Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships. The model was also validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2-5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2-3: 500 mg BID, Days 4-5: 250 mg BID, CQ phosphate), and other vulnerable populations (.., renal and hepatic impairment and elderly patients, Days 1-5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.

Aged ; Betacoronavirus ; COVID-19 ; Coronavirus Infections/psychology* ; Family ; Female ; Humans ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral/psychology* ; Retrospective Studies ; SARS-CoV-2 ; Severity of Illness Index

Objective: To evaluate the outcomes of myelodysplastic syndromes (MDS) patients who received HLA-matched sibling donor allogeneic peripheral blood stem cell transplantation (MSD-PBSCT) . Methods: The clinical data of 138 MDS patients received MSD-PBSCT from Sep. 2005 to Dec. 2017 were retrospectively analyzed, and the overall survival (OS) rate, disease-free survival (DFS) rate, relapse rate (RR) , non-relapse mortality (NRM) rate and the related risk factors were explored. Results: ①After a median follow-up of 1 050 (range 4 to 4 988) days, the 3-year OS and DFS rates were (66.6±4.1) % and (63.3±4.1) %, respectively. The 3-year cumulative incidence of RR and NRM rates were (13.9±0.1) % and (22.2±0.1) %, respectively. ②Univariate analysis showed that patients with grade Ⅲ-Ⅳ acute graft-versus-host disease (aGVHD) or hematopoietic cell transplantation comorbidity index (HCT-CI) ≥2 points or patients in very high-risk group of the Revised International Prognostic Scoring System (IPSS-R) had significantly decreased OS[ (42.9±13.2) %vs (72.9±4.2) %, χ(2)=8.620, P=0.003; (53.3±7.6) %vs (72.6±4.7) %, χ(2)=6.681, P=0.010; (53.8±6.8) %vs (76.6±6.2) %vs (73.3±7.7) %, χ(2)=6.337, P=0.042]. For MDS patients with excess blasts-2 (MDS-EB2) and acute myeloid leukemia patients derived from MDS (MDS-AML) , pre-transplant chemotherapy or hypomethylating agents (HMA) therapy could not improve the OS rate[ (60.4±7.8) %vs (59.2±9.6) %, χ(2)=0.042, P=0.838]. ③Multivariate analysis indicated that the HCT-CI was an independent risk factor for OS and DFS (P=0.012, HR=2.108, 95%CI 1.174-3.785; P=0.008, HR=2.128, 95%CI 1.219-3.712) . Conclusions: HCT-CI was better than the IPSS-R in predicting the outcomes after transplantation. The occurrence of grade Ⅲ-Ⅳ aGVHD is a poor prognostic factor for OS. For patients of MDS-EB2 and MDS-AML, immediate transplantation was recommended instead of receiving pre-transplant chemotherapy or HMA therapy.
Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute ; Myelodysplastic Syndromes ; Retrospective Studies ; Siblings ; Transplantation Conditioning ; Transplantation, Homologous

Objective: To understand the prevalence of alcohol use and related factors in HIV positive and HIV negative males. Methods: Baseline data were from the prospective cohort study of comparative HIV and aging research in Taizhou of Zhejiang province from January to December, 2017. The information about alcohol use in the last month was collected through a face-to-face questionnaire interview. Participants were categorized into non-current drinkers, light/moderate drinkers and heavy drinkers according to the US National Institute on Alcoholism and Alcohol Abuse (NIAAA) standard. Results: A total of 1 367 HIV positive males and 2 418 HIV negative males were included. Current alcohol use rate (35.2%, 481/1 367) and heavy alcohol use rate (5.0%, 24/481) were significantly lower in HIV positive males than in HIV negative males (48.0%, 1 161/2 418; 23.5%, 273/1 161), but the proportion of drinking wine and yellow rice wine were significantly higher (21.8%, 105/481; 9.1%, 44/481) in HIV positive males than in HIV negative males (13.5%, 157/1 161; 5.8%, 67/1 161). The multivariate multinomial logistic regression analysis results showed that larger waist circumference, current smoking and regular physical exercise were associated with heavy alcohol use behavior in HIV positive males, and age ≥30 years, current smoking, regular physical exercise, higher score of depressive symptoms, heterosexual transmission route and baseline CD₄⁺T cells counts of 200-499 cells/μl were significantly associated with mild/moderate alcohol use behavior in HIV positive males. Conclusions The alcohol use rate was significantly lower in HIV positive males than in HIV negative males in Taizhou. It is important to strengthen intervention on alcohol drinking behavior and chronic disease risk factors, such as larger waist circumference, smoking and so on.

Objective: To understand the characteristics of sleep disorder in HIV positive and negative individuals, and compare the distributions and epidemiologic characteristic of different subtypes of sleep disorder between two groups. Methods: Baseline data were from the prospective cohort study of comparative HIV and aging research in Taizhou of Zhejiang province from January to December, 2017. A total of 459 HIV positive patients and 798 HIV negative controls with sleep disorders (Pittsburg Sleep Quality Index >5 or at least one question with answers of "most nights" or "every night" for Jenkins Sleep Scale) were included in the analysis. Cluster analysis was conducted to identify the different subtypes of sleep disorder based on 15 sleep-related questions. Results: A total of 1 257 participants were divided into three groups (clusters), i.e. difficulty falling asleep and sleep keeping group (cluster 1), the mild symptoms group (cluster 2), and restless night and daytime dysfunction group (cluster 3), accounting for 19.4% (89/459), 63.8% (293/459) and 16.8% (77/459) in HIV positive group and 13.8% (110/798), 60.5% (483/798) and 25.7% (205/798) in HIV negative group (χ²=16.62, P<0.001). In HIV positive group, the patients in cluster 1 and 3 were older and had higher frailty score, the patients in cluster 1 had highest level of depression, and the more patients in cluster 3 had low body weight or overweight (χ²=13.29, P=0.039; χ²=23.33, P<0.001; χ²=25.71, P<0.001; χ²=15.37, P=0.004). In HIV-negative group, similar findings were found for age, depressive symptoms and frailty score. In addition, the proportion of those who were illiteracy or with primary school education level was significantly high in cluster 1, and the proportion of abnormal waist-to-hip ratio was significantly higher in cluster 1 and 3 (χ²=30.59, P<0.001; χ²=11.61, P=0.003). Conclusions The proportion of every subtype of sleep disorder in HIV positive individuals were different to those in HIV negative individuals. Mental and physical health status were the main factors affecting the prevalence of sleep disorder. It is necessary to conduct targeted interventions to improve sleep quality.

Objective: To investigate the distribution of mitochondrial haplogroups and their correlation with neurocognitive disorder (NCD) in HIV positive individuals. Methods: Baseline data were from the prospective cohort study of comparative HIV and aging research in Taizhou of Zhejiang province from January to December, 2017. A cross-sectional survey was performed in 448 HIV positive individuals. Sanger method was used for the sequencing and genotyping of whole mitochondrial genome of HIV positive individuals. NCD prevalence in the HIV positive individuals was assessed by Mini-mental State Examination (MMSE) in questionnaire interviews. Multivariable logistic regression analysis was performed to assess the associations between mtDNA haplogroups and NCD. Results: In this sample, mitochondrial haplogroups D (19.6%, 88/448), B (19.4%, 87/448) and F(17.0%, 76/448) were the most predominant haplogroups. The overall prevalence rate of NCD was 20.3% (91/448), and was high in haplogroups A (23.1%, 9/39), D (21.6%, 19/88), F (26.3%, 20/76) and M7 groups (26.1%, 12/46), respectively. In multivariable logistic regression analysis after adjusting confounding factors, such as age and gender, compared with haplogroup A, there were no differences in the prevalence rate of NCD among HIV positive individuals with haplogroup B, D, F, M7, M8, N9, and others. Conclusion The study explored primarily correlation between mitochondrial haplogroups and NCD among HIV positive individuals and suggested that there is no significant association between mitochondrial haplogroups and NCD, but further longitudinal investigation with large sample size of HIV positive population is needed to confirm this finding.

In order to comply with canceling the drug price addition policy in the new medical reform program, meet the requirements of meticulous management and intensified medication safety, and improve the efficiency of pharmacies, the hospital pharmaceutical supply chain must be rebuilt by modern logistics and information technologies. This article compared three models of current hospital pharmaceutical chain and considered the supply chain management model of cooperating with the third party as the most effective one in the aspects of cost, efficiency,quality control management and so on. System deployment and implementation Methods of this model were further elaborated from the aspects of Hospital Information System(HIS) reform, management strategy, system architecture and security.

The paper sets forth the system architecture of Traditional Chinese Medicine (TCM) for chronic disease tracking management platform based on remote monitoring technology,including business architecture,technical architecture and key technology modules;builds the new mode of chronic disease management and recovery based on household self-management and gives full play to the role of TCM in home care and disease prevention.

Most Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) patients often show rapid recurrence and development of ABL kinase domain (KD) mutation after tyrosine kinase inhibitor (TKI) treatment. To further investigate the mechanism of Ph(+) ALL fast relapse after TKI treatment, ABL KD mutation in 35 Chinese Ph(+) ALL with TKI resistance was detected by direct sequencing. The results showed that 77.1% (27/35) Ph(+) ALL patients with TKI resistance had ABL KD mutation and 55.6% (15/27) Ph(+) ALL patients with ABL KD mutation had T315I. Interestingly, 77.8% (21/27) Ph(+)ALL showed ABL mutation G: C→A:T, including T315I, E255K and E459K. Furthermore, all the Ph(+) ALL patients with two or more ABL KD mutations collaborated with complex chromosome abnormality and all the TKI-resistant Ph(+) ALL patients, whose karyotype progressed from simple t (9;22) into complex, developed ABL KD mutation. Moreover, the expression level of uracil-DNA glycosylase UNG2, which inhibits G:C→A:T transition in genomic DNA, decreased in Ph(+) ALL with TKI-resistance compared to that in newly diagnosis Ph(+) ALL. It is concluded that there is a high frequent ABL KD G:C→A:T mutation and a high genomic instability in Chinese TKI-resistant Ph(+) ALL. In addition, the decreased UNG2 expression in TKI-resistant Ph(+) ALL probably contributes to their high rate of ABL KD G:C→A:T mutation.
Adolescent ; Adult ; Asian Continental Ancestry Group ; genetics ; DNA Glycosylases ; genetics ; Drug Resistance, Neoplasm ; genetics ; Female ; Humans ; Male ; Middle Aged ; Point Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; Protein Kinase Inhibitors ; pharmacology ; Uracil-DNA Glycosidase ; genetics

10.3969/j.issn.1000-3606.2013.06.005