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1.  Correlates of sex trading among male non-injecting drug users in Myanmar: a cross-sectional study 
Background
Sex trading is a recognized risk factor for human immune deficiency virus infection and other sexually transmitted infections among non-injecting drug users (NIDUs). However, very little research has addressed the factors associated with sex trading among male NIDUs in Myanmar.
Methods
A cross-sectional study was conducted from January to February 2010 using the respondent-driven sampling method. In total, 210 NIDUs aged between 18 and 49 years, with no history of injecting drug use, and who used non-injected illicit drugs in the last 6 months were recruited. Face-to-face interviews were conducted using a structured questionnaire to collect information on participants’ sexual and drug use behaviors. Binary and multivariate logistic regressions were applied to analyze the resulting data.
Results
Of 210 NIDUs, 84 (40%) reported involvement in the sex trade during the last 3 months. In the adjusted model, factors associated with sex trade involvement included homosexual preference (adjusted odds ratio [AOR] 4.90; 95% confidence interval [CI] 1.61–14.95), having more than two partners (AOR = 3.88; 95% CI 1.55–9.72), had a regular job (AOR = 5.10; 95% CI 1.65–15.72), use of stimulant drugs rather than opiate (AOR = 2.38; 95% CI 1.10–5.15), and who used drugs more than twice per day.
Conclusions
More than one third of NIDUs were involved in sex trading. This study suggested that further comprehensive intervention programs that aim to reduce risk factors of trading sex among NIDUs may consider including NIDUs who used stimulant drugs, had regular/full-time jobs, used drugs more than twice per day, and had homosexual preferences.
doi:10.1186/s12954-016-0123-0
PMCID: PMC5139087  PMID: 27919289
Exchange sex; Sex trading; Drug users; Myanmar
2.  Accelerated Training of Skilled Birth Attendants in a Marginalized Population on the Thai-Myanmar Border: A Multiple Methods Program Evaluation 
PLoS ONE  2016;11(10):e0164363.
Background
To evaluate a skilled birth attendant (SBA) training program in a neglected population on the Thai-Myanmar border, we used multiple methods to show that refugee and migrant health workers can be given effective training in their own environment to become SBAs and teachers of SBAs. The loss of SBAs through resettlement to third countries necessitated urgent training of available workers to meet local needs.
Methods and Findings
All results were obtained from student records of theory grades and clinical log books. Qualitative evaluation of both the SBA and teacher programs was obtained using semi-structured interviews with supervisors and teachers. We also reviewed perinatal indicators over an eight-year period, starting prior to the first training program until after the graduation of the fourth cohort of SBAs.
Results
Four SBA training programs scheduled between 2009 and 2015 resulted in 79/88 (90%) of students successfully completing a training program of 250 theory hours and 625 supervised clinical hours. All 79 students were able to: achieve pass grades on theory examination (median 80%, range [70–89]); obtain the required clinical experience within twelve months; achieve clinical competence to provide safe care during childbirth. In 2010–2011, five experienced SBAs completed a train-the-trainer (TOT) program and went on to facilitate further training programs. Perinatal indicators within Shoklo Malaria Research Unit (SMRU), such as place of birth, maternal and newborn outcomes, showed no significant differences before and after introduction of training or following graduate deployment in the local maternity units. Confidence, competence and teamwork emerged from qualitative evaluation by senior SBAs working with and supervising students in the clinics.
Conclusions
We demonstrate that in resource-limited settings or in marginalized populations, it is possible to accelerate training of skilled birth attendants to provide safe maternity care. Education needs to be tailored to local needs to ensure evidence-based care of women and their families.
doi:10.1371/journal.pone.0164363
PMCID: PMC5053505  PMID: 27711144
3.  Opposite malaria and pregnancy effect on oral bioavailability of artesunate – a population pharmacokinetic evaluation 
Aim
The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7.
Methods
Non-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously.
Results
Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%.
Conclusions
The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.
doi:10.1111/bcp.12660
PMCID: PMC4594700  PMID: 25877779
artesunate; dihydroartemisinin; nonmem; population pharmacokinetics; post-partum women; pregnant women
4.  Consumption of fruits and vegetables and associations with risk factors for non-communicable diseases in the Yangon region of Myanmar: a cross-sectional study 
BMJ Open  2016;6(8):e011649.
Objectives
To explore the intake of fruits and vegetables in the Yangon region, Myanmar, and to describe associations between intake of fruits and vegetables (FV) and established risk factors for non-communicable diseases.
Design
2 cross-sectional studies, using the STEPs methodology.
Setting
Urban and rural areas of the Yangon region of Myanmar.
Participants
1486, men and women, 25–74 years, were recruited through a multistage cluster sampling method. Institutionalised people, military personnel, Buddhist monks and nuns were not invited. Physically and mentally ill people were excluded.
Results
Mean intake of fruit was 0.8 (SE 0.1) and 0.6 (0.0) servings/day and of vegetables 2.2 (0.1) and 1.2 (0.1) servings/day, in urban and rural areas, respectively. Adjusted for included confounders (age, sex, location, income, education, smoking and low physical activity), men and women eating ≥2 servings of fruits and vegetables/day had lower odds than others of hypertriglyceridaemia (OR 0.72 (95% CI 0.56 to 0.94)). On average, women eating at least 2 servings of fruits and vegetables per day had cholesterol levels 0.28 mmol/L lower than the levels of other women. When only adjusted for sex and age, men eating at least 2 servings of fruits and vegetables per day had cholesterol levels 0.27 mmol/L higher than other men.
Conclusions
A high intake of FV was associated with lower odds of hypertriglyceridaemia among men and women. It was also associated with cholesterol levels, negatively among women and positively among men.
doi:10.1136/bmjopen-2016-011649
PMCID: PMC5013453  PMID: 27566634
DIABETES & ENDOCRINOLOGY; EPIDEMIOLOGY
5.  Cost-Effectiveness Analysis of Different Testing Strategies that Use Antibody Levels to Detect Chronic Hepatitis C in Blood Donors 
PLoS ONE  2016;11(5):e0154625.
Aim. We conducted a cost-effectiveness analysis of seven hepatitis C virus (HCV) testing strategies in blood donors. Methods. Three of the seven strategies were based on HCV diagnosis and reporting guidelines in Mexico and four were from previous and current recommendations outlined by the CDC. The strategies that were evaluated determine antibody levels according to the signal-to-cut-off (S/CO) ratio and use reflex Immunoblot (IMB) or HCV RNA tests to confirm true positive (TP) cases of chronic HCV infection. Costs were calculated from the perspective of the Mexican Institute of Social Security (IMSS). A decision tree model was developed to estimate the expected number of true positive cases and costs for the base-case scenarios and for the sensitivity analyses. Results. Base-case findings indicate an extended dominance of the CDC-USA2 and CDC-USA4 options by the IMSS Mexico3 and IMSS-Mexico1 alternatives. The probabilistic sensitivity analyses results suggest that for a willingness-to-pay (WTP) range of $0–9,000 USD the IMSS-Mexico1 strategy is the most cost-effective of all strategies ($5,000 USD per TP). The IMSS-Mexico3, IMSS-Mexico2, and CDC-USA3 strategies are also cost-effective strategies that cost between $7,800 and $8,800 USD per TP case detected. The CDC-USA1 strategy was very expensive and not cost-effective. Conclusions. HCV antibody testing strategies based on the classification of two or three levels of the S/CO are cost-effective procedures to identify patients who require reflex IMB or HCV RNA testing to confirm chronic HCV infection.
doi:10.1371/journal.pone.0154625
PMCID: PMC4861301  PMID: 27159320
6.  Opposite malaria and pregnancy effect on oral bioavailability of artesunate – a population pharmacokinetic evaluation 
Aim
The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7.
Methods
Non-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously.
Results
Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%.
Conclusions
The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.
doi:10.1111/bcp.12660
PMCID: PMC4594700  PMID: 25877779
artesunate; dihydroartemisinin; nonmem; population pharmacokinetics; post-partum women; pregnant women
7.  Surveillance in Patients With Barrett's Esophagus for Early Detection of Esophageal Adenocarcinoma: A Systematic Review and Meta-Analysis 
Objectives:
Although endoscopic surveillance of patients with Barrett's esophagus (BE) has been widely implemented for early detection of esophageal adenocarcinoma (EAC), its justification has been debated. This systematic review aimed to evaluate benefits, safety, and cost effectiveness of surveillance for patients with BE.
Methods:
MEDLINE, EMBASE, EconLit, Scopus, Cochrane, and CINAHL were searched for published human studies that examined screening practices, benefits, safety, and cost effectiveness of surveillance among patients with BE. Reviewers independently reviewed eligible full-text study articles and conducted data extraction and quality assessment, with disagreements resolved by consensus. Random effects meta-analyses were performed to assess the incidence of EAC, EAC/high-grade dysplasia (HGD), and annual stage-specific transition probabilities detected among BE patients under surveillance, and relative risk of mortality among EAC patients detected during surveillance compared with those not under surveillance.
Results:
A total of 51 studies with 11,028 subjects were eligible; the majority were of high quality based on the Newcastle–Ottawa quality scale. Among BE patients undergoing endoscopic surveillance, pooled EAC incidence per 1,000 person-years of surveillance follow-up was 5.5 (95% confidence interval (CI): 4.2–6.8) and pooled EAC/HGD incidence was 7.7 (95% CI: 5.7–9.7). Pooled relative mortality risk among surveillance-detected EAC patients compared with nonsurveillance-detected EAC patients was 0.386 (95% CI: 0.242–0.617). Pooled annual stage-specific transition probabilities from nondysplastic BE to low-grade dysplasia, high-grade dysplasia, and EAC were 0.019, 0.003, and 0.004, respectively. There was, however, insufficient scientific evidence on safety and cost effectiveness of surveillance for BE patients.
Conclusions:
Our findings confirmed a low incidence rate of EAC among BE patients undergoing surveillance and a reduction in mortality by 61% among those who received regular surveillance and developed EAC. Because of knowledge gaps, it is important to assess safety of surveillance and health-care resource use and costs to supplement existing evidence and inform a future policy decision for surveillance programs.
doi:10.1038/ctg.2015.58
PMCID: PMC4816094  PMID: 26658838
8.  Improved Survival in Patients with Viral Hepatitis-Induced Hepatocellular Carcinoma Undergoing Recommended Abdominal Ultrasound Surveillance in Ontario: A Population-Based Retrospective Cohort Study 
PLoS ONE  2015;10(9):e0138907.
The optimal schedule for ultrasonographic surveillance of patients with viral hepatitis for the detection of hepatocellular carcinoma (HCC) remains unclear owing to a lack of reliable studies. We examined the timing of ultrasonography in patients with viral hepatitis-induced HCC and its impact on survival and mortality risk while determining predictors of receiving surveillance before HCC diagnosis. A population-based retrospective cohort analysis of patients with viral hepatitis-induced HCC in Ontario between 2000 and 2010 was performed using data from the Ontario Cancer Registry linked health administrative data. HCC surveillance for 2 years preceding diagnosis was assigned as: i) ≥2 abdominal ultrasound screens annually; ii) 1 screen annually; iii) inconsistent screening; and iv) no screening. Survival rates were estimated using the Kaplan-Meier method and parametric models to correct for lead-time bias. Associations between HCC surveillance and the risk of mortality after diagnosis were examined using proportional-hazards regression adjusting for confounding factors. Overall, 1,483 patients with viral hepatitis-induced HCC were identified during the study period; 20.2% received ≥1 ultrasound screen annually (routine surveillance) for the 2 years preceding diagnosis. The 5-year survival of those receiving routine surveillance was 31.93% (95% CI: 25.77–38.24%) and 31.84% (95% CI: 25.69–38.14%) when corrected for lead-time bias (HCC sojourn time 70 days and 140 days, respectively). This is contrasted with 20.67% (95% CI: 16.86–24.74%) 5-year survival in those who did not undergo screening. In the fully adjusted model, compared to unscreened patients, routine surveillance was associated with a lower mortality risk and a hazard ratio of 0.76 (95% CI: 0.64–0.91) and 0.81 (95% CI: 0.68–0.97), corrected for the respective lead-time bias. Our findings suggest that routine ultrasonography in patients with viral hepatitis is associated with improved survival and reduced mortality risk in a population-based setting. The data emphasizes the importance of surveillance for timely intervention in HCC-diagnosed patients.
doi:10.1371/journal.pone.0138907
PMCID: PMC4580446  PMID: 26398404
9.  A tool to improve competence in the management of emergency patients by rural clinic health workers: a pilot assessment on the Thai-Myanmar border 
Conflict and Health  2015;9:11.
Background
Shoklo Malaria Research Unit has been providing health care in remote clinics on the Thai-Myanmar border to refugee and migrant populations since 1986 and 1995, respectively. Clinics are staffed by local health workers with a variety of training and experience. The need for a tool to improve the competence of local health workers in basic emergency assessment and management was recognised by medical faculty after observing the case mix seen at the clinic and reviewing the teaching programme that had been delivered in the past year (Jan-13 to March-14).
Aims
To pilot the development and evaluation of a simple teaching tool to improve competence in the assessment and management of acutely unwell patients by local health workers that can be delivered onsite with minimal resources.
Methods
A structured approach to common emergencies presenting to rural clinics and utilizing equipment available in the clinics was developed. A prospective repeated-measures observed structured clinical examination (OSCE) assessment design was used to score participants in their competence to assess and manage a scenario based ‘emergency patient’ at baseline, immediately post-course, and 8 weeks after the delivery of the teaching course. The assessment was conducted at 3 clinic sites and staff participation was voluntary. Participants filled out questionnaires on their confidence with different scenario based emergency patients.
Results
All staff who underwent the baseline assessment failed to carry out the essential steps in initial emergency assessment and management of an unconscious patient scenario. Following delivery of the teaching session, all groups showed improved competence in both objective assessment and subjective confidence levels.
Conclusions
Structured and practical teaching and learning with minimal theory in this resource limited setting had a positive short-term effect on the competence of individual staff to carry out an initial assessment and manage an acutely unwell patient. Health-worker confidence likewise improved. Workplace assessments are needed to determine if this type of skills training impacts upon mortality or near miss mortality patients at the clinic.
Electronic supplementary material
The online version of this article (doi:10.1186/s13031-015-0041-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13031-015-0041-x
PMCID: PMC4395965  PMID: 25873993
Medical emergencies; Training; Paramedical staff; Low resource setting; Knowledge; Confidence
10.  Trends in relative survival in patients with a diagnosis of hepatocellular carcinoma in Ontario: a population-based retrospective cohort study  
CMAJ Open  2015;3(2):E208-E216.
Background
The incidence of hepatocellular carcinoma (HCC) is increasing and survival rates are poor. Our objectives were to estimate the relative survival over time in patients with HCC in Ontario and to examine potential factors associated with excess mortality risk.
Methods
We performed a population-based retrospective cohort analysis involving patients with a diagnosis of HCC in Ontario between 1990 and 2009 using data extracted from the Ontario Cancer Registry. Relative survival was estimated by controlling for background mortality using expected mortality from Ontario life tables. A generalized linear model was used to estimate the excess mortality risk for important factors.
Results
A total of 5645 patients had HCC diagnosed during the study period; 4412 (78.2%) of these patients were male. Improvements in 1-year relative survival were observed across all age groups over time: the highest was among those patients aged 60 years or younger who had a diagnosis of HCC during 2005–2009, with 1-year relative survival exceeding 50% for both sexes. However, the overall 5-year relative survival did not exceed 28%. The excess mortality risk decreased with increased years of follow-up, recent diagnosis, and curative or noncurative treatments for HCC, whereas excess mortality risk increased with age.
Interpretation
Although improving, the prognosis for HCC remains poor. Our findings highlight the importance of effective prevention and treatment for HCC to reduce the burden of disease and improve health care systems.
doi:10.9778/cmajo.20140118
PMCID: PMC4565177  PMID: 26389099
11.  The Effect of HIV-Hepatitis C Co-Infection on Bone Mineral Density and Fracture: A Meta-Analysis 
PLoS ONE  2014;9(7):e101493.
Objective
There is a variable body of evidence on adverse bone outcomes in HIV patients co-infected with hepatitis C virus (HCV). We examined the association of HIV/HCV co-infection on osteoporosis or osteopenia (reduced bone mineral density; BMD) and fracture.
Design
Systematic review and random effects meta-analyses.
Methods
A systematic literature search was conducted for articles published in English up to 1 April 2013. All studies reporting either BMD (g/cm2, or as a T-score) or incident fractures in HIV/HCV co-infected patients compared to either HIV mono-infected or HIV/HCV uninfected/seronegative controls were included. Random effects meta-analyses estimated the pooled odds ratio (OR) and the relative risk (RR) and associated 95% confidence intervals (CI).
Results
Thirteen eligible publications (BMD N = 6; Fracture = 7) of 2,064 identified were included with a total of 427,352 subjects. No publications reported data on HCV mono-infected controls. Meta-analysis of cross-sectional studies confirmed that low bone mineral density was increasingly prevalent among co-infected patients compared to HIV mono-infected controls (pooled OR 1.98, 95% CI 1.18, 3.31) but not those uninfected (pooled OR 1.47, 95% CI 0.78, 2.78). Significant association between co-infection and fracture was found compared to HIV mono-infected from cohort and case-control studies (pooled RR 1.57, 95% CI 1.33, 1.86) and compared to HIV/HCV uninfected from cohort (pooled RR 2.46, 95% CI 1.03, 3.88) and cross-sectional studies (pooled OR 2.30, 95% CI 2.09, 2.23).
Conclusions
The associations of co-infection with prevalent low BMD and risk of fracture are confirmed in this meta-analysis. Although the mechanisms of HIV/HCV co-infection’s effect on BMD and fracture are not well understood, there is evidence to suggest that adverse outcomes among HIV/HCV co-infected patients are substantial.
doi:10.1371/journal.pone.0101493
PMCID: PMC4102482  PMID: 25033046
12.  A Descriptive Model of Patient Readiness, Motivators, and Hepatitis C Treatment Uptake among Australian Prisoners 
PLoS ONE  2014;9(2):e87564.
Background
Hepatitis C virus infection (HCV) has a significant global health burden with an estimated 2%–3% of the world's population infected, and more than 350,000 dying annually from HCV-related conditions including liver failure and liver cancer. Prisons potentially offer a relatively stable environment in which to commence treatment as they usually provide good access to health care providers, and are organised around routine and structure. Uptake of treatment of HCV, however, remains low in the community and in prisons. In this study, we explored factors affecting treatment uptake inside prisons and hypothesised that prisoners have unique issues influencing HCV treatment uptake as a consequence of their incarceration which are not experienced in other populations.
Method and Findings
We undertook a qualitative study exploring prisoners' accounts of why they refused, deferred, delayed or discontinued HCV treatment in prison. Between 2010 and 2013, 116 Australian inmates were interviewed from prisons in New South Wales, Queensland, and Western Australia. Prisoners experienced many factors similar to those which influence treatment uptake of those living with HCV infection in the community. Incarceration, however, provides different circumstances of how these factors are experienced which need to be better understood if the number of prisoners receiving treatment is to be increased. We developed a descriptive model of patient readiness and motivators for HCV treatment inside prisons and discussed how we can improve treatment uptake among prisoners.
Conclusion
This study identified a broad and unique range of challenges to treatment of HCV in prison. Some of these are likely to be diminished by improving treatment options and improved models of health care delivery. Other barriers relate to inmate understanding of their illness and stigmatisation by other inmates and custodial staff and generally appear less amenable to change although there is potential for peer-based education to address lack of knowledge and stigma.
doi:10.1371/journal.pone.0087564
PMCID: PMC3937313  PMID: 24586281
13.  Spending of HIV resources in Asia and Eastern Europe: systematic review reveals the need to shift funding allocations towards priority populations 
Introduction
It is increasingly important to prioritize the most cost-effective HIV interventions. We sought to summarize the evidence on which types of interventions provide the best value for money in regions with concentrated HIV epidemics.
Methods
We conducted a systematic review of peer-reviewed and grey literature reporting measurements of cost-effectiveness or cost-benefit for HIV/AIDS interventions in Asia and Eastern Europe. We also collated HIV/AIDS spending assessment data from case-study countries in the region.
Results
We identified 91 studies for inclusion, 47 of which were from peer-reviewed journals. Generally, in concentrated settings, prevention of mother-to-child transmission programmes and prevention programmes targeting people who inject drugs and sex workers had lower incremental cost-effectiveness ratios than programmes aimed at the general population. The few studies evaluating programmes targeting men who have sex with men indicate moderate cost-effectiveness. Collation of prevention programme spending data from 12 countries in the region (none of which had generalized epidemics) indicated that resources for the general population/non-targeted was greater than 30% for eight countries and greater than 50% for five countries.
Conclusions
There is a misalignment between national spending on HIV/AIDS responses and the most affected populations across the region. In concentrated epidemics, scarce funding should be directed more towards most-at-risk populations. Reaching consensus on general principles of cost-effectiveness of programmes by epidemic settings is difficult due to inconsistent evaluation approaches. Adopting a standard costing, impact evaluation, benefits calculation, analysis and reporting framework would enable cross comparisons and improve HIV resource prioritization and allocation.
doi:10.7448/IAS.17.1.18822
PMCID: PMC3936108  PMID: 24572053
HIV; cost-benefit analyses; programme evaluation; systematic review; concentrated epidemics; Asia; Eastern Europe; cost-effectiveness
14.  Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects 
AIM
To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.
METHODS
In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4 mg kg−1) on the first day and oral ARS (4 mg kg−1) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4 mg kg−1 day−1) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).
RESULTS
I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ng ml−1 h)/(mg kg−1)] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P = 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P = 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P = 0.084).
CONCLUSIONS
This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.
doi:10.1111/j.1365-2125.2011.04103.x
PMCID: PMC3370352  PMID: 21950338
artesunate; dihyroartemisinin; malaria; pharmacokinetics; post partum; pregnancy
15.  Influence of Socioeconomic Status on Survival of Hepatocellular Carcinoma in the Ontario Population; A Population-Based Study, 1990–2009 
PLoS ONE  2012;7(7):e40917.
Background
Research has shown that people from higher socioeconomic status (SES) have better hepatocellular carcinoma (HCC) survival outcomes, although no such research has been carried out in Canada. We aimed to assess if an association between SES and HCC survival existed in the Canadian context.
Methodology/Prinicpal Findings
We conducted a population-based cohort study linking HCC cases identified in the Ontario Cancer Registry between 1990 and 2009 to administrative and hospital data. Logistic regression and chi-squared tests were used to evaluate associations between SES (income quintile) and covariates. The Kaplan-Meier method was used to estimate survival. Sequential analysis of the proportional-hazards models were used to determine the association between SES and HCC survival controlling for potential prognostic covariates. During the period 1990–2009, 5,481 cases of HCC were identified. A significant association was found between SES and curative treatment (p = 0.0003), but no association was found between SES and non-curative treatment (p = 0.064), palliative treatment (p = 0.680), or ultrasound screening (p = 0.615). The median survival for the lowest SES was 8.5 months, compared to 8.8 months for the highest SES group. The age- and sex-adjusted proportional-hazards model showed statistically significant difference in HCC survival among the SES groups, with hazard ratio 0.905 (95% confidence intervals 0.821, 0.998) when comparing highest to lowest SES group. Further adjustments indicated that potentially curative treatment was the likely explanation for the association between SES and HCC survival.
Conclusions/Significance
Our findings suggest that a 10% HCC survival advantage exists for the higher SES groups. This association between SES and HCC survival is most likely a reflection of lack of access to care for low SES groups, revealing inequities in the Canadian healthcare system.
doi:10.1371/journal.pone.0040917
PMCID: PMC3396620  PMID: 22808283
16.  Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria▿† 
Antimicrobial Agents and Chemotherapy  2011;55(12):5500-5506.
Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P = 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P = 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P = 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P = 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml, P = 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.
doi:10.1128/AAC.05067-11
PMCID: PMC3232755  PMID: 21947392
17.  Health status utilities and the impact of pressure ulcers in long-term care residents in Ontario 
Quality of Life Research  2009;19(1):81-89.
Purpose
To estimate health status utilities in long-term care (LTC) residents in Ontario, both with and without pressure ulcers (PUs), and to determine the impact of PU on health-related quality of life (HRQOL).
Methods
A retrospective population-based study was carried out using Minimum Data Set (MDS) health assessment data among all residents in 89 LTC homes in Ontario who had a full MDS assessment between May 2004 and November 2007. The Minimum Data Set-Health Status Index (MDS-HSI) was used to measure HRQOL. A stepwise regression was used to determine the impact of PU on MDS-HSI scores.
Results
A total of 1,498 (9%) of 16,531 LTC residents had at least one stage II PU or higher. The mean ± SD MDS-HSI scores of LTC residents without PU and those with PU were 0.36 ± 0.17 and 0.26 ± 0.13, respectively (p < 0.001). Factors associated with lower MDS-HSI scores included: older age; being female; having a PU; recent hip fracture; multiple comorbid conditions; bedfast; incontinence; Changes in Health, End-stage disease and Symptoms and Signs; clinically important depression; treated with a turning/repositioning program; taking antipsychotic medications; and use of restraints.
Conclusions
LTC residents with PU had slightly though statistically significantly lower HRQOL than those without PU. Comorbidity contributed substantially to the low HRQOL in these populations. Community-weighted MDS-HSI utilities for LTC residents are useful for cost-effectiveness analyses and help guide health policy development.
doi:10.1007/s11136-009-9563-2
PMCID: PMC2804787  PMID: 20033300
Health-related quality of life; Long-term care; Minimum Data Set; Health Status Index; Ontario/Canada; Utilities
18.  Health-state utilities in a prisoner population: a cross-sectional survey 
Background
Health-state utilities for prisoners have not been described.
Methods
We used data from a 1996 cross-sectional survey of Australian prisoners (n = 734). Respondent-level SF-36 data was transformed into utility scores by both the SF-6D and Nichol's method. Socio-demographic and clinical predictors of SF-6D utility were assessed in univariate analyses and a multivariate general linear model.
Results
The overall mean SF-6D utility was 0.725 (SD 0.119). When subdivided by various medical conditions, prisoner SF-6D utilities ranged from 0.620 for angina to 0.764 for those with none/mild depressive symptoms. Utilities derived by the Nichol's method were higher than SF-6D scores, often by more than 0.1. In multivariate analysis, significant independent predictors of worse utility included female gender, increasing age, increasing number of comorbidities and more severe depressive symptoms.
Conclusion
The utilities presented may prove useful for future economic and decision models evaluating prison-based health programs.
doi:10.1186/1477-7525-7-78
PMCID: PMC2741437  PMID: 19715571
19.  Biological and Molecular Characteristics of Mycobacterium tuberculosis Clinical Isolates with Low-Level Resistance to Isoniazid in Japan▿  
Journal of Clinical Microbiology  2008;46(7):2263-2268.
We reevaluated the BACTEC MGIT 960 antimicrobial susceptibility testing system (MGIT 960 AST) by using 1,112 isolates of Mycobacterium tuberculosis. When the results of MGIT 960 AST were compared with that of the proportion method using Ogawa medium (Ogawa PM), discrepant results were obtained for 30 strains with isoniazid, all resistant by MGIT 960 AST but susceptible by Ogawa PM. For 93% of the strains that produced discrepant results, the MIC was 0.4 or 0.8 μg/ml, showing resistance by the proportion method using Middlebrook agar plates. Furthermore, it was also established by analyses of the katG and inhA genes that strains resistant only by MGIT 960 AST have a low level of isoniazid (INH) resistance, indicating that MGIT 960 AST is a reliable method. Ninety-six strains were resistant to 0.1 μg/ml INH by MGIT 960 AST. When they were divided into three groups, Low-S (susceptible at 0.2 μg/ml), Low-R (resistant at 0.2 μg/ml), and High-R (resistant at 1.0 μg/ml), by Ogawa PM, 43.3% of the Low-S strains had mutations in the promoter region of inhA and no mutations were detected in katG codon 315, while 61.7% of the High-R strains had katG codon 315 mutations or a gross deletion of katG. These results suggest that mutations in inhA are associated with low-level resistance to INH and katG codon 315 mutations are associated with high-level resistance to INH. In addition, the analyses demonstrated some relationship of mutations in the inhA gene with ethionamide resistance for the Low-S strains, but not for the High-R strains.
doi:10.1128/JCM.00561-08
PMCID: PMC2446907  PMID: 18508939
20.  The Effect of Hepatitis C Virus Infection on Health-Related Quality of Life in Prisoners 
Journal of Urban Health   2006;83(2):275-288.
Hepatitis C virus (HCV) infection in prisoners represents an important public health problem. However, there is very little information about HCV-related health-related quality of life (HRQOL). We examined the effect of HCV antibody positivity, HCV viremia, and being a prisoner on prisoners'' HRQOL. Population-based health surveys incorporating HCV screening were conducted among prisoners at New South Wales (NSW), Australia, correctional centers in 1996 and 2001. HCV antibody and HCV RNA status were determined from venous blood sampling. HRQOL and mood status were assessed using the Short Form-36 (SF-36) Health Survey and Beck Depression Inventory (BDI). Comparison of HRQOL scores between HCV antibody negative, HCV antibody positive/non-viremic, and HCV antibody positive/viremic and assessment of temporal change in HRQOL between 1996 and 2001 within groups were made using ANCOVA adjusting for confounders. Factors associated with HRQOL were determined in linear regression models. Analyses between HCV antibody negative (n = 423), HCV positive/non-viremic (n = 89), and HCV positive/viremic (n = 178) prisoners found no measurable effect of HCV on HRQOL, including that attributable to HCV viremia. Compared to uninfected Australian population norms, prisoners had lower HRQOL irrespective of HCV status. The prevalence of ‘moderate’ to ‘severe’ depressive symptoms was greater in the HCV antibody positive/viremic group than the HCV antibody positive/non-viremic group or the HCV antibody negative group. Selected demographic factors (age), co-morbidity, severity of depressive symptoms and medical care utilization influenced HRQOL. There was evidence to support the effect of knowledge of HCV status on HRQOL. In conclusion, our findings contrast with previous studies in non-prisoner groups in which HCV infection appears to decrease overall HRQOL. Non-HCV factors may override HCV-specific HRQOL impairment in this population. Targeted management strategies are required to improve HRQOL of prisoners.
doi:10.1007/s11524-005-9015-4
PMCID: PMC2527173  PMID: 16736376
Australia; HCV; Prisoner; Quality of life; SF-36
21.  Artesunate/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects 
AIM
To determine if reported lower plasma concentrations of artemisinin derivatives for malaria in pregnancy result from reduced oral bioavailability, expanded volume of distribution or increased clearance.
METHODS
In a sequentially assigned crossover treatment study, pregnant women with uncomplicated falciparum malaria received i.v. artesunate (i.v. ARS) (4 mg kg−1) on the first day and oral ARS (4 mg kg−1) on the second, or, oral on the first and i.v. on the second, in both groups followed by oral ARS (4 mg kg−1 day−1) for 5 days. Plasma concentrations of ARS and dihyroartemisinin (DHA) were measured by liquid chromatography-mass-spectrometry on days 0, 1, 2 and 6. Controls were the same women restudied when healthy (3 months post partum).
RESULTS
I.v. ARS administration resulted in similar ARS and DHA pharmacokinetics in pregnant women with malaria (n = 20) and in controls (n = 14). Oral administration resulted in higher total drug exposure in pregnancy [AUC (95% CI) in (ng ml−1 h)/(mg kg−1)] of 55.1 (30.1, 100.0) vs. 26.5 (12.2, 54.3) for ARS, P = 0.002 and 673 (386, 1130) vs. 523 (351, 724) for DHA, P = 0.007. The corresponding median absolute oral bioavailability (F%) was 21.7 (12.6, 75.1) vs. 9.9 (6.0, 36.81) for ARS (P = 0.046) and 77.0 (42.2, 129) vs. 72.7 (42.0, 87.7) for DHA, P = 0.033. Total DHA exposure was lower at day 6 in pregnant women with malaria (P < 0.001) compared with day 0 or 1, but not in the controls (P = 0.084).
CONCLUSIONS
This study demonstrates the effects of malaria on oral ARS drug disposition are greater than those of pregnancy. This probably results from a disease related reduction in first pass metabolism. The data are reassuring regarding current dosing recommendations.
doi:10.1111/j.1365-2125.2011.04103.x
PMCID: PMC3370352  PMID: 21950338
artesunate; dihyroartemisinin; malaria; pharmacokinetics; post partum; pregnancy
22.  Malaria epidemiology in central Myanmar: identification of a multi-species asymptomatic reservoir of infection 
Malaria Journal  2017;16:16.
Background
The spread of artemisinin-resistant Plasmodium falciparum is a global health concern. Myanmar stands at the frontier of artemisinin-resistant P. falciparum. Myanmar also has the highest reported malaria burden in Southeast Asia; it is integral in the World Health Organization’s plan to eliminate malaria in Southeast Asia, yet few epidemiological data exist for the general population in Myanmar.
Methods
This cross-sectional, probability household survey was conducted in Phyu township, Bago Region (central Myanmar), during the wet season of 2013. Interviewers collected clinical and behavioural data, recorded tympanic temperature and obtained dried blood spots for malaria PCR and serology. Plasmodium falciparum positive samples were tested for genetic mutations in the K13 region that may confer artemisinin resistance. Estimated type-specific malaria PCR prevalence and seroprevalence were calculated, with regression analysis to identify risk factors for seropositivity to P. falciparum. Data were weighted to account for unequal selection probabilities.
Results
1638 participants were sampled (500 households). Weighted PCR prevalence was low (n = 41, 2.5%) and most cases were afebrile (93%). Plasmodium falciparum was the most common species (n = 19. 1.1%) and five (26%) P. falciparum samples harboured K13 mutations. Plasmodium knowlesi was detected in 1.0% (n = 16) and Plasmodium vivax was detected in 0.4% (n = 7). Seroprevalence was 9.4% for P. falciparum and 3.1% for P. vivax. Seroconversion to P. falciparum was 0.003/year in the whole population, but 16-fold higher in men over 23 years old (LR test p = 0.016).
Discussion
This is the first population-based seroprevalence study from central Myanmar. Low overall prevalence was discovered. However, these data suggest endemic transmission continues, probably associated with behavioural risk factors amongst working-age men. Genetic mutations associated with P. falciparum artemisinin resistance, the presence of P. knowlesi and discrete demographic risk groups present opportunities and challenges for malaria control. Responses targeted to working-age men, capable of detecting sub-clinical infections, and considering all species will facilitate malaria elimination in this setting.
doi:10.1186/s12936-016-1651-5
PMCID: PMC5217255  PMID: 28056979
Malaria; Myanmar; Prevalence; Serology; Transmission; Artemisinin; Resistance; Risk factors; Elimination
23.  HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver 
JCI Insight  null;1(21):e87058.
Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis. Notably, this “maladaptive repair” phenotype was recapitulated in mice that lack S1P1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P1 enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.
Activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) in mice stimulates liver regeneration and inhibits fibrosis.
doi:10.1172/jci.insight.87058
PMCID: PMC5161208  PMID: 28018969
24.  Minimal Nocturnal Oxygen Saturation Predicts Future Subclinical Carotid Atherosclerosis: The Wisconsin Sleep Cohort 
Journal of sleep research  2015;24(6):680-686.
SUMMARY
Previous data on the associations between nocturnal oxygen saturation parameters and carotid atherosclerosis are conflicting. We examined the prospective associations of nocturnal oxygen saturation (SaO2) and cardiovascular disease (CVD) risk factors with carotid intima-media thickness (IMT) and plaques. We used data on 689 Wisconsin Sleep Cohort participants who had baseline overnight polysomnography followed by carotid ultrasonography a mean (standard deviation) of 7.8 (2.5) years later. Far wall common carotid IMT was measured using B-mode ultrasound. Bilateral common, bifurcation, and internal carotid artery segments were evaluated for plaque score. Participants were 56 (8) years old (55% male); 32% had hypertension and mean body-mass index was 31 (7) kg/m2. Mean and minimum nocturnal SaO2 were 95% (2) and 86% (7), respectively. Mean percent sleep time with SaO2 <90% was 2% (8). Both mean (odds ratio [OR]=0.60 lower plaque count per 5% higher mean SaO2, 95% CI=0.38–0.96, p=0.033) and minimum SaO2 (OR=0.88 lower plaque count per 5% higher minimum SaO2, 95% CI=0.80–0.97, p=0.013) predicted carotid plaque score after adjusting for age, sex and body-mass index. Minimum SaO2 predicted future plaque score after adding adjustment for traditional CVD risk factors (OR=0.90 lower plaque count per 5% higher minimum SaO2, 95% CI=0.81–0.99, p=0.038). Mean SaO2 was not associated with carotid IMT after CVD risk factor adjustment. We conclude that minimum nocturnal SaO2 is an independent predictor of future carotid plaque burden. Other nocturnal SaO2 parameters are not associated with future carotid IMT or plaques after adjusting for traditional CVD risk factors.
doi:10.1111/jsr.12321
PMCID: PMC4626295  PMID: 26096939
Atherosclerosis; Carotid arteries; Epidemiology; Sleep apnea; Ultrasound
25.  Distinct iris gene expression profiles of primary angle closure glaucoma and primary open angle glaucoma and their interaction with ocular biometric parameters 
Abstract
Background
This study aimed to evaluate differences in iris gene expression profiles between primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG) and their interaction with biometric characteristics.
Design
Prospective study.
Participants
Thirty‐five subjects with PACG and thirty‐three subjects with POAG who required trabeculectomy were enrolled at the Singapore National Eye Centre, Singapore.
Methods
Iris specimens, obtained by iridectomy, were analysed by real‐time polymerase chain reaction for expression of type I collagen, vascular endothelial growth factor (VEGF)‐A, ‐B and ‐C, as well as VEGF receptors (VEGFRs) 1 and 2. Anterior segment optical coherence tomography (ASOCT) imaging for biometric parameters, including anterior chamber depth (ACD), anterior chamber volume (ACV) and lens vault (LV), was also performed pre‐operatively.
Main Outcome Measures
Relative mRNA levels between PACG and POAG irises, biometric measurements, discriminant analyses using genes and biometric parameters.
Results
COL1A1, VEGFB, VEGFC and VEGFR2 mRNA expression was higher in PACG compared to POAG irises. LV, ACD and ACV were significantly different between the two subgroups. Discriminant analyses based on gene expression, biometric parameters or a combination of both gene expression and biometrics (LV and ACV), correctly classified 94.1%, 85.3% and 94.1% of the original PACG and POAG cases, respectively. The discriminant function combining genes and biometrics demonstrated the highest accuracy in cross‐validated classification of the two glaucoma subtypes.
Conclusions
Distinct iris gene expression supports the pathophysiological differences that exist between PACG and POAG. Biometric parameters can combine with iris gene expression to more accurately define PACG from POAG.
doi:10.1111/ceo.12743
PMCID: PMC5111746  PMID: 26988898
biometrics; iris; PACG; POAG

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