Population pharmacokinetics and dose optimization of levofloxacin in elderly patients with pneumonia.

AIMS: Levofloxacin is a quinolone antibiotic with a broad antibacterial spectrum. It is frequently used in elderly patients with pneumonia. The pharmacokinetic profile of elderly patients changes with age, but data on the pharmacokinetics of levofloxacin in these patients are limited. The aim of this study was to establish a population pharmacokinetic model of levofloxacin in elderly patients with pneumonia and to optimize individualized dosing regimens based on this newly developed model. METHODS: This is a prospective, open-label pharmacokinetic study in elderly patients with pneumonia. Blood samples were collected using an opportunistic approach. The plasma concentrations of levofloxacin were determined by high-performance liquid chromatography. A population pharmacokinetic model was established using nonlinear mixed-effect model software. Monte Carlo simulations were used for dose simulation and dose optimization. RESULTS: Data from 51 elderly patients with pneumonia were used for the population pharmacokinetic analysis. A one-compartment model with first-order elimination was most suitable for describing the data, and the estimated glomerular filtration rate was the only covariate that had a significant impact on the model. The final model estimated that the mean clearance of levofloxacin in elderly patients with pneumonia was 5.26 L/h. Monte Carlo simulation results showed that the optimal dosing regimen for levofloxacin was 750 mg once a day in elderly patients with pneumonia, with a minimum inhibitory concentration of 2 mg/L. CONCLUSIONS: The population pharmacokinetic model of levofloxacin in elderly patients with pneumonia was established, and the dose optimization of levofloxacin was completed through Monte Carlo simulation.

Do high house prices promote the development of China's real economy? Empirical evidence based on the decomposition of real estate price.

Moderate rising of house prices are beneficial to the economic development. However, over high house prices worsen the economic distortions and thus hinder the development of the real economy. We use the stochastic frontier models to calculate the fundamental value in the housing in Chinese large and medium cities, and then obtain indexes which could measure the house prices' deviations from the fundamental value. With the macroeconomic data in the city-level, this paper empirically investigates the effects of the house prices' deviations on macro-economic variables like consumption, investment and output. The study reveals that the housing bubble exists in most Chinese cities, and first-tier cities fare the worst. House prices over the fundamental value, which could increase the scale of real estate investment, bring adverse impacts on GDP, as it causes declining civilian consumption and discourages real economy's investment and production. The encouragement and the discouragement on macroeconomy caused by house prices' deviation from its basic value take turns to play a key role in the process of China' eco-nomic growth. In the early stage of China's economic growth, the encouragement effect predominates. As urbanization and industrialization gradually upgrade to a higher level, the discouragement effect takes charge.

Evolutionary dynamics in financial markets with heterogeneities in investment strategies and reference points.

In nature and human societies, the effects of homogeneous and heterogeneous characteristics on the evolution of collective behaviors are quite different from each other. By incorporating pair pattern strategies and reference point strategies into an agent-based model, we have investigated the effects of homogeneous and heterogeneous investment strategies and reference points on price movement. In the market flooded with the investors with homogeneous investment strategies or homogeneous reference points, large price fluctuations occur. In the market flooded with the investors with heterogeneous investment strategies or heterogeneous reference points, moderate price fluctuations occur. The coexistence of different kinds of investment strategies can not only refrain from the occurrence of large price fluctuations but also the occurrence of no-trading states. The present model reveals that the coexistence of heterogeneous populations, whether they are the individuals with heterogeneous investment strategies or heterogeneous reference points of stock prices, is an important factor for the stability of the stock market.

Assessment of breast lesions by the Kaiser score for differential diagnosis on MRI: the added value of ADC and machine learning modeling.

OBJECTIVES: To evaluate the diagnostic performance of Kaiser score (KS) adjusted with the apparent diffusion coefficient (ADC) (KS+) and machine learning (ML) modeling. METHODS: A dataset of 402 malignant and 257 benign lesions was identified. Two radiologists assigned the KS. If a lesion with KS > 4 had ADC > 1.4 × 10-3 mm2/s, the KS was reduced by 4 to become KS+. In order to consider the full spectrum of ADC as a continuous variable, the KS and ADC values were used to train diagnostic models using 5 ML algorithms. The performance was evaluated using the ROC analysis, compared by the DeLong test. The sensitivity, specificity, and accuracy achieved using the threshold of KS > 4, KS+ > 4, and ADC ≤ 1.4 × 10-3 mm2/s were obtained and compared by the McNemar test. RESULTS: The ROC curves of KS, KS+, and all ML models had comparable AUC in the range of 0.883-0.921, significantly higher than that of ADC (0.837, p < 0.0001). The KS had sensitivity = 97.3% and specificity = 59.1%; and the KS+ had sensitivity = 95.5% with significantly improved specificity to 68.5% (p < 0.0001). However, when setting at the same sensitivity of 97.3%, KS+ could not improve specificity. In ML analysis, the logistic regression model had the best performance. At sensitivity = 97.3% and specificity = 65.3%, i.e., compared to KS, 16 false-positives may be avoided without affecting true cancer diagnosis (p = 0.0015). CONCLUSION: Using dichotomized ADC to modify KS to KS+ can improve specificity, but at the price of lowered sensitivity. Machine learning algorithms may be applied to consider the ADC as a continuous variable to build more accurate diagnostic models. KEY POINTS: • When using ADC to modify the Kaiser score to KS+, the diagnostic specificity according to the results of two independent readers was improved by 9.4-9.7%, at the price of slightly degraded sensitivity by 1.5-1.8%, and overall had improved accuracy by 2.6-2.9%. • When the KS and the continuous ADC values were combined to train models by machine learning algorithms, the diagnostic specificity achieved by the logistic regression model could be significantly improved from 59.1 to 65.3% (p = 0.0015), while maintaining at the high sensitivity of KS = 97.3%, and thus, the results demonstrated the potential of ML modeling to further evaluate the contribution of ADC. • When setting the sensitivity at the same levels, the modified KS+ and the original KS have comparable specificity; therefore, KS+ with consideration of ADC may not offer much practical help, and the original KS without ADC remains as an excellent robust diagnostic method.

Cost-effectiveness evaluation of different control strategies for Clonorchis sinensis infection in a high endemic area of China: A modelling study.

Clonorchiasis is an important food-borne parasitic disease caused by Clonorchis sinensis infection. The evaluation of long-term cost-effectiveness of control strategies is important for disease control and prevention. The present study aimed to assess the cost-effectiveness of the three recommended strategies (i.e., WHO, Chinese and Guangdong strategies) and different combinations of commonly used measures (i.e., preventive chemotherapy, information, education, and communication (IEC) and environmental improvement) on clonorchiasis. The study area, Fusha town in Guangdong Province, was a typical high endemic area in China. The analysis was based on a multi-group transmission model of C. sinensis infection. We set the intervention duration for 10 years and post-intervention period for 50 years. The corresponding costs and DALYs were estimated. Strategies with incremental cost-effectiveness ratios (ICERs) less than 1/5 of the willingness-to-pay threshold were identified as highly cost-effective strategies. The optimal control strategy was obtained using the next best comparator method. The ICERs of Guangdong strategy were $172 (95% CI: $143-$230) US for praziquantel and $106 (95% CI: $85-$143) US for albendazole, suggesting the highest cost-effectiveness among the three recommended strategies. For praziquantel, 470 sets of control strategies were identified as highly cost-effective strategies for achieving infection control (prevalence<5%). The optimal strategy consisted of chemotherapy targeted on at-risk population, IEC and environmental improvement, with coverages all being 100%, and with the ICER of $202 (95% CI: $168-$271) US. The results for transmission control (prevalence<1%) and albendazole were obtained with the same procedures. The findings may help to develop control policies for C. sinensis infection in high endemic areas. Moreover, the method adopted is applicable for assessment of optimal strategies in other endemic areas.

Osteogenic inducer sustained-release system promotes the adhesion, proliferation, and differentiation of osteoblasts on titanium surface.

OBJECTIVE: Biomaterial can be locally applied to promote the osseointegration of dental implants. This study aimed to fabricate an osteogenic inducer (OI) sustained-release system and to evaluate its effects on the adhesion, proliferation, and differentiation of osteoblasts on titanium surfaces. METHODS: First of all, different contents of OI solution were added to the poly (lactic-co-glycolic acid) (PLGA) gel individually to investigate the best physical properties and drug-release rate. Moreover, osteoblasts were isolated from the calvaria of two-month-old New Zealand rabbits through sequential enzymatic digestion. Osteoblasts were seeded onto the surface of Ti disks (control group), Ti coated with PLGA gel (PLGA group), and Ti coated with the OI sustained-release system (PLGA+OI group). Cell adhesion was observed by scanning electron microscopy. Cell proliferation was analyzed by cell counting kit-8. Cell differentiation was tested by alizarin red staining, alkaline phosphatase (ALP) activity and osteogenic-related gene expression. RESULTS: The OI sustained-release system contained 15% OI solution had appropriate physical properties and drug-release rate. The osteoblasts in the PLGA+OI group were in a typical spindle shape with a considerable number indicating the promotion of adhesion and proliferation. The expression of early and late stage osteoblast differentiation genes in the PLGA+OI group were significantly higher than that of the control group and PLGA group at each time point. The PLGA group showed accelerated adhesion and differentiation but reduced proliferation compared with the control. CONCLUSION: The OI sustained-release system promotes the adhesion, proliferation, and differentiation of osteoblasts on titanium surfaces. This system is a cost-effective osteoconductive biomaterial that might be promising for use in dental implantation.

Integrated assessment of CDK1 upregulation in thyroid cancer.

Cyclin-dependent kinase 1 (CDK1) has a unique role in cell cycle regulation, as it is crucial for cell cycle progression and cell division. The aim of the present study was to use a combination of various detection methods to examine the expression and clinical significance of CDK1 in thyroid cancer (THCA). We used in-house tissue microarrays, immunohistochemistry, public RNA-sequencing, gene microarrays, and meta-analyses to conduct a comprehensive analysis of the role of CDK1 in the occurrence and development of THCA. CDK1 protein expression was notably higher in THCA tissues than in non-cancer tissues as evidenced by the in-house tissue microarrays. The expression of CDK1 protein was also significantly higher in pathologic T3-T4 than in T1-T2 samples. The pooled standardized mean difference (SMD) for CDK1 was 0.71 (95% CI, 0.46-0.95) including a total of 931 THCA and 585 non-cancerous thyroid tissue samples. An aggregation of the immunohistochemistry results and the RNA-sequencing/microarray findings gave a pooled SMD for CDK1 expression of 2.13 (95% CI, 1.30-2.96). The final area under curve (AUC) for the summarized receiver operating characteristic (sROC) was 0.7941 using all 1102 cases of THCA and 672 cases of controls. KEGG analysis with the co-expressed genes of CDK1 in THCA demonstrated the top enriched pathways to be the cell cycle, thyroid hormone synthesis, autoimmune thyroid disease, etc. In summary, we reveal the overexpression of CDK1 in THCA based on multiple detection methods that combine independent cohorts. However, further studies are required to elucidate the molecular mechanisms of CDK1 that promotes the biological aggressiveness of THCA cells.

[Responses of ecosystem carbon budget to increasing nitrogen deposition in differently degraded Leymus chinensis steppes in Inner Mongolia, China].

Based on a field manipulative nitrogen (N) addition experiment, the effects of atmospheric N deposition level change on the plant biomass and net primary productivity (NPP), soil respiration (Rs) and net ecosystem exchange (NEE) were investigated respectively in 2009 and 2010 in two differently degraded Leymus chinensis steppes in Inner Mongolia of China, and the difference in the response of NEE to equal amount of N addition [10 g x (M2 x a)(-1), MN] between the two steppes was also discussed. The results indicated that for the light degraded Leymus chinensis steppe (site A) , the average plant aboveground biomass (AGB) in MN treatment were 21.5% and 46.8% higher than those of CK in these two years. But for the moderate degraded Leymus chinensis steppe (site B), the N addition decreased the plant AGB and ANPP in 2009, while showed positive effects in 2010. N addition increased the belowground biomass (BGB) of the both sites and belowground NPP (BNPP) of site B in both years, but decreased the BNPP of site A in 2010. The increase of N input in the two steppes did not change the seasonal variation of Rs. The cumulative annual soil C emissions in MN treatment in site A showed an increase of about 14.6% and 25.7% of those in the CK respectively for these two years, while were decreased by about 10.4% and 11.3%, respectively in site B. The NEE of MN treatments, expressed by C, for the two steppes were 59.22 g x (m2 x a)(1) and 166.68 g x (m2 x a)(-1), as well as 83.27 g x (m2 x a)(-1) and 117.47 g x (m2 x a)(-1), respectively in these two years. The increments in NEE originated from N addition for these two years were 15.79 g x (M2 x a)(-1) and 82.94 g x (M2 x a)(-1) in site A and 74.54 g x (M2 x a)(-1) and 101.23 g x (M2 x a)(-1) in site B. The N input per unit could obtain greater C sink effect in the steppe with lower initial N level.

Prospective echocardiographic assessment of cardiac structure and function in Chinese persons living with HIV.

BACKGROUND: Persons living with human immunodeficiency virus (HIV) are at increased risk of developing cardiovascular disease. Few studies have focused on echocardiographic abnormalities in this population. METHODS: China AIDS Clinical Trial 0810 is a prospective, multicenter cohort study of persons living with HIV (PLWH). We performed an echocardiography substudy of 325 PLWH. We examined the prevalence of left ventricular systolic dysfunction (LVSD), diastolic dysfunction (DD), pulmonary arterial hypertension (PAH), and increased left ventricular mass (ILVM) in antiretroviral therapy (ART)-naive PLWH at baseline and week 48 after initiation of ART. RESULTS: Compared with age- and sex-matched healthy controls, PLWH had a higher prevalence of DD (16.5% vs 7.2%, P < .027) and a marginally significant higher prevalence of LVSD (7.3% vs 2.1%, P = .056). The increase in the prevalence of DD from baseline to week 48 in PLWH was marginally significant (P = .056). No significant difference was observed in the prevalence of LVSD, PAH, or ILVM at baseline and week 48 in PLWH. In logistic regression analysis of all participants, age was significantly associated with LVSD; HIV infection, age, and hypertension were associated with DD whereas HIV infection and hypertension were associated with ILVM at baseline. Logistic regression analysis of PLWH showed that only age was significantly associated with LVSD and DD. CONCLUSIONS: The prevalence of echocardiographic abnormalities was significantly higher in ART-naive PLWH than in controls. HIV infection was significantly associated with cardiac abnormalities. No significant change in echocardiographic abnormalities was observed after 48 weeks of ART. Longer-term prospective studies are warranted.

A cross-national comparative study of orphan drug policies in the United States, the European Union, and Japan: towards a made-in-China orphan drug policy.

Rare diseases can severely impact patient life quality as well as impose a serious burden on society. But research and development for drugs to treat these disorders has stagnated because of lack of demand, insufficient knowledge of pathophysiological mechanisms, and too few patients for clinical trials. In several countries--the United States, the EU, and Japan--specific legislation has been enacted to encourage pharmaceutical companies to expedite the development of drugs for rare diseases, orphan drugs, and to assure access to them. We analyze the strengths and weaknesses of the incentives in these laws and describe the status of rare diseases in China. We offer some recommendations for orphan drug legislation in China, based on local research on rare diseases.

Progress of the National Pediatric Free Antiretroviral Therapy program in China.

In 2003, the Chinese Government initiated a free antiretroviral therapy (ART) program focusing on adult AIDS patients. Pediatric antiretroviral (ARV) formulations were yet unavailable. It was not until July 2005, with the initiation of a two-stage program implemented by the Chinese Ministry of Health, that pediatric formulations became accessible in China. Initially, the pediatric ART program was piloted in six provinces with the highest incidences of pediatric HIV/AIDS. The pilot stage allowed the Chinese Center for Disease Control and Prevention (CCDC) to finalize entry criteria, treatment regimen, and patient monitoring and follow-up procedures. The second stage commenced at the end of 2006 when the program was scaled-up nationally. In order to guarantee treatment of pediatric patients, extensive training in the selection of appropriate ARV drug regimen and dosage was provided to doctors, often through on-site collaboration with domestic and international experts. The CCDC simultaneously established a pediatric ARV management system and a pediatric ART information system. CD4 count and other laboratory tests are being routinely performed on these pediatric patients. By the end of June 2009, 1529 pediatric patients had received ARV under the national program. However, challenges remain. Firstly, many children infected with HIV/AIDS live in rural areas where the treatment quality is hindered by the limited number of medical facilities and skilled medical workers. Secondly, much of the pediatric ARV drug supply depends on donation. An effort needs to be made by the Chinese Government to establish China's own drug procurement and supply system.

Analysis of the main nucleosides in Cordyceps sinensis by LC/ESI-MS.

A sensitive, selective and reliable liquid chromatography-mass spectrometry coupled with electrospray ionization interface method for simultaneous separation and determination of thymine, adenine, adenosine and cordycepin in Cordyceps sinensis has been established. The optimum separation for these analytes was achieved using a gradient elution system and a 2.0 x 150 mm Shimadzu VP-ODS column. 2-Chloroadenosine was used as internal standard for this assay. [M+H]+ ions at m/z 127, 136, 268, 252 and 302 were chosen and selective ion monitoring (SIM) mode was used for quantitative analysis of the four main nucleosides. The regression equations were linear in the range of 1.0-117.5 microg x mL(-1) for thymine, 1.8-127.0 microg x mL(-1) for adenine, 0.6-114.0 microg x mL(-1) for adenosine and 0.5-107.5 microg x mL(-1) for cordycepin. The limits of quantitation (LOQ) and detection (LOD) were 1.0 and 0.2 microg x mL(-1) for thymine, 1.8 and 0.6 microg x mL(-1) for adenine, 0.6 and 0.1 microg x mL(-1) for adenosine and 0.5 and 0.1 microg x mL(-1) for cordycepin, respectively. The recoveries of the four nucleosides ranged from 98.47 to 99.32%. The developed method was successfully used to determine nucleosides in Cordyceps sinensis from different sources.

[A retrospective cohort study on reduction of AIDS mortality among patients enrolled in national-free antiretroviral treatment programme in two cities in China].

OBJECTIVE: To determine the effect of national free highly active antiretroviral treatment (HAART) on reduction of mortality and relevant risk factors among adult Acquired immunodeficiency syndrome (AIDS) patients. METHODS: A retrospective cohort study was conducted and all AIDS patients diagnosed before Aug. 30th, 2008 in Zhumadian, Henan province, and Fuyang, Anhui province were enrolled in this study, where HAART initiated in early time. The data and information were collected such as AIDS progress, diagnosis, treatment, death and et al. RESULTS: Among 10,394 AIDS patients, the mean age was (41.7 +/- 9.3) year-old, 50.3% (5233/10,394) were male, 85.0% (8808/10,394) were married, 95.1% (9880/10,394) were farmers, and 81.2% (8438/10,394) were former plasma donors (FPDs). The coverage of HAART increased from 5.2% in 2002 to 66.5% in 2008. Conversely, the overall mortality declined from 35.4/100 person-years in 2002 to 5.9/100 person-years in 2008. In a multivariate Cox proportional hazards analysis, the greatest risk factor for mortality was non-HAART, with a hazard ratio (HR) 4.3 (95%CI: 4.0 - 4.7). Among treated patients, compared with higher CD(4)(+) T cell counts (> 200 cells/microl), those initiating therapy with lower CD(4)(+) T cell counts, were at greater risk to death (< 50 cells/microl, HR = 7.9; 50 - 199 cells/microl, HR = 2.8). Number of opportunistic infections (OIs) was risk to mortality (HR = 2.1). In addition, other risk factors included male, age (>or= 50 years old), and other infection way except FPDs (HR were 1.4, 1.6 and 1.8). CONCLUSION: The national free treatment program has significantly reduced the AIDS mortality rate among HIV-infected FPDs through the use of generic antiretroviral drugs in rural clinical settings. The effective reduction of AIDS mortality could be realized through increased coverage of therapy.