Modeling methodologies developed for studying pharmacokinetic(PK)/pharmacodynamic(PD) processes confront many challenges related in part to the severe restrictions on the number and type of measurements that are available from laboratory experiments and clinical trials, as well as the variability in the experiments and the uncertainty associated with the processes themselves. Bayesian methods have provided a framework for PK/PD modeling and drug development that can address some of the above-mentioned challenges. This paper presents two illustrations of the application of Bayesian methods: the first involves a population modeling study of the cellular kinetics of the antiretroviral compound Lamivudine in the PBMCs of HIV-1 infected adolescents; the second uses a population mixture modeling approach to identifying hidden subpopulations that can not be identified by available measured covariates.

OBJECTIVETo investigate the impact of novel P2Y(12) receptor inhibitors including prasugrel or ticagrelor on platelet reactivity in patients with acute coronary syndrome (ACS) receiving percutaneous coronary intervention (PCI), and provide clinical data for novel oral P2Y(12) receptor inhibitors use among Chinese patients.

METHODSBetween October 2011 to February 2014, 174 consecutive patients (135 males; (67.8±11.8) years old) with ACS undergoing PCI in Kiang Wu Hospital, Macau were prospectively enrolled in this study. Oral aspirin and one P2Y(12) receptor inhibitor were administered for 5 days or above after PCI, patients were divided into clopidogrel, prasugrel and ticagrelor groups in accordance with the agent administered. Platelet reactivity of the patients was detected by VerifyNow P2Y(12) reaction unit (PRU); and the high on-treatment platelet reactivity (HPR) and non-HPR were defined as PRU≥208 and PRU<208 respectively. Patients with HPR during clopidogrel therapy were switched either to prasugrel or ticagrelor, or continued the same treatment; and then the platelet reactivity was monitored again.

RESULTSThere were 113 clopidogrel cases (64.9%), 20 prasugrel cases (11.5%) and 41 ticagrelor cases (23.6%). Fifty-seven cases (32.8%) were defined as HPR post P2Y(12) receptor inhibitor use, in which 55 cases (55/113, 48.7%) were treated with clopidogrel. The degree of inhibition of platelet reactivity was significantly different in patients on clopidogrel, prasugrel and ticagrelor therapy, percent inhibition assayed by the VerifyNow P2Y(12) system was 28.2%±23.5%, 61.4%±26.7% and 81.3%±19.8% respectively (P<0.05). Different degree of platelet reactivity was achieved by the 3 P2Y(12) receptor inhibitors at multiple time points. The among-group differences in platelet reactivity became apparent at the early treatment stage (P<0.05). Platelet aggregation decreased significantly in patients switched from clopidogrel to prasugrel or ticagrelor (P<0.05).

CONCLUSIONNovel oral P2Y(12) receptor inhibitors are more effective in inhibiting platelet reactivity in ACS patients, and our results show that novel oral P2Y(12) receptor inhibitors provide a new option for ACS patients with HPR post clopidogrel or high-risk features of ischemic complications, including stent thrombosis and post-PCI ischemic events.

Acute Coronary Syndrome ; Adenosine ; analogs & derivatives ; Aged ; Aspirin ; Blood Platelets ; Female ; Humans ; Male ; Percutaneous Coronary Intervention ; Platelet Aggregation ; Platelet Aggregation Inhibitors ; Platelet Function Tests ; Prasugrel Hydrochloride ; Prospective Studies ; Ticlopidine ; analogs & derivatives

Objective: To investigate the frailty status and related determinants among the elderly in China. Methods: Frailty index (FI) was applied to evaluate the frailty status of the elderly. Data used in this study was from the China Health and Retirement Longitudinal Study (CHARLS) in 2011-2015. Binary logistic regression analysis was carried out to identify the determinants related to the status on frailty. Results: The prevalence rates of frailty in the elderly were 18.7%, 20.6% and 28.4% in 2011, 2013 and 2015, respectively. Being female or elderly under advanced age, were both associated with the higher level of FI. Factors as hip fracture, falls, alcohol intake more than once a month, and less participation in social activities etc., might serve as the risk factors for frailty. Conclusion: Chinese elderly showed relatively high prevalence on frailty and with annual increasing trend. The status of frailty was related to factors as adverse events and unhealthy lifestyles. Comprehensive intervention strategies should be adopted in early life of the elderly to delay the development process of frailty.
Accidental Falls ; Aged ; Alcohol Drinking ; China/epidemiology* ; Female ; Frail Elderly ; Frailty/ethnology* ; Hip Fractures ; Humans ; Longitudinal Studies

Objective: To understand the characteristics of HIV infected persons without long term disease progress [also known as long term non-progressors (LTNPs)], and related factors in Guangxi Zhuang Autonomous Region (Guangxi). Methods: Data of persons living with HIV and receiving no antiretroviral therapy in Guangxi by the end of 2016 were collected from the national HIV/AIDS comprehensive control and prevention information system of China. Results: By the end of 2016, there were 313 LTNPs in Guangxi, accounting for 2.3% of those being reported for more than 10 years, 5.4% of those being reported for more than 10 years and surviving, and 26.6% of those being reported for more than 10 years, surviving and receiving no antiretroviral therapy. Among the LTNPs, 87.2%(273) were men, 94.9% (297) were aged ≤ 40 years, 32.3% (101) were farmers, 55.6% (174) were single, divorced or widowed, 69.3% (217) were of Han ethnic group, 68.1% (213) were injecting drug users, and 52.1% (163) were from custody facilities. Multiple logistic regression analysis indicated that factors associated with delayed disease progression included age ≤40 years (compared with age >40 years, aOR=1.55, 95%CI: 1.31-3.12) and injection drug use (compared with sexual transmission, aOR=1.23, 95%CI: 1.10-1.74). Conclusions: A number of LTNPs existed in HIV-infected individuals in Guangxi. Further research are needed to identify the related factors, and it is necessary to conduct large sample size studies on host immunology, genetics and the virology of HIV to explore the related mechanism.
Adolescent ; Adult ; Age Distribution ; China/epidemiology* ; Drug Users/statistics & numerical data* ; Ethnicity/statistics & numerical data* ; HIV Infections/ethnology* ; Humans ; Male ; Socioeconomic Factors

OBJECTIVEFructose-1, 6-diphosphate (FDP), serving as a cellular energy substance, has shown its roles in the treatment of hypoxic-ischemic encephalopathy and myocardial damage. The present study aimed at exploring the potentiality of the protective effect of FDP against ultrastructural damage of the hippocampus caused by febrile seizures (FS) in rats.

METHODSThirty-six 21-day-old male Sprague-Dawley rats were randomly divided into three groups: untreated FS (control), high-dose FDP-treated FS and low-dose FDP-treated FS. FS were induced by hyperthermal bath. Thirty minutes before FS induction, rats in the high-dose and low-dose FDP-treated groups received a peritoneal injection of FDP at a dosage of 50 and 25 mg per 100 g of body weight respectively, whereas the same volume of 0.9% sodium chloride solution were injected to the rats in the control group. Transmission electron microscopy was used to examine the ultrastructural pathologic changes of neurons and organelles as well as the features of synaptic morphological parameters in the hippocampal CA1 area.

RESULTSNeuronal degeneration and necrosis, mitochondria swelling, polyribosomes disaggregation from endoplasmic reticula, and golgiosomes dilation in the hippocampal CA1 area in the two FDP intervention groups were less severe compared with the control group. FDP treatment resulted in significant increases in postsynaptic density thickness (F=12.47, P<0.01), synaptic active zone length (F=14.75, P<0.01) and synaptic interface curvature (F=3.77, P<0.05), as well as a shorter interspace of neural synapses (F=7.29, P<0.01) when compared with the control group. There were no significant differences in the ultrastructural changes between the two FDP treatment groups.

CONCLUSIONSFDP can ameliorate ultrastructural damage in the hippocampus caused by FS in rats. However, further research is warranted for a reasonable and effective dosage of FDP.

Animals ; Fructosediphosphates ; therapeutic use ; Hippocampus ; ultrastructure ; Male ; Neuroprotective Agents ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Seizures, Febrile ; drug therapy ; pathology

BACKGROUNDBispectral index (BIS) is considered very useful to guide anesthesia care in elderly patients, but its use is controversial for the evaluation of the adequacy of analgesia. This study compared the BIS changes in response to loss of consciousness (LOC) and loss of somatic response (LOS) to nociceptive stimuli between elderly and young patients receiving intravenous target-controlled infusion (TCI) of propofol and remifentanil.

METHODSThis study was performed on 52 elderly patients (aged 65-78 years) and 52 young patients (aged 25-58 years), American Society of Anesthesiologists physical status I or II. Anesthesia was induced with propofol administered by TCI. A standardized noxious electrical stimulus (transcutaneous electrical nerve stimulation, [TENS]) was applied (50 Hz, 80 mA, 0.25 ms pulses for 4 s) to the ulnar nerve at increasing remifentanil predicted effective-site concentration (Ce) until patients lost somatic response to TENS. Changes in awake, prestimulus, poststimulus BIS, heart rate, mean arterial pressure, pulse oxygen saturation, predicted plasma concentration, Ce of propofol, and remifentanil at both LOC and LOS clinical points were investigated.

RESULTSBISLOCin elderly group was higher than that in young patient group (65.4 ± 9.7 vs. 57.6 ± 12.3) (t = 21.58, P < 0.0001) after TCI propofol, and the propofol Ce at LOC was 1.6 ± 0.3 μg/ml in elderly patients, which was significantly lower than that in young patients (2.3 ± 0.5 μg/ml) (t = 7.474, P < 0.0001). As nociceptive stimulation induced BIS to increase, the mean of BIS maximum values after TENS was significantly higher than that before TENS in both age groups (t = 8.902 and t = 8.019, P < 0.0001). With increasing Ce of remifentanil until patients lost somatic response to TENS, BISLOSwas the same as the BISLOCin elderly patients (65.6 ± 10.7 vs. 65.4 ± 9.7), and there were no marked differences between elderly and young patient groups in BISawake, BISLOS, and Ce of remifentanil required for LOS.

CONCLUSIONIn elderly patients, BIS can be used as an indicator for hypnotic-analgesic balance and be helpful to guide the optimal administration of propofol and remifentanil individually.

TRIAL REGISTRATIONCTRI Reg. No: ChiCTR-OOC-14005629; http://www.chictr.org.cn/showproj.aspx?proj=9875.

Adult ; Aged ; Electroencephalography ; drug effects ; Female ; Humans ; Male ; Middle Aged ; Movement Disorders ; physiopathology ; Pain ; physiopathology ; Piperidines ; pharmacology ; Propofol ; pharmacology ; Transcutaneous Electric Nerve Stimulation ; Unconsciousness ; physiopathology

Cytomegalovirus (CMV) is distinct among members of the Herpesviridae family for having the largest dsDNA genome (230 kb). Packaging of large dsDNA genome is known to give rise to a highly pressurized viral capsid, but molecular interactions conducive to the formation of CMV capsid resistant to pressurization have not been described. Here, we report a cryo electron microscopy (cryoEM) structure of the murine cytomegalovirus (MCMV) capsid at a 9.1 Å resolution and describe the molecular interactions among the ∼3000 protein molecules in the MCMV capsid at the secondary structure level. Secondary structural elements are resolved to provide landmarks for correlating with results from sequence-based prediction and for structure-based homology modeling. The major capsid protein (MCP) upper domain (MCPud) contains α-helices and β-sheets conserved with those in MCPud of herpes simplex virus type 1 (HSV-1), with the largest differences identified as a "saddle loop" region, located at the tip of MCPud and involved in interaction with the smallest capsid protein (SCP). Interactions among the bacteriophage HK97-like floor domain of MCP, the middle domain of MCP, the hook and clamp domains of the triplex proteins (hoop and clamp domains of TRI-1 and clamp domain of TRI-2) contribute to the formation of a mature capsid. These results offer a framework for understanding how cytomegalovirus uses various secondary structural elements of its capsid proteins to build a robust capsid for packaging its large dsDNA genome inside and for attaching unique functional tegument proteins outside.
Amino Acid Sequence ; Capsid Proteins ; chemistry ; metabolism ; ultrastructure ; Cryoelectron Microscopy ; Models, Molecular ; Molecular Sequence Data ; Muromegalovirus ; chemistry ; ultrastructure ; Protein Binding ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary

Objective: To understand the status, attitude and related risk factors on smoking among 18-65 years old patients with hypertension, diabetes, dyslipidemia, chronic obstructive pulmonary disease (COPD) or asthma in Beijing. Methods: Data was gathered from the 2014 Beijing Non-communicable and Chronic Disease Surveillance Program. Multiple classified cluster sampling method was used and 19 815 participants aged 18-65 were sampled from 16 districts in Beijing. Results: Among all the 18 405 participants, male hypertensive patients showed a higher rate on current smoking than the other groups (χ(2)=17.695, P<0.001). Male patients with dyslipidemia had higher current smoking rate than the other groups (χ(2)=39.292, P<0.001). However, female patients with COPD or with asthma showed higher rate on current smoking than the other groups (χ(2)=6.276, P=0.012), (χ(2)=8.245, P=0.004). Among the smokers, hypertensive patients presented lower rate (χ(2)=20.487, P<0.001) on intention of smoking concession, than the other groups. Patients with COPD showed greater intention in quitting smoking (χ(2)=6.085, P=0.048), than the other groups. Male patients with diabetes (χ(2)=9.219, P=0.010) or dyslipidemia (χ(2)=13.513, P=0.001) who had stopped smoking tobacco appeared having higher rates in keeping the current status. Results from logistic regression analyses showed that smoking was the risk factor for hypertension (OR=1.17), dyslipidemia (OR=1.25), COPD (OR=1.78), and asthma (OR=1.57). Conclusions: Patients with certain kinds of chronic diseases showed higher rate of current smoking and lower rate of quitting. Cigarette consumption appeared an important risk factor for patients with hypertension, dyslipidemia, COPD, or asthma in Beijing.
Adolescent ; Adult ; Aged ; Asthma/epidemiology* ; Beijing/epidemiology* ; Chronic Disease/epidemiology* ; Diabetes Mellitus/epidemiology* ; Female ; Humans ; Hypertension/epidemiology* ; Intention ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/epidemiology* ; Risk Factors ; Smokers ; Smoking/psychology* ; Smoking Cessation ; Nicotiana/adverse effects*

Objective: To understand the epidemiological and etiological characteristics of mumps in Fujian province, 2005-2017. Methods: All the reported mumps cases were collected through the National Notifiable Disease Information Management System, 2005-2017. Active search and interviews were conducted to collect the information on vaccination of mumps. Throat swab specimens were collected for cells culture, genotyping and gene sequence analysis on mumps virus (MuV). Results: A total of 83 959 cases of mumps were reported in Fujian province from 2005 to 2017, with an average annual incidence of 17.6 per 100 000. Since 2007, the incidence appeared increasing but then decreasing, reaching the lowest level (7.5 per 100 000), after the setup of a monitoring program. Annually, the onset time of mumps showed an obvious two seasonal peaks, one from April to July, with a weakening trend, and the other from October to January with a rising trend. Most of the mumps cases occurred among students, kindergarten and scattered children (89.2%, 5 814/6 517), children aged 5-9 years (38.8%, 2 527/6 517), with cases reported from every region. Program from the pathogen surveillance showed that the transmission chain of G genotype mumps virus did exist in Fujian. Data from the sequence analysis revealed that mutations in the nucleotide of G genotype strain in 2015 had led to mutation of 6 amino acid sites in the SH gene coding region, resulting in the differences appearing in both nucleotide and amino acid homology with type A vaccine strain. Conclusions: The incidence of mumps decreased annually, in Fujian. Prevention programs should focus on primary and secondary school students. In Fujian province, we also noticed the transmission chain of mumps G genotype with some amino acid mutations in the SH gene coding region. Monitor programs on both epidemiologic and etiology, should be strengthened.
Child ; Child, Preschool ; China/epidemiology* ; Genotype ; Humans ; Incidence ; Mumps/epidemiology* ; Mumps virus/pathogenicity* ; Phylogeny ; Sequence Analysis

Objective: To understand the impact of HIV and Mycobacterium tuberculosis (MTB) co-infectious (HIV/MTB) on related mortality in Guangxi Zhuang Autonomous Region, provide evidence for the development of a better HIV/MTB co-infection control and prevention program. Methods: A multiple cross-systems check (MCSC) approach was used to confirm the HIV/MTB co-infection individuals on data related to treatment, follow-up, epidemiological comprehensive and Tuberculosis (TB) special report system. Social demography characteristics, incidence of TB among HIV positive individuals, HIV incidence among MTB infection persons etc., were described. We compared the mortalities and related risks between HIV/MTB co-infection and mono HIV positive individuals as well as between the HIV/MTB co-infection and mono MTB infection persons, using both the Chi Square test and the Cox's proportional hazard regression model (Cox). Results: Reported data showed that the incidence of MTB co-infection in the HIV cohort was 17.72% (2 533/14 293), while HIV incidence in the TB patients was 5.57% (2 351/42 205), respectively. The mortality of HIV/MTB co-infection in the HIV/AIDS cohort was 15.16% (384/2 533) within one-year of observation and was significantly higher than the mortality (13.63%,1 603/11 760) of mono HIV positive individuals (P<0.000 1). The percentage of the HIV/AIDS death cases was 19.33% (384/1 987) who registered and died in the 2011 calendar year were caused by MTB co-infection. Among all the HIV/MTB co-infection patients who had been identified from the HIV cohort, 60.05% (1 521/2 533) had initiated ART, 15.48% (392/2 533) had been cured for TB and 27.48% (696/2 533) had been under complete TB regimen. Among the confirmed HIV/MTB cases from the TB cohort, the cure rate of TB was 19.70% (463/2 351) and the percentage of completed TB regimen was 37.26% (876/2 351). The percentage of the individuals whose CD(4)(+) T lymphocyte cells count appeared less than 200 cell/μl was 64.13% (785/1 224), upon the HIV diagnoses were made. Compared with individuals who were under mono HIV infection, the mortality risk on HIV/MTB co-infection was 1.17 times higher during the five-year observation period, then the patients with only mono MTB infection and the mortality risk in patients with HIV/MTB co-infection was 25.68 times higher under the 12-month observation period. Conclusions: Both the incidence and mortality of HIV/MTB appeared high in Guangxi, with mortality and the risk of mortality in the HIV/MTB co-infection group significantly higher than that in both the HIV mono infection and the MTB mono infections groups. Both the rate of antiretroviral treatment coverage and the cure rate of TB treatment should be increased in no time as well as the capability of early TB case-finding among people living with HIV.
China/epidemiology* ; Coinfection/epidemiology* ; Female ; HIV ; HIV Infections/virology* ; Humans ; Male ; Mycobacterium tuberculosis ; Tuberculosis/virology*