Phaik Yeong Cheah

Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker

Summary Background Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. Methods We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Findings Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Interpretation Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Funding Wellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.

Improving the radical cure of vivax malaria (IMPROV): a study protocol for a multicentre randomised, placebo-controlled comparison of short and long course primaquine regimens

Plasmodium vivax malaria is a major cause of morbidity and recognised as an important contributor to mortality in some endemic areas. The current recommended treatment regimen for the radical cure of P. vivax includes a schizontocidal antimalarial, usually chloroquine, combined with a 14 day regimen of primaquine. The long treatment course frequently results in poor adherence and effectiveness. Shorter courses of higher daily doses of primaquine have the potential to improve adherence and thus effectiveness without compromising safety. The proposed multicentre randomised clinical trial aims to provide evidence across a variety of endemic settings on the safety and efficacy of high dose short course primaquine in glucose-6-phosphate-dehydrogenase (G6PD) normal patients. This study is designed as a placebo controlled, double blinded, randomized trial in four countries: Indonesia, Vietnam, Afghanistan and Ethiopia. G6PD normal patients diagnosed with vivax malaria are randomized to receive either 7 or 14 days high dose primaquine or placebo. G6PD deficient (G6PDd) patients are allocated to weekly primaquine doses for 8 weeks. All treatment is directly observed and recurrent episodes are treated with the same treatment than allocated at the enrolment episode. Patients are followed daily until completion of treatment, weekly until 8 weeks and then monthly until 1 year after initiation of the treatment. The primary endpoint is the incidence rate (per person year) of symptomatic recurrent P. vivax parasitaemia over 12 months of follow-up, for all individuals, controlling for site, comparing the 7 versus 14-day primaquine treatment arms. Secondary endpoints are other efficacy measures such as incidence risk at different time points. Further endpoints are risks of haemolysis and severe adverse events. This study has been approved by relevant institutional ethics committees in the UK and Australia, and all participating countries. Results will be disseminated to inform P. vivax malaria treatment policy through peer-reviewed publications and academic presentations. Findings will contribute to a better understanding of the risks and benefits of primaquine which is crucial in persuading policy makers as well as clinicians of the importance of radical cure of vivax malaria, contributing to decreased transmission and a reduce parasite reservoir. ClinicalTrials.gov Identifier: NCT01814683. Registered March 18, 2013

Epidemiology of prostatitis: new evidence for a world-wide problem

We review new data on the epidemiology of chronic prostatitis. These population-based studies used reasonable case-definitions to survey various populations from North America, Europe and Asia. Overall, 2–10% of adult men suffer from symptoms compatible with chronic prostatitis at any time and approximately 15% of men suffer from symptoms of prostatitis at some point in their lives. Other epidemiologic data suggest that chronic prostatitis may be associated with an increased risk for development of benign prostatic hyperplasia and prostate cancer. These data suggest that chronic prostatitis is an important international health care problem that merits increased priority from clinicians and researchers.

Adverse Impact of Sexual Dysfunction in Chronic Prostatitis/Chronic Pelvic Pain Syndrome

OBJECTIVES To examine the prevalence, characteristics, and impact of sexual dysfunction in our primary care referral population. METHODS Participants seeking treatment for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) were recruited from general urology clinics. The subjects completed the National Institutes of Health-Chronic Prostatitis Symptom Index, International Index of Erectile Function-5, and selected questions from the University of Washington Symptom Score. Additional information on demographics and medical and treatment history were also obtained. Sexual dysfunction was defined as self-reported erectile dysfunction (ED) or ejaculatory difficulty, or both. RESULTS Of 296 participants with CP/CPPS, 214 (72.3%) reported sexual dysfunction. The National Institutes of Health-Chronic Prostatitis Symptom Index total score averaged 22.5 +/- 6.9 for participants with sexual dysfunction compared with 20.4 +/- 7.8 for participants who did not report sexual dysfunction (P = 0.03). Of the 214 participants with sexual dysfunction, 54 (25.0%) complained of ED only, 71 (33.4%) complained of ejaculatory difficulties only, and 89 (41.6%) complained of both ED and ejaculatory difficulties. Men reporting both ED and ejaculatory difficulty reported worse CP/CPPS symptoms (analysis of variance, P = 0.042) and worse quality of life (analysis of variance, P = 0.006) than men without sexual dysfunction. CONCLUSIONS Sexual dysfunction was reported by almost three quarters of patients with CP/CPPS. Patients with CP/CPPS and sexual dysfunction experienced substantially worse symptoms, particularly worse quality of life, than other patients with CP/CPPS. Sexual dysfunction merits consideration as an important aspect of CP/CPPS and a potential outcome measure.

Randomized, Double-Blind, Placebo-Controlled Trial of Monthly versus Bimonthly Dihydroartemisinin-Piperaquine Chemoprevention in Adults at High Risk of Malaria

ABSTRACT Intermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day-treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49 Plasmodium falciparum, 63 P. vivax, and 2 P. ovale). The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both, P < 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (P < 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area where P. vivax and multidrug-resistant P. falciparum malaria are endemic.

Clinical Research in Resource-Limited Settings: Enhancing Research Capacity and Working Together to Make Trials Less Complicated

Our aim is to raise awareness of the issues faced by researchers in developing countries and to introduce an initiative we are developing. We propose that the gaps and issues we have outlined could be largely addressed by building a community of researchers from all the various roles who will be able to access the information, guidance and resources they need, whilst also be able to share methods and pragmatic operational practices that have been locally derived and known to work. Some examples include template consent forms, data management systems, and example protocols and laboratory sample collection and handling methods. We emphasize that this initiative is entirely based on an ethos of collaboration, open access, and sharing practice; indeed it will only be successful if research groups both use the resource and contribute to its development. The development of a prototype of web site for this initiative is underway and can be found at http://pilot.globalhealthtrials.org/. We are making this public at this early juncture as we are seeking involvement from our colleagues right from the outset in line with the open and collaborative ethos that is envisaged. Therefore, we encourage colleagues to become part of this initiative by providing content, commenting on the Web site, and sharing their operational tools. We also welcome all those engaged in trials to register and build their own personal professional development record to track their career and training record, and to provide a review structure.

Terazosin Therapy for Patients With Female Lower Urinary Tract Symptoms: A Randomized, Double-Blind, Placebo Controlled Trial

PURPOSE We determined the clinical efficacy and safety of terazosin in the treatment of patients with female lower urinary tract symptoms. MATERIALS AND METHODS A total of 100 females 20 to 70 years old who met the inclusion criteria of total International Prostate Symptom Score 8 or greater, symptom duration 1 or more months, and did not meet any exclusion criteria were entered into the study. Subjects were randomized to receive terazosin or placebo in titrated dose from 1 mg od, 1 mg twice daily to 2 mg twice daily during 14 weeks. Successful treatment outcomes use primary end point of International Prostate Symptom Score quality of life 2 or less and secondary end point of total International Prostate Symptom Score 7 or less. Other outcome measures included International Prostate Symptom Score individual item scores, Kings Health Questionnaire quality of life domains, objective assessment parameters of 24-hour frequency volume chart, maximum flow rate and post-void residual urine. RESULTS Using a primary end point, 32 of 40 (80%) evaluable terazosin subjects responded in contrast to 22 of 40 (55%) evaluable placebo subjects (p <0.02). The secondary end point revealed a successful outcome in 85% of terazosin subjects vs 55% in placebo (p <0.01). Of the 7 International Prostate Symptom Score individual item scores, only item scores of frequency and straining showed statistically significant reductions with terazosin (p <0.01). All Kings Health Questionnaire quality of life domains except domain of severity measures showed statistically significant improvement with terazosin (p <0.05). There were no differences between treatment groups in all objective assessment parameters. Of all evaluable subjects 23 of 40 (58%) on placebo experienced adverse events vs 16 of 40 (40%) on terazosin (p >0.05). CONCLUSIONS Terazosin proved to be more effective and safe than placebo in patients with female lower urinary tract symptoms.

Improved high-performance liquid chromatographic analysis of terazosin in human plasma

A simple, sensitive and reproducible high-performance liquid chromatography (HPLC) method was developed for the determination of terazosin in human plasma. The method involves a one-step single solvent extraction procedure using dichloromethane with a 0.25 ml plasma sample. Recovery values were all greater than 90% over the concentration range 0.25-100 ng/ml. Terazosin was found to adsorb to glass or plastic tubes, but this could be circumvented by using disposable plastic tubes. Also, rinsing the injector port with methanol after each injection helped to prevent any carry-over effect. The internal standard, prazosin, did not exhibit this problem. The method has a quantification limit of 0.25 ng/ml. The within- and between-day coefficient of variation and accuracy values were all less than 7% over the concentration range 0.25-100 ng/ml and hence the method is suitable for use in pharmacokinetic studies of terazosin.

Clinical research: time for sensible global guidelines

Clinical research is being slowly strangled by bureaucracy because guidelines that were developed for product-registration trials are being applied rigidly to all types of clinical research. Complex, often confusing, and readily misinterpreted regulations, and their consequent spiralling costs, are a dangerous disincentive to medical progress. The problem is already serious and is now being exported to the developing world—which can least aff ord it. Populations in developing countries are under-represented in all areas of clinical research, yet those regions of the world that carry the highest disease burdens obviously decision, which is based on willingness to pay, perhaps varied by modifi ers (such as to reward innovation and support end-of-life drugs), and with a broader perspective than used by NICE to address, for instance, the benefi ts of getting people re-employed and reducing their need for carers. Evidence-based decisions that are made before drugs are launched, rather than after they are used in the real world, will off er greater uncertainty, and will need diffi cult judgements requiring clinical involvement. Decisions might need to be reviewed again as evidence emerges, termed “coverage with evidence development” and, theoretically at least, prices might go up or down. Here, rather than with the risk-sharing scheme used for interferon beta, there will need to be explicit agreement on what new evidence is needed and to what timescale. Clearly, NICE will have a major role in this new process, including in the production of guidelines to support clinical use, although no longer with the problem of having to say no to new medicines but, instead, indicating what price will allow a yes. Eff ective engagement between industry and govern ment will be crucial, as will recognition that the UK benefi ts from having a thriving and profi table biopharmaceutical industry. The Pharmaceutical Price Regulation Scheme has traditionally allowed pharmaceutical companies to charge premium prices and, because the UK is widely used as a pricing reference for other countries, new medicines have been launched early in the UK, allowing patients to benefi t earlier. Should manufacturers sideline the UK and launch later, this might adversely aff ect employment, biomedical science, and patients. Whether the price to the NHS will address these broad issues, or whether incentives to industry might be better managed in other ways, is arguable. Diffi culties are always likely to arise for an innovative drug, in an area of unmet need, where the incremental benefi t is small. Value-based pricing seems to benefi t the NHS and patients, and NICE will remain central. Although cost savings might be implicit, they may not occur, especially if there is pricing to the threshold. Ultimately, although there are a number of potential diffi culties to overcome, the biggest challenge could come from primary care in England. Whereas NICE recommendations were mandatory, general practice consortia might choose not to purchase some of the more costly, but cost-eff ective, new developments, and therefore postcode prescribing will once more be under the media spotlight.

Consent and community engagement in diverse research contexts: reviewing and developing research and practice

Consent and community engagement (CE) in health research are two aspects of a single concern—that research is carried out in a respectful manner where social value is maximized. There are important overlaps and interdependencies between consent and CE; for example, CE can provide insights into how best to tailor consent to context and can be an important component of consent processes. Engaging communities can also have intrinsic and instrumental value beyond consent; for example, as a means of showing respect and identifying appropriate ways of working respectfully. In this paper we critically examine how CE and consent processes are characterized, conducted, and evaluated in diverse health research contexts, and propose a preliminary research agenda to support future learning in these critical areas.Consent and community engagement (CE) in health research are two aspects of a single concern-that research is carried out in a respectful manner where social value is maximized. There are important overlaps and interdependencies between consent and CE; for example, CE can provide insights into how best to tailor consent to context and can be an important component of consent processes. Engaging communities can also have intrinsic and instrumental value beyond consent; for example, as a means of showing respect and identifying appropriate ways of working respectfully. In this paper we critically examine how CE and consent processes are characterized, conducted, and evaluated in diverse health research contexts, and propose a preliminary research agenda to support future learning in these critical areas.