Neuropsychological impact of Sanda training on athlete attention performance.

Background: Sanda, a martial art that primarily involves punching, kicking, and throwing techniques, requires athletes to maintain high levels of concentration during combat. Sanda principally involves striking the opponent to secure victory, with trauma frequently occurring to the head; however, it remains unclear whether prolonged training enhances or impairs the athletes' attentional capacities. This study aimed to investigate the impact of Sanda training on athletes' attention by employing attention network tests. Methods: A retrospective analysis was conducted on 37 professional Sanda athletes from a certain sports academy; 38 college students from the same institution majoring in physical education were recruited as the control group. Control participants had no prior experience in Sanda training, and the Sanda and control groups were matched in terms of sex, age, and education level. The Attention Network Test (ANT) was administered to both groups to compare differences in efficiency across the alerting, orienting, and executive control networks. Results: Compared to the control group, the Sanda athletes exhibited significantly higher executive control network efficiency values and executive control network efficiency ratios (P < 0.05). There were no significant differences between the Sanda group and the control group regarding the efficiency values of the alerting and orienting networks (P > 0.05). Additionally, total accuracy and total reaction time between the Sanda athletes and control participants showed no statistically significant differences (P > 0.05). Conclusion: Sanda practice has detrimental effects on attention, including a decrease in the efficiency of the executive control network and a prolongation of the total reaction time. Therefore, athletes should improve attention training and use head protection to prevent frequent head impacts during training.

Qualitative and quantitative analysis of solid renal tumors by high-frame-rate contrast-enhanced ultrasound.

OBJECTIVE: To analyze the characteristics of high-frame-rate contrast-enhanced ultrasound (H-CEUS) in solid renal tumors using qualitative and quantitative methods. METHODS: Seventy-five patients who underwent preoperative conventional ultrasound (US), conventional contrast-enhanced ultrasound (C-CEUS), and H-CEUS examination of renal tumors were retrospectively analyzed, with a total of 89 renal masses. The masses were divided into the benign (30 masses) and malignant groups (59 masses) based on the results of enhanced computer tomography and pathology. The location, diameter, shape, border, calcification, and color doppler blood flow imaging (CDFI) of the lesions were observed by US, and the characteristics of the C-CEUS and H-CEUS images were qualitatively and quantitatively analyzed. The χ² test or Fisher's exact probability method was used to compare the US image characteristics between the benign and malignant groups, and the image characteristics of C-CEUS and H-CEUS between the benign and malignant groups. Moreover, the nonparametric Mann-Whitney test was used to compare the differences in C-CEUS and H-CEUS time-intensity curve (TIC) parameters. RESULTS: Significant differences in gender, surgical approach, echogenicity, and CDFI were observed between the malignant and benign groups (p = 0.003, < 0.001, < 0.001, = 0003). Qualitative analysis also revealed significant differences in the mode of wash-out and fill-in direction between C-CEUS and H-CEUS in the malignant group (p = 0.041, 0.002). In addition, the homogeneity of enhancement showed significant differences between the two contrast models in the benign group (p = 0.009). Quantitative analysis indicated that the TIC parameters peak intensity (PI), deceleration time (DT) /2, area under the curve (AUC), and mean transition time (MTT) were significantly lower in the H-CEUS model compared to the C-CEUS model in both the benign and malignant groups. (all p < 0.001). In contrast, ascending slope of rise curve (AS) was significantly higher in the H-CEUS model compared to the C-CEUS model in the malignant group (p = 0.048). CONCLUSIONS: In renal tumors, H-CEUS shows clearer internal enhancement of the mass and the changes in the wash-out period. The quantitative TIC parameters PI, DT/2, AUC, and MTT were lower in H-CEUS compared to C-CEUS. Both the quantitative and qualitative analyses indicated that H-CEUS better displays the characteristics of solid renal masses compared with C-CEUS.

Association of Sleep Duration with Risk of All-Cause and Cause-Specific Mortality Among American Adults: A Population-Based Cohort Study.

Objective: To examine potential factors affecting sleep duration and explore its association with the risk of mortality among adults in the United States. Methods: The study population consisted of adults aged 26 to 79 years who participated in the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2016. Sleep duration was classified into three categories: short (<7 hours), optimal (7-8 hours), and long (≥9 hours). The associations between sleep duration and both all-cause mortality and cause-specific mortality (including heart disease, tumors, cerebrovascular disease, and others) were examined in the overall population and subgroups using weighted Cox regression models. Dose-response associations between sleep duration and risk of all-cause mortality were explored using restricted cubic spline (RCS) analyses. Additionally, a multinomial logistic regression analysis was conducted to investigate potential factors that influence sleep duration in adults. Results: The study included a total of 24,141 subjects, with a population-weighted mean age of 48.93 years. Over 30% of the subjects exhibited unhealthy sleep habits. Fully adjusted models revealed that both short sleep duration (HR=1.169, 95% CI 1.027-1.331) and long sleep duration (HR=1.286, 95% CI 1.08-1.531), were associated with an increased risk of all-cause mortality. The RCS curves showed a U-shaped relationship between sleep duration and risk of all-cause mortality. Subgroup analyses showed a significant association between poor sleep patterns and all-cause mortality among adults aged 26-64 years, males, and non-Hispanic whites. Furthermore, multinomial logistic regression identified several predictors associated with short and long sleep durations. Conclusion: Both short and long sleep duration are associated with an increased risk of all-cause mortality, with a U-shaped dose-response relationship. It is imperative to implement appropriate primary prevention strategies aimed at monitoring and providing health education to populations at risk of developing unhealthy sleep patterns.

Quorum-Sensing Signal DSF Inhibits the Proliferation of Intestinal Pathogenic Bacteria and Alleviates Inflammatory Response to Suppress DSS-Induced Colitis in Zebrafish.

The imbalance of gut microbiota is an important factor leading to inflammatory bowel disease (IBD). Diffusible signal factor (DSF) is a novel quorum-sensing signal that regulates bacterial growth, metabolism, pathogenicity, and host immune response. This study aimed to explore the therapeutic effect and underlying mechanisms of DSF in a zebrafish colitis model induced by sodium dextran sulfate (DSS). The results showed that intake of DSF can significantly improve intestinal symptoms in the zebrafish colitis model, including ameliorating the shortening of the intestine, reducing the increase in the goblet cell number, and restoring intestinal pathological damage. DSF inhibited the upregulation of inflammation-related genes and promoted the expression of claudin1 and occludin1 to protect the tightness of intestinal tissue. The gut microbiome analysis demonstrated that DSF treatment helped the gut microbiota of the zebrafish colitis model recover to normal at the phylum and genus levels, especially in terms of pathogenic bacteria; DSF treatment downregulated the relative abundance of Aeromonas hydrophila and Staphylococcus aureus, and it was confirmed in microbiological experiments that DSF could effectively inhibit the colonization and infection of these two pathogens in the intestine. This study suggests that DSF can alleviate colitis by inhibiting the proliferation of intestinal pathogens and inflammatory responses in the intestine. Therefore, DSF has the potential to become a dietary supplement that assists in the antibiotic and nutritional treatment of IBD.

Age-Related Differences in Vancomycin-Associated Nephrotoxicity and Efficacy in Methicillin-Resistant Staphylococcus aureus Infection: A Comparative Study between Elderly and Adult Patients.

Elderly patients (age ≥ 65 years) are susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections, with potential for more adverse treatment outcomes or complications compared to younger adults (18-64 years). This study compared vancomycin-associated nephrotoxicity and efficacy in elderly and adult patients and investigated the correlation between vancomycin pharmacokinetic/pharmacodynamic (PK/PD) indices and clinical outcomes. A prospective study was conducted in 10 hospitals in Shanghai from October 2012 to November 2019. A total of 164 patients with MRSA infections were enrolled, including 83 elderly and 81 adult patients. Vancomycin therapeutic drug monitoring (TDM) was performed in all patients, indicating significantly higher vancomycin trough concentrations (Ctrough), 24-h area under the curve (AUC24) values, and AUC24/minimum inhibitory concentration (AUC24/MIC) values in elderly patients compared to adult patients. The incidence of vancomycin-associated nephrotoxicity was nearly three times higher in elderly patients (18.1% vs. 6.2%, p = 0.020), despite similar clinical and microbiological efficacy. Of particular importance, a Ctrough > 20 mg/L was found as an independent factor of nephrotoxicity in elderly patients. Further analysis of patients with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 also revealed that elderly patients had significantly higher vancomycin-related PK/PD indices and more nephrotoxicity than adult patients. In conclusion, elderly patients receiving vancomycin therapy face a higher risk of nephrotoxicity, which requires close vancomycin TDM, especially when the Ctrough exceeds 20 mg/L.

The Diagnostic Value of Ultrasound-guided Attenuation Parameter (UGAP) in metabolic fatty liver disease.

OBJECTIVES: To evaluate the diagnostic value of ultrasound-guided attenuation parameter (UGAP) in metabolic fatty liver disease (MAFLD) and to explore the correlation between the attenuation coefficient (AC) value of UGAP and commonly used clinical obesity indicators. METHODS: A total of 121 subjects who had physical examinations from November 2021 to March 2022 were prospectively selected; the height, weight, and waist circumference (WC) of all subjects were collected, and conventional ultrasound and UGAP examinations for all subjects. RESULTS: Under the standard of conventional ultrasound, among the 121 subjects, 53 had normal liver, 42 had mild fatty liver, 21 had moderate fatty liver, and 5 had severe fatty liver. The mean AC value of 121 patients was 0.66 ± 0.13 dB/cm/MHz. The best cut-off values for diagnosing mild, moderate, and severe fatty liver were 0.65dB/cm/MHz, 0.72dB/cm/MHz, and 0.83dB/cm/MHz, respectively. The area under the curve (AUC) values were 0.891, 0.929, and 0.914, respectively. When grouped by WC, there was a statistically significant difference in AC value between the normal group and the obese group (t=-4.675, P<0.001). Overall WC and within group WC were moderately correlated with the AC value of UGAP (P<0.001). CONCLUSIONS: UGAP has a good diagnostic value in the quantitative evaluation of liver steatosis in MAFLD, and the change of WC can reflect the occurrence of liver steatosis to a certain extent.

A randomised, double-blind, placebo-controlled, first-in-human phase I study to characterise the safety, pharmacokinetics and immunogenicity of 9MW1411 in healthy Chinese subjects.

INTRODUCTION: 9MW1411 is a humanised monoclonal antibody against Staphylococcus aureus alpha-toxin. The safety, pharmacokinetics (PK) and immunogenicity of 9MW1411 should be characterised in humans before further clinical development. METHODS: A single-centre, randomised, double-blind, placebo-controlled phase I clinical study was conducted in humans for the first time. A total of 42 healthy Chinese subjects were randomised to receive a single ascending dose of 9MW1411 (200, 600, 1500, 3000 or 5000 mg) or placebo. Safety, PK parameters and anti-drug antibody (ADA) were analysed. Monte Carlo simulations (MCS) were performed to predict the probability of target attainment (PTA) after single dose IV administration of 1500, 3000 and 5000 mg of 9MW1411. RESULTS: Thirty-four subjects received 9MW1411, completed the study and were included in data analysis. Five cases of drug-related AEs occurred in four subjects. All the adverse events (AEs) were mild or moderate. The Cmax, AUC0-t and AUC0-∞ of 9MW1411 increased with dose after IV administration of 200 to 5000 mg 9MW1411. The mean Cmax increased from 85.40 ± 5.43 to 2082.11 ± 343.10 µg/mL and AUC0-∞ from 29,511.68 ± 5550.91 to 729,985.49 ± 124,932.18 h·µg/mL. The elimination half-life (T1/2) was 19-23 days. 9MW1411 ADA was positive in three subjects. MCS indicated that a single dose of 3000 or 5000 mg 9MW1411 could achieve PTA > 90% for S. aureus. CONCLUSIONS: 9MW1411 has shown a good safety profile in healthy Chinese subjects after a single dose up to 5000 mg. A single dose of 3000 mg 9MW1411 is appropriate for use in subsequent studies.

Population pharmacokinetics and exposure-safety of lipophilic conjugates prodrug DP-VPA in healthy Chinese subjects for dose regime exploring.

Phospholipid-valproic acid (DP-VPA)is a prodrug for treating epilepsy. The present study explored the pharmacokinetics (PK) and exposure safety of DP-VPA to provide a basis for future studies exploring the safe dosage and therapeutic strategies for epilepsy. The study included a randomized placebo-controlled dose-escalation tolerance evaluation trial and a randomized triple crossover food-effect trial in healthy Chinese volunteers. A population pharmacokinetic (PopPK) model was established to analyze the PK of DP-VPA and active metabolite VPA. The exposure safety was assessed with the adverse drug reaction (ADR) in CNS. The PopPK of DP-VPA and metabolite VPA fitted a two-compartment model coupling one-compartment with Michaelis-Menten metabolite kinetics and first-order elimination. The absorption processes after single oral administration of DP-VPA tablet demonstrated nonlinear characteristics, including 0-order kinetic phase and time-dependent phase fitting Weibull distribution. The final model indicated that the DP-VPA PK was significantly affected by dosage and food. The exposure-safety relationship demonstrated a generalized linear regression; mild/moderate ADRs occurred in some subjects with 600 mg and all subjects with 1500 mg of DP-VPA, and no severe ADRs were reported up to 2400 mg. In conclusion, the study established a PopPK model describing the processing of DP-VPA and VPA in healthy Chinese subjects. DP-VPA showed good tolerance after a single dose of 600-2400 mg with nonlinear PK and was affected by dosage and food. Based on the association between neurological ADRs and higher exposure to DP-VPA by exposure-safety analysis, 900-1200 mg was recommended for subsequent study of safety and clinical effectiveness.

Contrast-enhanced Ultrasound of Xanthogranulomatous Endometritis: A Case Report and Literature Review.

Xanthogranulomatous endometritis (XGE) is a rare inflammatory disease, which can easily misdiagnose as cancer in imaging diagnosis. Diagnosis of XGE relies on histopathological examination and immunohistochemistry. In this study, a case of a 72-year-old female with XGE and elevated CA125 is presented, which was misdiagnosed as endometrial cancer in transvaginal ultrasonography and ovarian cystadenocarcinoma in CT. However, the features of XGE on the contrast-enhanced ultrasound (CEUS) were different from that of endometrial cancer. The patient finally underwent laparoscopic hysterectomy and bilateral adnexectomy. The histopathological examination and immunohistochemistry suggested xanthogranulomatous endometritis (histiocytic endometritis). This case report manifests that CEUS may be a new noninvasive diagnostic method for XGE, which may reduce extensive tissue sampling and unnecessary hysterectomies for patients.

Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis.

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0-24h, 106.79 vs. 97.07 h µg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 µg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0-48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0-48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. Clinical Trial Registration: https://chinadrugtrials.org.cn, identifier: CTR20171377.

A simple and rapid HPLC-MS/MS method for therapeutic drug monitoring of amikacin in dried matrix spots.

Individualized treatment of amikacin under the guidance of therapeutic drug monitoring (TDM) is important to reduce the occurrence of toxicity and improve clinical efficacy. In the present study, we developed and validated a simple and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentration of amikacin in dried matrix spots (DMS) which the matrix is serum. DMS samples were obtained by spotting volumetric blood onto Whatman 903® cards. Samples were punched into 3 mm diameter discs and extracted with 0.2 % formic acid in water. The HILIC column (2.1 mm × 100 mm, 3.0 µm) under gradient elution was applied, and the analysis time was 3 min per injection. The mass spectrometry transitions were m/z 586.3 → 163.0 for amikacin and m/z 591.4 → 163.1 for D5-amikacin. Full validation was conducted for DMS method, and the method was applied for the amikacin TDM and compared with serum method. The linearity was ranged from 0.5 to 100 mg/L. Both within-run and between-run accuracy and precision of DMS ranged from 91.8 % to 109.6 % and 3.6 % to 14.2 %, respectively. The matrix effect was 100.5 %-106.5 % of DMS method. Amikacin remained stable in DMS for at least 6 days at room temperature, 16 days at 4 °C, 86 days at -20 °C and -70 °C. A good agreement between the DMS method and serum method has been shown in Bland-Altman plots and Passing-Bablok regression. All of the results demonstrated that the DMS methods can be a favorable replacement for amikacin TDM.

Population pharmacokinetics of levornidazole in healthy subjects and patients, and sequential dosing regimen proposal using pharmacokinetic/pharmacodynamic analysis.

Although sequential treatment with levornidazole has been used for anaerobic infection in clinical practice, there is no evidence-based dosing regimen. This study aimed to evaluate the pharmacokinetics (PK) of levornidazole in healthy subjects and patients, and to propose an evidence-based sequential dosing regimen by pharmacokinetic/pharmacodynamic (PK/PD) analysis. A population PK model was built using the data of 116 Chinese subjects, including 88 healthy young subjects, 12 healthy elderly subjects, and 16 patients with intra-abdominal anaerobic infection. PK/PD analysis was performed combining the minimum inhibitory concentration (MIC) values of levornidazole against 375 anaerobic strains. Four sequential dosing regimens (500 mg q12h, 1000 mg loading dose followed by 500 mg q12h, 750 mg q24h, and 1000 mg q24h) were evaluated in terms of cumulative fraction of response (CFR) and probability of target attainment (PTA) by Monte Carlo simulation. The concentration data of levornidazole and its active metabolites were described adequately by two- and one-compartment models, respectively. Body weight was identified as a significant covariate of levornidazole clearance. Simulations showed that satisfactory PTA (>90%) was achieved for the four dosing regimens when MIC ≤1 mg/L. Considering the simulation results, patients' safety and compliance, levornidazole 750 mg intravenous infusion q24h for 2 days followed by 750 mg oral dose q24h for 5 days was optimal for Bacteroides spp. with an identified MIC ≤1 mg/L.

Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses of Mirogabalin in Healthy Chinese Participants: A Randomized, Double-Blind, Placebo-Controlled Study.

INTRODUCTION: Mirogabalin is a treatment option for patients with neuropathic pain; however, safety, tolerability, and pharmacokinetics (PK) data specifically for Chinese individuals are limited to a single-dose study. We aimed to assess these for both single- and multiple-dose mirogabalin in healthy Chinese participants. METHODS: In this randomized, double-blind, placebo-controlled, phase I study, 54 healthy Chinese men and women aged 18-45 years were randomly allocated to receive single- (5, 10, or 15 mg, daily) or multiple-dose (5 mg titrated to 15 mg, twice-daily, over 22 days) oral mirogabalin or placebo. In each of three single-dose groups, 10 participants received mirogabalin and 2 received placebo; in the multiple-dose group, 14 participants received mirogabalin and 4 received placebo. The primary endpoints were PK, safety, and tolerability variables, including treatment-emergent adverse events (TEAEs), laboratory tests, and vital signs. PK data were collected for both single- and multiple-dose cohorts and evaluated by non-compartmental analysis. RESULTS: Single- and multiple-dose mirogabalin was generally well tolerated with no deaths, serious TEAEs, or TEAEs leading to treatment discontinuation. Frequently reported TEAEs included dizziness, nystagmus, increased blood triglycerides, headache, and increased blood uric acid and creatine phosphokinase. Single-dose mirogabalin was rapidly absorbed (median time to maximum plasma concentration, 1.00 h) and eliminated (mean terminal elimination half-life, 2.57-3.08 h). The exposure was approximately dose-proportional. In the multiple-dose cohort, the trough plasma concentration increased dose-proportionally, and exposure and clearance were comparable to that following a single 15-mg dose. The mean cumulative amount excreted into urine up to 48 h post-dose increased in a dose-proportional manner, the mean cumulative percentage excreted into urine was 61.9%-74.3%, and renal clearance remained relatively constant. CONCLUSION: Consistent with previous phase I studies in other populations, mirogabalin was safe and well tolerated in healthy Chinese participants at single and multiple doses of up to 15 mg twice-daily.

Safety and clinical efficacy of linezolid in children: a systematic review and meta-analysis.

BACKGROUND: We aimed to evaluate the tolerability and efficacy of linezolid in children for treating suspected and diagnosed Gram-positive bacterial infections. METHODS: A systematic literature search was conducted up to April 23, 2021, using linezolid and its synonyms as search terms. Two reviewers independently identified and extracted relevant randomized controlled trials and prospective cohort studies. The extracted studies were included in a single-rate meta-analysis of adverse events and clinical outcomes using random-effects models. RESULTS: A total of 1082 articles were identified, and nine studies involving 758 children were included in the meta-analysis. The overall proportion of adverse events was 8.91% [95% confidence interval (CI) = 1.64%-36.52%], with diarrhea (2.24%), vomiting (2.05%), and rash (1.72%) being the most common. The incidences of thrombocytopenia and anemia were 0.68% and 0.16%, respectively. Some specific adverse events, including rash and gastrointestinal events, were more frequent in the oral administration subgroup. In terms of efficacy, the overall proportion of clinical improvement was 88.80% (95% CI = 81.31%-93.52%). Children with a history of specific bacteriological diagnosis or concomitant antibiotic therapy had a 1.13-fold higher clinical improvement than children without such histories. The proportion of microbial eradication was 92.68% (95% CI = 84.66%-96.68%). The proportion of all-cause mortality was 0.16% (95% CI = 0.00%-7.75%). CONCLUSIONS: Linezolid was well-tolerated in pediatric patients and was associated with a low frequency of adverse events, such as anemia, thrombocytopenia, and neutropenia. Moreover, linezolid was effective in children with diagnosed and suspected Gram-positive infections.

Recombinant Virus-like Particles of Human Parvovirus B19 with the Internal Location of VP1 Unique Region Produced by Hansenula polymorpha.

Human parvovirus B19 (HPV B19) is pathogenic to human, which can cause fifth disease, transient aplastic crisis, arthritis, myocarditis, autoimmune disorders, hydrops fetalis, and so on. Currently, no approved vaccines or antiviral drugs are available against HPV B19, and thus the development of effective vaccines is needed. The capsid of HPV B19 is composed of two types of proteins, i.e., the major capsid protein VP2 and the minor protein VP1. Previous experimental studies have shown that the dominant immune responses against HPV B19 are elicited by VP1, especially the unique region on the N-terminus of VP1. It has been found that VP2 alone or VP2 and VP1 together can assemble into virus-like particle (VLP). The VLP structure formed by VP2 has been resolved, however, the location of VP1 in the capsid, especially the location of VP1 unique region with strong immunogenicity, is still not clear. In the present work, using the Hansenula polymorpha expression system developed by our laboratory, two kinds of recombinant HPV B19 VLPs were expressed, i.e., the VLP co-assembled by VP1 and VP2 (VP1/VP2 VLP) and the VLP whose VP1 content was improved (VP1h/VP2 VLP). The expression, purity, and morphology of these two VLPs were characterized, and then their immunogenic properties were investigated and compared with those of the VLP containing VP2 alone (VP2 VLP) previously developed by our group. Furthermore, the location of the VP1 unique region in the VLPs was determined by using the immunogold electron microscopy (IGEM). Our experimental results show that the VP1h/VP2 VLP elicits a stronger neutralization against the HPV B19 than VP2 and VP1/VP2 VLPs, which implies that the increase of VP1 content significantly improves the level of neutralizing antibodies. In addition, the IGEM observations suggest that the unique region of VP1 may be located inside the recombinant VLP. The VLPs recombinantly expressed by our Hansenula polymorpha system may serve as a promising candidate immunogen for HPV B19 vaccine development.

Pharmacokinetics and Safety of Doripenem in Healthy Chinese Subjects and Monte Carlo Dosing Simulations.

The aim of this study was to investigate the pharmacokinetics (PK) of doripenem in healthy Chinese subjects and evaluate the optimal dosage regimens of doripenem. A randomized, single-dose, three-period, self-crossover controlled extended-infusion clinical trial was conducted with 12 healthy Chinese subjects. Plasma and urine samples were collected to determine doripenem concentrations. Non-compartmental and population PK analysis were performed to characterize the PK of doripenem. The Monte Carlo simulation was employed to optimize dosing regimens based on the probability of target attainment of doripenem against pathogens with different minimum inhibitory concentrations (MIC). All 12 healthy Chinese subjects completed the study, and the doripenem was well tolerated. The study showed linearity relationships in the peak plasma concentration and the area under the concentration-time curve after intravenous infusion of doripenem from 0.25 g to 1.0 g. The cumulative urinary recovery rate of doripenem was 68.1-72.0% within 24 h. PPK modeling showed a two-compartmental model, with first-order elimination presenting the best fit for doripenem PK. Monte Carlo simulation results showed that 1.0 g q12h or 0.5 g q8h was an optimal regimen for pathogens susceptible to doripenem (MIC ≤ 1 mg/L); while high dose and extended infusion (1 g, q8h, 4 h infusion) was proposed for unsusceptible pathogens (2 ≤ MIC ≤ 8 mg/L). In the dose range of 0.25 to 1.0 g, doripenem showed linear pharmacokinetics. Doripenem at 1.0 g with a prolonged infusion time of 4 h was predicted to be effective against pathogens with MICs as high as 8 mg/L.

Pharmacokinetics and Pharmacodynamics of Colistin Methanesulfonate in Healthy Chinese Subjects after Multi-Dose Regimen.

Colistin methanesulfonate (CMS) is an important treatment option for infections caused by carbapenem-resistant Gram-negative organisms (CROs). This study evaluated the pharmacokinetic/pharmacodynamic (PK/PD) profiles and safety of CMS in Chinese subjects following a recommended dosage. A total of 12 healthy Chinese subjects received CMS injections at 2.5 mg/kg once every 12 h for 7 consecutive days. The PK/PD profiles of the active form of CMS, colistin, against CROs were analyzed with the Monte Carlo simulation method. No serious adverse events were observed. The average steady-state plasma concentrations of CMS and colistin were 4.41 ± 0.75 µg/mL and 1.27 ± 0.27 µg/mL, and the steady-state exposures (AUC0−12,ss) were 52.93 ± 9.05 h·µg/mL and 15.28 ± 3.29 h·µg/mL, respectively. Colistin, at its minimum inhibitory concentration (MIC) of 0.5 µg/mL, has >90% probability to reduce CROs by ≥1 log. The PK/PD breakpoints for the ≥1 log kill were ≥MIC90 for carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa, but were ≤MIC50 for carbapenem-resistant Acinetobacter baumannii. The recommended dose regimen of CMS for 7 consecutive days was safe in Chinese subjects. The systemic exposure of colistin showed a high probability of being sufficient for most CROs, but was not sufficient for some carbapenem-resistant A. baumannii.

Clinical Pharmacology and Utility of Contezolid in Chinese Patients with Complicated Skin and Soft-Tissue Infections.

This study aimed to build a population pharmacokinetic (PopPK) model for contezolid tablet (MRX-I) in healthy subjects and adults with complicated skin and soft-tissue infections (cSSTIs) to further evaluate the efficacy and safety of contezolid and recommend the optimal dosing regimen based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. PopPK analysis was performed using a nonlinear mixed-effects model (NONMEM) to examine the effects of age, body weight, sex, liver and renal functions, albumin, food, dosage strength, and subject type on the PK parameters of contezolid. PK/PD analysis was combined with the MIC of contezolid, clinical/microbiological efficacy, and nonclinical study data. Adverse events (AEs) and study drug-related AEs reported were summarized to examine the relationship between contezolid exposure level and safety measures. A two-compartment model was built. An exponential model was used to describe the interindividual variation. A proportional model was used to describe the intraindividual variation of PK parameters. Good clinical and microbiological efficacy are expected for the infections caused by S. aureus when contezolid is administered at 600 mg or 800 mg every 12 h (q12h). The area under the concentration-time curve from 0 to 24 h at steady state and maximum concentration of drug in serum at steady state of contezolid did not show significant association with the incidence of any AE. The dosing regimen of contezolid at 800 mg q12h administered postprandially for 7 to 14 days is expected to achieve satisfactory clinical and microbiological efficacy in cSSTIs, which is slightly better than that of 600 mg contezolid. This administration has been added to the prescribing information of contezolid tablets.

Case Report: Therapeutic Drug Monitoring of Polymyxin B During Continuous Renal Replacement Therapy in Two Pediatric Patients: Do Not Underestimate Extracorporeal Clearance.

Background: Polymyxin B has become the last choice for patient with carbapenem-resistant bacterial infection. However, the optimal dosing of polymyxin B in critically ill children receiving continuous renal replacement therapy (CRRT) remains unclear. Case Presentation: Two cases of critically ill pediatric patients (7 years old) with acute kidney injury requiring continuous renal replacement (CRRT) received polymyxin B treatment due to carbapenem-resistant organism bloodstream infections. Therapeutic drug monitoring (TDM) of polymyxin B was carried out by liquid chromatography tandem mass spectrometry (LC-MS/MS). The average steady-state plasma concentration (Css,avg) of 2-4 mg/L was set as the target level. Initial polymyxin B dose was 1 mg/kg every 12 h, and the Css,avg at 4-5th dosing were 1.76 and 1.06 mg/L for patient 1 and patient 2, respectively. TDM-guided polymyxin B dose was escalated to 2 mg/kg every 12 h for both patients, resulting in the Css,avg of 2.60 and 1.73 mg/L, and the infection was controlled subsequently. Css,avg of polymyxin B with the same dosing regimens and infusion length were different during CRRT and after termination of CRRT for both patients (2.60 mg/L vs. 4.94 mg/L with 2 mg/kg every 12 h in 2 h infusion for patient 1; and 1.73 mg/L vs. 3.53 mg/L with 2 mg/kg every 12 h in 2 h infusion for patient 2). The estimation of drug exposure (estimated by AUCss,12h at the same dose) during CRRT and cessation of CRRT showed that 45% and 51% of polymyxin B was cleared during CRRT. Conclusion: Our study showed high clearance of polymyxin B through CRRT, and supplanted dosing of polymyxin B is necessary in pediatric patients undergoing CRRT.

Proteomic Response Revealed Signaling Pathways Involving in the Mechanism of Polymyxin B-Induced Melanogenesis.

Polymyxin B is a last-line antibiotic for extensively resistant Gram-negative bacterial infection. Skin hyperpigmentation is a serious side effect induced by polymyxin B that severely compromises the psychological health and compliance of patients. The literature lacks mechanistic studies that explain how hyperpigmentation occurs, and this substantially hinders the development of intervention strategies and improved compliance. SK-MEL-2 cells were used for the polymyxin B-induced hyperpigmentation mechanism study. Melanin content and tyrosinase activity were measured after polymyxin B treatment. Tandem mass tag (TMT)-labeling quantitative proteomics was employed to investigate the response of SK-MEL-2 cells to polymyxin B treatment. Real-time quantitative PCR and Western blot were applied to validate the mRNA and protein levels of related genes and proteins. The melanin content and tyrosinase activity were significantly upregulated after polymyxin B treatment in SK-MEL-2 cells at 48 h and 72 h. Quantitative proteomics showed that 237 proteins were upregulated and 153 proteins were downregulated in the 48 h group, and 49 proteins were upregulated and 49 proteins were downregulated in the 72 h group. The differentially expressed proteins were involved in pathways such as lysosome, PI3K/Akt signaling pathway, and calcium signaling pathway. The upregulation of melanogenic enzymes and microphthalmia-associated transcription factor (MITF) was validated by qPCR and Western blot. Meanwhile, phosphorylation of PI3K, ß-catenin, and cyclic-AMP response binding protein (CREB) in response to polymyxin B treatment was observed. The present study reveals the proteomic response of polymyxin B-induced melanogenesis in SK-MEL-2 cells for the first time. Signaling pathways, including melanin biosynthesis, PI3K/Akt, and calcium signaling pathways may be involved in the mechanism of melanogenesis. IMPORTANCE Polymyxin B-induced skin hyperpigmentation seriously affects the psychological health and compliance of patients. This study provides a proteomic clue to the mechanism at the cellular level for understanding polymyxin B-induced hyperpigmentation, contributing to a follow-up investigation of the corresponding PI3K/Akt signaling transduction pathway and calcium signaling pathway. The elucidation of its underlying mechanism is of great significance for patients' compliance improvement, intervention strategy, and new drug development.