Working towards consensus on methods used to elicit participant-reported safety data in uncomplicated malaria clinical drug studies: a Delphi technique study

BACKGROUND: Eliciting adverse event (AE) and non-study medication data reports from clinical research participants is integral to evaluating drug safety. However, using different methods to question participants yields inconsistent results, compromising the interpretation, comparison and pooling of data across studies. This is particularly important given the widespread use of anti-malarials in vulnerable populations, and their increasing use in healthy, but at-risk individuals, as preventive treatment or to reduce malaria transmission. METHODS: Experienced and knowledgeable anti-malarial drug clinical researchers were invited to participate in a Delphi technique study, to facilitate consensus on what are considered optimal (relevant, important and feasible) methods, tools, and approaches for detecting participant-reported AE and non-study medication data in uncomplicated malaria treatment studies. RESULTS: Of 72 invited, 25, 16 and 10 panellists responded to the first, second and third rounds of the Delphi, respectively. Overall, 68% (68/100) of all questioning items presented for rating achieved consensus. When asking general questions about health, panellists agreed on the utility of a question/concept about any change in health, taking care to ensure that such questions/concepts do not imply causality. Eighty-nine percent (39/44) of specific signs and symptoms questions were rated as optimal. For non-study medications, a general question and most structured questioning items were considered an optimal approach. The use of mobile phones, patient diaries, rating scales as well as openly engaging with participants to discuss concerns were also considered optimal complementary data-elicitation tools. CONCLUSIONS: This study succeeded in reaching consensus within a section of the anti-malarial drug clinical research community about using a general question concept, and structured questions for eliciting data about AEs and non-study medication reports. The concepts and items considered in this Delphi to be relevant, important and feasible should be further investigated for potential inclusion in a harmonized approach to collect participant-elicited anti-malarial drug safety data. This, in turn, should improve understanding of anti-malarial drug safety

Efficacy of sulphadoxine-pyrimethamine with or without artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in southern Mozambique: a randomized controlled trial

BACKGROUND: An artemisinin-based combination therapy, artesunate (AS) plus sulphadoxine-pyrimethamine (SP), was compared to SP monotherapy to provide evidence of further treatment options in southern Mozambique. METHODS: Between 2003 and 2005, 411 patients over one year and 10 kg with uncomplicated Plasmodium falciparum malaria were randomly allocated SP (25/1.25 mg per kg day 0) or AS/SP (as above plus 4 mg/kg artesunate days 0, 1 and 2). Allocation was concealed, but treatment was open-label except to microscopists. The primary objective was the relative risk of treatment failure, which was assessed using World Health Organization response definitions modified to a 42-day follow-up. RESULTS: Of the 411 subjects enrolled, 359 (87.3%) completed the follow up period (SP n = 175, AS/SP n = 184). A survival analysis including 408 subjects showed that the polymerase chain reaction-adjusted cure rates were 90.4% (95% confidence interval [CI] 84.9%-93.9%) and 98.0% (95% CI 94.8%-99.3%) for SP and AS/SP respectively. Multivariable analysis showed that treatment with AS/SP decreased the relative hazard of treatment failure by 80% compared to SP (hazard ratio [HR] 0.2; 95% CI 0.1-0.6) and age over seven years decreased the relative hazard of failure by 70% (HR 0.3; 95% CI 0.1-0.9), when compared to younger age. However, having a quintuple dhfr/dhps mutation increased the relative hazard of failure compared to fewer mutations (HR 3.2; 95% CI 1.3-7.5) and baseline axillary temperature increased the relative hazard of failure by 50% for each degreesC increase (HR 1.5; 95% CI 1.1-2.2). CONCLUSION: While both treatments were efficacious, AS plus SP significantly decreased the relative hazard of treatment failure compared to SP monotherapy Artesunate plus sulphadoxine-pyrimethamine, but not sulphadoxine-pyrimethamine monotherapy, met the current WHO criteria of >95% efficacy for policy implementation.TRIAL REGISTRATION:NCT00203736 and NCT0020381

Amino Alkynylisoquinoline and Alkynylnaphthyridine Compounds Potently Inhibit Acute Myeloid Leukemia Proliferation in Mice

B ackground: Acute myeloid leukemia (AML) remains one of the most lethal, rarely cured cancers, despite decades of active development of AML therapeutics. Currently, the 5-year survival of AML patients is about 30% and for elderly patients, the rate drops to b10%. About 30% of AML patients harbor an activating mutation in the tyrosine kinase domain (TKD) of Fms-Like Tyrosine kinase 3 (FLT3) or a FLT3 internal tandem duplication (FLT3-ITD). In- hibitors of FLT3, such as Rydapt that was recently approved by the FDA, have shown good initial response but pa- tients often relapse due to secondary mutations in the FLT3 TKD, like D835Y and F691 L mutations. Methods: Alkynyl aminoisoquinoline and naphthyridine compounds were synthesized via Sonogashira coupling. The compounds were evaluated for their in vitro and in vivo effects on leukemia growth. Findings: The compounds inhibited FLT3 kinase activity at low nanomolar concentrations. The lead compound, HSN431, also inhibited Src kinase activity. The compounds potently inhibited the viability of MV4–11 and MOLM-14 AML cells with IC50 values b1 nM. Furthermore, the viability of drug-resistant AML cells harboring the D835Y and F691 L mutations were potently inhibited. In vivo efficacy studies in mice demonstrated that the compounds could drastically reduce AML proliferation in mice. Interpretation: Compounds that inhibit FLT3 and downstream targets like Src (for example HSN431) are good leads for development as anti-AML agents

Effect of Repeated Anthelminthic Treatment on Malaria in School Children in Kenya: A Randomized, Open-Label, Equivalence Trial.

BACKGROUND: School children living in the tropics are often concurrently infected with plasmodium and helminth parasites. It has been hypothesized that immune responses evoked by helminths may modify malaria-specific immune responses and increase the risk of malaria. METHODS: We performed a randomized, open-label, equivalence trial among 2436 school children in western Kenya. Eligible children were randomized to receive either 4 repeated doses or a single dose of albendazole and were followed up during 13 months to assess the incidence of clinical malaria. Secondary outcomes were Plasmodium prevalence and density, assessed by repeat cross-sectional surveys over 15 months. Analysis was conducted on an intention-to-treat basis with a prespecified equivalence range of 20%. RESULTS: During 13 months of follow-up, the incidence rate of malaria was 0.27 episodes/person-year in the repeated treatment group and 0.26 episodes/person-year in the annual treatment group (incidence difference, 0.01; 95% confidence interval, -.03 to .06). The prevalence and density of malaria parasitemia did not differ by treatment group at any of the cross-sectional surveys. CONCLUSIONS: Our findings suggest that repeated deworming does not alter risks of clinical malaria or malaria parasitemia among school children and that school-based deworming in Africa may have no adverse consequences for malaria. CLINICAL TRIALS REGISTRATION: NCT01658774

Eliciting adverse effects data from participants in clinical trials.

BACKGROUND: Analysis of drug safety in clinical trials involves assessing adverse events (AEs) individually or by aggregate statistical synthesis to provide evidence of likely adverse drug reactions (ADR). While some AEs may be ascertained from physical examinations or tests, there is great reliance on reports from participants to detect subjective symptoms, where he/she is often the only source of information. There is no consensus on how these reports should be elicited, although it is known that questioning methods influence the extent and nature of data detected. This leaves room for measurement error and undermines comparisons between studies and pooled analyses. This review investigated comparisons of methods used in trials to elicit participant-reported AEs. This should contribute to knowledge about the methodological challenges and possible solutions for achieving better, or more consistent, AE ascertainment in trials. OBJECTIVES: To systematically review the research that has compared methods used within clinical drug trials (or methods that would be specific for such trials) to elicit information about AEs defined in the protocol or in the planning for the trial. SEARCH METHODS: Databases (searched to March 2015 unless indicated otherwise) included: Embase; MEDLINE; MEDLINE in Process and Other Non-Indexed Citations; Cochrane Methodology Register (July 2012); Cochrane Central Register of Controlled Trials (February 2015); Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects (January 2015); Health Technology Assessment database (January 2015); CINAHL; CAB Abstracts; BIOSIS (July 2013); Science Citation Index; Social Science Citation Index; Conference Proceedings Citation Index - Science. The search used thesaurus headings and synonyms for the following concepts: (A): Adverse events AND measurement; (B): Participants AND elicitation (also other synonyms for extraction of information about adverse effects from people); (C): Participants AND checklists (also other synonyms as for B). Pragmatic ways were used to limit the results whilst trying to maintain sensitivity. There were no date or sample size restrictions but only reports published in English were included fully, because of resource constraints as regards translation. SELECTION CRITERIA: Two types of studies were included: drug trials comparing two or more methods within- or between-participants to elicit participant-reported AEs, and research studies performed outside the context of a trial to compare methods which could be used in trials (evidenced by reference to such applicability). Primary outcome data included AEs elicited from participants taking part in any such clinical trial. We included any participant-reported data relevant for an assessment of drug-related harm, using the original authors' terminology (and definition, where available), with comment on whether the data were likely to be treatment-emergent AEs or not. DATA COLLECTION AND ANALYSIS: Titles and abstracts were independently reviewed for eligibility. Full texts of potentially eligible citations were independently reviewed for final eligibility. Relevant data were extracted and subjected to a 100% check. Disagreements were resolved by discussion, involving a third author. The risk of bias was independently assessed by two authors. The Cochrane 'Risk of bias' tool was used for reports comparing outcomes between participants, while for within-participant comparisons, each study was critically evaluated in terms of potential impact of the design and conduct on findings using the framework of selection, performance, detection, attrition, reporting, and other biases. An attempt was made to contact authors to retrieve protocols or specific relevant missing information. Reports were not excluded on the basis of quality unless data for outcomes were impossible to compare (e.g. where denominators differed). A narrative synthesis was conducted because differences in study design and presentation meant that a quantitative meta-analysis was not possible. MAIN RESULTS: The 33 eligible studies largely compared open questions with checklist-type questions or rating scales. Two included participant interviews. Despite different designs, populations and details of questioning methods, the narrative review showed that more specific questioning of participants led to more AEs detected compared to a more general enquiry. A subset of six studies suggested that more severe, bothersome, or otherwise clinically relevant AEs were reported when an initial open enquiry was used, while some less severe, bothersome, or clinically relevant AEs were only reported with a subsequent specific enquiry. However, two studies showed that quite severe or debilitating AEs were only detected by an interview, while other studies did not find a difference in the nature of AEs between elicitation methods. No conclusions could be made regarding the impact of question method on the ability to detect a statistically significant difference between study groups. There was no common statistical rubric, but we were able to represent some effect measures as a risk ratio of the proportion of participants with at least one AE. This showed a lower level of reporting for open questions (O) compared to checklists (CL), with a range for the risk ratios of 0.12 to 0.64. AUTHORS' CONCLUSIONS: This review supports concerns that methods to elicit participant-reported AEs influence the detection of these data. There was a risk for under-detection of AEs in studies using a more general elicitation method compared to those using a comprehensive method. These AEs may be important from a clinical perspective or for patients. This under-detection could compromise ability to pool AE data. However, the impact on the nature of the AE detected by different methods is unclear. The wide variety and low quality of methods to compare elicitation strategies limited this review. Future studies would be improved by using and reporting clear definitions and terminology for AEs (and other important variables), frequency and time period over which they were ascertained, how they were graded, assessed for a relationship to the study drug, coded, and tabulated/reported. While the many potential AE endpoints in a trial may preclude the development of general AE patient-reported outcome measurement instruments, much could also be learnt from how these employ both quantitative and qualitative methods to better understand data elicited. Any chosen questioning method needs to be feasible for use by both staff and participants

Fluctuation solution theory of pure fluids

Citation: Ploetz, E. A., Pallewela, G. N., & Smith, P. E. (2017). Fluctuation solution theory of pure fluids. Journal of Chemical Physics, 146(9), 13. doi:10.1063/1.4977040Fluctuation Solution Theory (FST) provides an alternative view of fluid thermodynamics in terms of pair fluctuations in the particle number and excess energy observed for an equivalent open system. Here we extend the FST approach to provide a series of triplet and quadruplet particle and excess energy fluctuations that can also be used to help understand the behavior of fluids. The fluctuations for the gas, liquid, and supercritical regions of three fluids (H2O, CO2, and SF6) are then determined from accurate equations of state. Many of the fluctuating quantities change sign on moving from the gas to liquid phase and, therefore, we argue that the fluctuations can be used to characterize gas and liquid behavior. Further analysis provides an approach to isolate contributions to the excess energy fluctuations arising from just the intermolecular interactions and also indicates that the triplet and quadruplet particle fluctuations are related to the pair particle fluctuations by a simple power law for large regions of the phase diagram away from the critical point. Published by AIP Publishing

Eliciting harms data from trial participants: how perceptions of illness and treatment mediate recognition of relevant information to report

Background: There is no consensus on the ideal methodology for eliciting participant-reported harms, but question methods influence the extent and nature of data detected. This gives potential for measurement error and undermines meta-analyses of adverse effects. We undertook to identify barriers to accurate and complete reporting of harms data, by qualitatively exploring participants’ experiences of illness and treatment, and reporting behaviours; and compared the number and nature of data detected by three enquiry methods. Methods: Participants within antiretroviral/antimalarial interaction trials in South Africa and Tanzania were asked about medical history, treatments and/or adverse events by general enquiries followed by checklists. Those reporting differently between these two question methods were invited to an in-depth interview and focus group discussion. Health narratives were analysed to investigate accuracy and completeness of case record form data and to understand reasons for differential reporting between question methods. Outcomes were the number and nature of data by question method, themes from qualitative analyses and a theoretical interpretation of participants’ experiences. Results: We observed a cumulative increase in sensitivity of detection of all types of reports while progressing from general enquiry, through checklist, to in-depth interview. Questioning detail and terminology influenced participants’ recognition of health issues and treatments. Reporting patterns and vocabulary suggest influence from the relative importance that illnesses and treatments have for participants. Perceptions were often dichotomised (e.g. ‘street’ versus clinic treatments, symptoms experienced versus tests and examinations performed, chronic versus acute illness, persistent versus intermittent symptoms, activity- versus malaria-related symptoms) and this differentiation extended to ideas of relevance to report. South African participants displayed a ‘trial citizenship’, taking responsibility for the impact of their reporting on trial results, and even reaching reporting decisions by consensus. In contrast, Tanzanians perceived their role more as patients than participants; the locus of responsibility for knowing information relevant to the trial fell with trial staff as doctors rather than with themselves. Conclusions: Our observations of how reporting relates to participant perceptions inside and outside trials could help optimise how harms data are elicited. Questions reflecting the different ways that biomedically defined illness and treatment data are perceived by participants may help them understand relevance for reporting. We will theorise how these two disparate trial environments may have influenced how participants understood their role, as this could help researchers achieve empowered participation in similar trials

Silicon based substrate with yttrium silicate environmental/thermal barrier layer

A barrier layer for a silicon containing substrate which inhibits the formation of gaseous species of silicon when exposed to a high temperature aqueous environment comprises a yttrium silicate