle-stimulating hormone, prolactin, progesterone, testosterone, luteinizing hormone, and 17-ß-estradiol (E2)] were measured at admission. To evaluate the prognostic significance of sex hormone levels, Cox proportional hazard models and Kaplan-Meier analyses were applied. Results: Of the 157 subjects, 13 (8.28%) deceased within 30 days. The deceased subjects had lower progesterone (P = 0.021) and E2 (P < 0.001) levels than the surviving group. Higher progesterone (HR = 0.168, 95% CI = 0.037-0.673) and E2 (HR = 0.857, 95% CI = 0.690-0.968) levels were the key protective factors for 30-day mortality in older women undergoing hip fracture surgery. Survival analysis showed that subjects with lower E2 or/and progesterone levels had a significantly higher percentage of 30-day mortality (log-rank test, P < 0.05). Conclusion: E2 and progesterone might be effective predictors of 30-day mortality in older women undergoing hip fracture surgery.

Association Between 17-ß-Estradiol and Interleukin-8 and Visual Field Progression in Postmenopausal Women with Primary Angle Closure Glaucoma.

PURPOSE: To investigate an association between sex hormones and inflammatory cytokines, and to determine whether baseline 17-ß-estradiol (E2) and interleukin-8 (IL-8) are associated with visual field (VF) progression in postmenopausal women with primary angle closure glaucoma (PACG). DESIGN: A prospective cross-sectional and cohort study. PARTICIPANTS: The cross-sectional study enrolled 200 postmenopausal women with PACG and 151 healthy postmenopausal women as normal control subjects. A total of 105 postmenopausal women with PACG were included and followed up for ≥2 years in the cohort study. METHODS: All participants were evaluated for levels of baseline sex hormones (follicle-stimulating hormone, prolactin, progesterone, testosterone, luteinizing hormone, and E2) and inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, IL-10, and C-reactive protein) and underwent VF examinations. The cross-sectional study was conducted to establish risk factors for postmenopausal women with PACG using logistic regression analysis. The cohort study was designed to identify factors that could be used to predict VF progression in postmenopausal women with PACG using multivariate Cox regression analyses. The main outcome measures included factors associated with VF progression over time. RESULTS: Decreased E2 (odds ratio 0.88 [95% confidence interval {CI} 0.78-0.99], P = .007) and increased IL-8 (odds ratio 1.12 [95% CI 1.01-1.23], P < .001) levels were risk factors in postmenopausal women with PACG. A significant negative correlation was observed between IL-8 levels and E2 (r = -0.21, P = .02). Multivariable regression analyses revealed a significant correlation between E2 levels and visual field mean deviation (MD) (B = -0.16, P = .04 [95% CI -.09 to -.003) and between IL-8 levels and MD (B = 0.36, P < .001 [95% CI 0.01-0.02]). During follow-up, 48 (45.71%) patients showed VF progression. Lower baseline E2 (hazard ratio 0.85 [95% CI 0.82-0.88], P = .04) and higher baseline IL-8 levels (hazard ratio 1.01 [95% CI 1.00-1.02], P = .004) were associated with progression of glaucoma. Patients with lower E2 levels had a significantly higher rate of PACG progression (log-rank test P < .001), similar to those with higher IL-8 levels (log-rank test P = .04). CONCLUSIONS: Decreased E2 and increased IL-8 levels at baseline are significant predictors of VF progression in postmenopausal women with PACG.

Accuracy Improvement of IOL Power Prediction for Highly Myopic Eyes With an XGBoost Machine Learning-Based Calculator.

Purpose: To develop a machine learning-based calculator to improve the accuracy of IOL power predictions for highly myopic eyes. Methods: Data of 1,450 highly myopic eyes from 1,450 patients who had cataract surgeries at our hospital were used as internal dataset (train and validate). Another 114 highly myopic eyes from other hospitals were used as external test dataset. A new calculator was developed using XGBoost regression model based on features including demographics, biometrics, IOL powers, A constants, and the predicted refractions by Barrett Universal II (BUII) formula. The accuracies were compared between our calculator and BUII formula, and axial length (AL) subgroup analysis (26.0-28.0, 28.0-30.0, or ≥30.0 mm) was further conducted. Results: The median absolute errors (MedAEs) and median squared errors (MedSEs) were lower with the XGBoost calculator (internal: 0.25 D and 0.06 D2; external: 0.29 D and 0.09 D2) vs. the BUII formula (all P ≤ 0.001). The mean absolute errors and were 0.33 ± 0.28 vs. 0.45 ± 0.31 (internal), and 0.35 ± 0.24 vs. 0.43 ± 0.29 D (external). The mean squared errors were 0.19 ± 0.32 vs. 0.30 ± 0.36 (internal), and 0.18 ± 0.21 vs. 0.27 ± 0.29 D2 (external). The percentages of eyes within ±0.25 D of the prediction errors were significantly greater with the XGBoost calculator (internal: 49.66 vs. 29.66%; external: 78.28 vs. 60.34%; both P < 0.05). The same trend was in MedAEs and MedSEs in all subgroups (internal) and in AL ≥30.0 mm subgroup (external) (all P < 0.001). Conclusions: The new XGBoost calculator showed promising accuracy for highly or extremely myopic eyes.

Uric Acid Provides Protective Role in Red Blood Cells by Antioxidant Defense: A Hypothetical Analysis.

Uric acid (UA) is a major antioxidant molecule in the human blood, and it has been linked with cell longevity. However, it is unclear whether serum UA levels are associated with red blood cell (RBC) indexes. This cross-sectional study included 10,759 Chinese subjects, recruited from the Shanghai Xuhui Central Hospital from January 2014 to December 2017. The participants were categorized into gender groups and then further divided into three different subgroups according to their UA reference range as follows: low (male (UA < 0.202 mmol/l), female (UA < 0.143 mmol/l)), normal (male (0.417 mmol/l > UA ≥ 0.202 mmol/l), female (0.339 mmol/l > UA ≥ 0.143 mmol/l)), and high (male (UA ≥ 0.417 mmol/l), female (UA ≥ 0.339 mmol/l)). The associations of UA levels with RBC parameters were analyzed using 1-way ANOVA, Pearson correlations, and multivariate linear regression. The levels of mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, RBCs, and hemoglobin were lowest in the low UA group, followed by the normal UA group and high UA group (p < 0.001). Pearson analysis showed that there was a statistically significant correlation between UA levels with mean corpuscular hemoglobin, mean corpuscular hemoglobin concentrations, mean corpuscular volumes, RBC counts, and hemoglobin (p < 0.05). Multiple linear regression analysis suggested that there were statistically significant positive correlations between UA levels and RBC counts (B = 0.245, p < 0.001, 95% CI = 0.003 to 0.092), as well as UA levels and hemoglobin concentrations (B = 0.138, p < 0.001, 95% CI = 0.002 to 0.082). Furthermore, similar results were observed in both the male and female subgroups. The serum UA levels may be independently associated with RBC parameters, regardless of sex, and UA may protect RBCs owing to its antioxidant effect.

Extent and cost of inappropriate use of tumour markers in patients with pulmonary disease: a multicentre retrospective study in Shanghai, China.

OBJECTIVES: The currently implemented healthcare reform in China requires substantial capital investment. Although overtreatment results in serious waste, inappropriate laboratory use is widespread, and overuse of tumour markers (TMs) has attracted increasing attention. DESIGN: Retrospective study. SETTING: The respiratory, thoracic surgery and oncology departments of three hospitals in Shanghai from 2014 to 2015. PARTICIPANTS: Patients with chronic obstructive pulmonary disease (COPD) and primary bronchogenic lung cancer (PLC). Based on clinical guidelines and physician experience, the criteria of suitability of TM examinations were determined, and the number, cost and proportion of inappropriate TM requests were analysed. RESULTS: The area under the receiver operating characteristic curve for carcinoembryonic antigen+cytokeratin fragment 21-1+squamous cell carcinoma antigen+neuron-specific enolase in patients with COPD and PLC was 0.813, in accordance with the cost-effectiveness principle, indicating good clinical and health economics values. In the 2706 patients, 12 496-16 956 (58.27%-79.06%) of TM requests were inappropriate. Furthermore, the involved expense was 650 200-1 014 156 yuan, accounting for 7.69%-12.00% of examination expenses and 1.35%-2.11% of hospitalisation costs. CONCLUSIONS: We found that the inappropriate use of TMs was widespread for patients with pulmonary disease. Clinicians should use TMs strictly according to the guidelines to effectively manage laboratory resources and control costs.

LC-MS/MS Method for Serum Creatinine: Comparison with Enzymatic Method and Jaffe Method.

Accurate quantification of creatinine (Cre) is important to estimate glomerular filtration rate (GFR). Differences among various methods of Cre quantification were previously noted. This study aims to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for serum Cre and compare this method with clinical routine methods. LC-MS/MS analysis was performed on API 4000 triple quadrupole mass spectrometer coupled with an Agilent 1200 liquid chromatography system. After adding isotope-labeled Cre-d3 as internal standard, serum samples were prepared via a one-step protein precipitation with methanol. The LC-MS/MS method was compared with frequently used enzymatic method and Jaffe method. This developed method, with a total run time of 3 min, had a lower limit of quantification of 4.4 µmol/L, a total imprecision of 1.15%-3.84%, and an average bias of 1.06%. No significant matrix effect, carryover, and interference were observed for the LC-MS/MS method. The reference intervals of serum Cre measured by LC-MS/MS assay were 41-79 µmol/L for adult women, and 46-101 µmol/L for adult men. Using LC-MS/MS as a reference, the enzymatic method showed an average bias of -2.1% and the Jaffe method showed a substantial average bias of 11.7%. Compared with the LC-MS/MS method, significant negative bias was observed for the enzymatic and Jaffe methods in hemolytic and lipimic samples. We developed a simple, specific, and accurate LC-MS/MS method to analyze serum Cre. Discordance existed among different methods.

Curcumin protects mice from coxsackievirus B3-induced myocarditis by inhibiting the phosphatidylinositol 3 kinase/Akt/nuclear factor-κB pathway.

Viral myocarditis is an inflammation of the myocardium, and coxsackievirus B3 (CVB3) is one of the most important etiologic agents. Curcumin is an active ingredient of Curcumin longa, which has been used as a traditional Chinese herb for the treatment of various inflammatory diseases. The aim of this study was to explore the therapeutic effect of curcumin on CVB3-induced myocarditis and the underlying mechanism. Our results showed that treatment with curcumin could significantly attenuate CVB3-induced myocarditis, as demonstrated by improved weight loss, increased survival rate, reduced serological level cardiac enzymes, and improved heart histopathology. Of importance, curcumin administration was revealed to significantly reduce the systemic and local myocardial expression of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL) 6, and IL-1ß, in the CVB3-infected mice. Further study showed that curcumin treatment significantly inhibited the CVB3-induced activation of nuclear factor-κB (NF-κB), a key transcription factor in the pathogenesis of inflammation, in a phosphatidylinositol 3 kinase (PI3K)/Akt pathway-dependent manner. These data indicate that curcumin has protective effect against CVB3-induced myocarditis by inhibiting PI3K/Akt/NF-κB signaling pathway and thus reducing the inflammatory response.

Pharmacokinetic properties and bioequivalence of two sulfadoxine/pyrimethamine fixed-dose combination tablets: a parallel-design study in healthy Chinese male volunteers.

BACKGROUND: Sulfadoxine/pyrimethamine fixed-dose combination (FDC) tablet is the long-acting portion of the antimalaria product Artecospe(®), coblister containing artesunate tablets plus sulfadoxine/pyrimethamine FDC tablets. This study was conducted to support the efficacy and tolerability of the sulfadoxine/pyrimethamine FDC tablet in the World Health Organization's (WHO) Prequalification of Medicines Programme, as well as to obtain marketing authorization in China. OBJECTIVE: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and the branded reference formulation of sulfadoxine/pyrimethamine FDC tablets, and to assess the bioequivalence of the 2 products in healthy Chinese volunteers. METHODS: This single-dose, open-label, randomized, parallel-group study was conducted in healthy Chinese male volunteers who were randomly assigned (1:1) to receive a single 1500/75-mg dose (3 × 500/25-mg tablets) of either the test or reference formulation after a 12-hour overnight fast. Seventeen blood samples were obtained over a 168-hour interval, and plasma concentrations of sulfadoxine and pyrimethamine were determined by 2 separate validated liquid chromatography-isotopic dilution mass spectrometry methods. Pharmacokinetic properties (C(max), AUC(0-72), AUC(0-168), and T(max)) were calculated and analyzed statistically. The 2 formulations were to be considered bioequivalent if 90% CIs for the log-transformed ratios of C(max) and AUC(0-72) were within the predetermined bioequivalence range of 80% to 125%, in accordance with the guidelines of WHO and China's Food and Drug Administration (FDA). Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12-lead ECGs, and subject interviews on adverse events (AEs). RESULTS: Forty-six healthy subjects completed the study. The mean values of sulfadoxine C(max) (183.07 and 165.15 mg/L), AUC(0-72) (11,036.52 and 10,536.78 mg/L/h), and AUC(0-168) (22,247.05 and 21,761.02 mg/L/h) were not significantly different between the test and reference formulations, respectively. The same was true for pyrimethamine (0.55 and 0.58 mg/L, 29.85 and 31.44 mg/L/h, and 56.18 and 59.27 mg/L/h, respectively). The 90% CIs for the log-transformed ratios of C(max), AUC(0-72), and AUC(0-168) of both sulfadoxine (105.4%-116.6%, 99.3%-110.6%, and 96.4%-108.1%) and pyrimethamine (88.8%-100.9%, 89.5%-101.0%, and 88.3%-101.6%) were within the acceptance limits for bioequivalence. A total of 7 mild AEs were reported in 7 subjects (15.2%). CONCLUSIONS: The findings from this single-dose (1500/75-mg) study suggest that the test and reference formulations of sulfadoxine/pyrimethamine FDC 500/25-mg tablet have similar pharmacokinetic profiles both in terms of rate and extent of absorption. The formulations met WHO's and China's FDA regulatory criteria for bioequivalence in these healthy Chinese volunteers under fasting conditions. Both formulations were generally well-tolerated.

Glycyrrhizin administration ameliorates coxsackievirus B3-induced myocarditis in mice.

In this study, the authors explored the therapeutic effect of glycyrrhizin (GL) on Coxsackievirus B3 (CVB3)-induced myocarditis and its possible mechanisms involved. The results of this study showed that GL exhibited a profound amelioration of CVB3-induced myocarditis, as evidenced by improved weight loss profile, less increased serological levels of cardiac enzymes, less myocardial inflammation and increased survival rate. Further study showed that this effect was not due to the viral clearance but ascribed to weakened proinflammatory responses, as evidenced by significantly reduced expression of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß and interleukin-6. Moreover, the authors demonstrated that GL administration inhibited CVB3-induced nuclear factor-κB activity efficiently by blocking the degradation of nuclear factor -κB inhibitor IκBκ. These data suggest that GL can effectively attenuate the severity of CVB3-induced myocarditis and may present as a new therapeutic approach for the treatment of viral myocarditis.