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Siegfried discusses the first reported randomized controlled trial of whether circumcision protects against HIV, published in PLoS Medicine.

Background Transparent and complete publications of randomised controlled trials (RCT) ought to comply with the guidelines of the CONSORT Statement, which stipulates sample size calculation as an important aspect of trial planning. The objective of this study was to analyse and compare the reporting of statistical sample size calculations in RCT papers on the treatment of age-related macular degeneration (AMD), glaucoma and cataract published in 2018. Material and methods This study comprises a total of 113 RCT papers (RCT-P) published in 2018 (AMD: 14, glaucoma: 28, cataract: 71), in English or German, and identified through an internet-based literature search in PubMed and EMBASE. The primary outcome measure of the study was the number of trials providing a complete description of the underlying sample case calculation on the basis of the variables required (significance level, expected outcomes, power, and resulting sample size). Results Of the RCTs reviewed, 64% (AMD), 61% (glaucoma) and 31% (cataract) provided a justification of the number of patients included. A complete description of the described studies’ sample size calculation including all the necessary values (primary outcome measure of this study) was described by 21% of the AMD, 29% of the cataract and 18% of the glaucoma RCT publications (in total: 24 of 113 (21%) at a confidence interval of 95%: [13%; 29%]). Conclusion All three treatment areas analysed lacked reporting quality regarding the justification of the number of patients included in a clinical trial based on a sample size calculation required for ethical reasons. More than half of all RCT publications reviewed did not provide all of the required information on statistical sample size calculation, and thus lacked transparency and completeness. It is therefore urgently required to involve methodologists in a study’s planning and publishing processes to ensure that methodology descriptions are transparent and of high quality.

Fundamental scientific advances can take decades to translate into improvements in human health. Shortening this interval would increase the rate at which scientific discoveries lead to successful treatment of human disease. One way to accomplish this would be to identify which advances in knowledge are most likely to translate into clinical research. Toward that end, we built a machine learning system that detects whether a paper is likely to be cited by a future clinical trial or guideline. Despite the noisiness of citation dynamics, as little as 2 years of postpublication data yield accurate predictions about a paper’s eventual citation by a clinical article (accuracy = 84%, F1 score = 0.56; compared to 19% accuracy by chance). We found that distinct knowledge flow trajectories are linked to papers that either succeed or fail to influence clinical research. Translational progress in biomedicine can therefore be assessed and predicted in real time based on information conveyed by the scientific community’s early reaction to a paper., Fundamental scientific advances can take decades to translate into improvements in human health. This study shows that a machine learning model can accurately predict whether an article is likely to be cited by a future clinical trial or guideline, using as little as two years of post-publication citation data.

Quality circles or peer review groups, and similar structured small groups of 6-12 health care professionals meet regularly across Europe to reflect on and improve their standard practice. There is debate over their effectiveness in primary health care, especially over their potential to change practitioners' behaviour. Despite their popularity, we could not identify broad surveys of the literature on quality circles in a primary care context. Our scoping review was intended to identify possible definitions of quality circles, their origins, and reported effectiveness in primary health care, and to identify gaps in our knowledge. We searched appropriate databases and included any relevant paper on quality circles published until December 2017. We then compared information we found in the articles to that we found in books and on websites. Our search returned 7824 citations, from which we identified 82 background papers and 58 papers about quality circles. We found that they originated in manufacturing industry and that many countries adopted them for primary health care to continuously improve medical education, professional development, and quality of care. Quality circles are not standardized and their techniques are complex. We identified 19 papers that described individual studies, one paper that summarized 3 studies, and 1 systematic review that suggested that quality circles can effectively change behaviour, though effect sizes varied, depending on topic and context. Studies also suggested participation may affirm self-esteem and increase professional confidence. Because reports of the effect of quality circles on behaviour are variable, we recommend theory-driven research approaches to analyse and improve the effectiveness of this complex intervention.

BACKGROUND: Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. OBJECTIVES: We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. METHODS: Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. RESULTS: Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P

Background Effective risk communication is challenging. Ensuring potential trial participants’ understand ‘risk’ information presented to them is a key aspect of the informed consent process within clinical trials, yet minimal research has looked specifically at how to communicate probabilities to support decisions about trial participation. This study reports a systematic review of the literature focusing on presentation of probabilistic information or understanding of risk by potential trial participants. Methods A search strategy for risk communication in clinical trials was designed and informed by systematic reviews of risk communication in treatment and screening contexts and supplemented with trial participation terms. Extracted data included study characteristics and the main interventions/findings of each study. Explanatory studies that investigated the methods for presenting probabilistic information within participant information leaflets for a clinical trial were included, as were interventions that focused on optimising understanding of probabilistic information within the context of a clinical trial. Results The search strategy identified a total of 4931 studies. Nineteen papers were selected for full text screening, and seven studies included. All reported results from risk communication studies that aimed to support potential trial participants’ decision making set within hypothetical trials. Five of these were randomised comparisons of risk communication interventions, and two were prospectively designed, non-randomised studies. Study interventions focused on probability presentation, risk framing and risk interpretation with a wide variety of interventions being evaluated and considerable heterogeneity in terms of outcomes assessed. Studies show conflicting findings when it comes to how best to present information, although numerical, particularly frequency formats and some visual aids appear to have promise. Conclusions The evidence base surrounding risk communication in clinical trials indicates that there is as yet no clear optimal method for improving participant understanding, or clear consensus on how it affects their willingness to participate. Further research into risk communication within trials is needed to help illuminate the mechanisms underlying risk perception and understanding and provide appropriate ways to present and communicate risk in a trial context so as to further promote informed choices about participation. A key focus for future research should be to investigate the potential for learning in the evidence on risk communication from treatment and screening decisions when applied to decisions about trial participation.

During the West African Ebola Virus Disease (EVD) epidemic from 2014 to 2016, a variety of technologies travelled considering the context of the emergency: a highly contagious fast-killing disease outbreak with no known remedy and a rapidly increasing number of cases. The Ebola-Tx clinical trial tested the efficacy of Convalescent Plasma (CP) as a treatment for EVD in Guinea. This paper is based on ethnographic research in the Ebola-Tx trial and focuses on the introduction of a mobile plasma collection centre, referred to as the ‘Plasma Mobile’, equipped with plasmapheresis and pathogen inactivation technologies, as well as how the transfer itself of this technology entailed complex effects on CP donors as trial participants (i.e. providers of the therapeutic product), directly involved staff and more broadly on the trial implementation as a whole. The transfer led to the emergence of a dimension of hope as CP donors hoped that the plasma would cure and, as providers of the therapeutic, hoped it would decrease their stigmatization and the economic impact of the disease. We conclude that, in light of the intricate effects that the transfer of such health technology can entail–in the localization to the specific context, as well as in the consequences they can have on actors involved in the implementation of such technologies–global health technologies should be put at the services of next epidemic and pandemic (preparedness) on condition that they are accompanied by an understanding of the technologies’ own cultural meanings and social understandings., Author summary The Ebola-Tx trial tested the efficacy of Convalescent Plasma (CP) as a treatment for Ebola Virus Disease (EVD) in Guinea during the 2014–2016 West African outbreak. As part of the trial, a bus equipped with plasmapheresis and pathogen inactivation technologies, referred to as the ‘Plasma Mobile’, was used to collect plasma from Ebola survivors, hence recruited as CP donors. Previous studies on clinical trials during the EVD outbreak in West Africa showed positive impact triggered by the introduction of technologies such as improvements in work conditions and care. In our ethnographic research on the Plasma Mobile as transferred technology, we show that technologies contributed to bringing less stress and mistrust in the (highly sensitive issue of the) use of blood products. The organization of the technology in the Plasma Mobile aimed at avoiding mistakes and improving staff performance. In sum, we describe the effects of technologies in staff and CP donors, including the hope for new and improved futures for donors and EVD patients. These results may shed light upon epidemic preparedness, for instance on the need for providing cultural meaning and social understandings to the transfer of technologies.

BackgroundIn oncology, the aim of dose-finding phase I studies is to find the maximum tolerated dose for further studies. The use of combinations of two or more agents is increasing. Several dose-finding designs have been proposed for this situation. Numerous publications have however pointed out the complexity of evaluating therapies in combination due to difficulties in choosing between different designs for an actual trial, as well as complications related to their implementation and application in practice.MethodsIn this work, we propose R functions for Wang and Ivanova's approach. These functions compute the dose for the next patients enrolled and provide a simulation study in order to calibrate the design before it is applied and to assess the performance of the design in different scenarios of dose-toxicity relationships. This choice of the method was supported by a simulation study which the aim was to compare two designs in the context of an actual phase I trial: i) in 2005, Wang and Ivanova developed an empirical three-parameter model-based method in Bayesian inference, ii) in 2008, Yuan and Yin proposed a simple, adaptive two-dimensional dose-finding design. In particular, they converted the two-dimensional dose-finding trial to a series of one-dimensional dose-finding sub-trials by setting the dose of one drug at a fixed level. The performance assessment of Wang's design was then compared with those of designs presented in the paper by Hirakawa et al. (2015) in their simulation context.Results and conclusionIt is recommended to assess the performances of the designs in the context of the clinical trial before beginning the trial. The two-dimensional dose-finding design proposed by Wang and Ivanova is a comprehensive approach that yields good performances. The two R functions that we propose can facilitate the use of this design in practice.

BackgroundScreening, brief intervention, and referral to treatment (SBIRT) for risky substance use is infrequently included in routine healthcare in low-resourced settings. A SBIRT programme, adopted by the Western Cape provincial government within an alcohol harm reduction strategy, employed various implementation strategies executed by a diverse team to translate an evidence-based intervention into services at three demonstration sites before broader programme scale-up. This paper evaluates the implementation of this programme delivered by facility-based counsellors in South African emergency centres.MethodGuided by the Consolidated Framework for Implementation Research, this mixed methods study evaluated the feasibility, acceptability, appropriateness and adoption of this task-shared SBIRT programme. Quantitative data were extracted from routinely collected health information. Qualitative interviews were conducted with 40 stakeholders in the programme's second year.ResultsIn the first year, 13 136 patients were screened and 4 847 (37%) patients met criteria for risky substance use. Of these patients, 83% received the intervention, indicating programme feasibility. The programme was adopted into routine services and found to be acceptable and appropriate, particularly by stakeholders familiar with the emergency environment. These stakeholders highlighted the burden of substance-related harm in emergency centres and favourable patient responses to SBIRT. However, some stakeholders expressed scepticism of the behaviour change approach and programme compatibility with emergency centre operations. Furthermore, adoption was both facilitated and hampered by a top-down directive from provincial leadership to implement SBIRT, while rapid implementation limited effective engagement with a diverse stakeholder group.ConclusionThis is one of the first studies to address SBIRT implementation in low-resourced settings. The results show that SBIRT implementation and adoption was largely successful, and provide valuable insights that should be considered prior to implementation scale-up. Recommendations include ensuring ongoing monitoring and evaluation, and early stakeholder engagement to improve implementation readiness and programme compatibility in the emergency setting.

The development of a new drug is an extremely high-risk enterprise. The attrition rates of development projects and the average costs for each launched product are daunting, and the completion of a development program requires a very long time horizon. These facts imply that there are huge potential gains, should one be able to improve efficiency and enhance decision-making capabilities. In this paper, we argue that substantial gains can be achieved by adapting a holistic view of drug development. Historically, too much planning, design and decision-making in the pharmaceutical development has been based on locally optimising separate parts of the development program, and too often important sources of uncertainty are ignored. We propose instead a model-based approach built on two essential pillars; (1) an integrated holistic view of the development program, including post-launch marketing and sales, with all parts evaluated simultaneously; (2) an explicit appreciation of all relevant sources of uncertainty. Computer simulations are utilised to evaluate the properties of the program options at hand, and to provide valuable quantitative decision support. Applications of this modelling approach have proven to add large value to development projects in terms of better program options being generated and more value-adding decisions taken.

I am in complete agreement with the suggestion by Matthew Falagas [1] that a unique author identification number (UAIN) would represent a major improvement for the use of databases of scientific publications. In this regard, I perceive that he has not mentioned several other important advantages that a UAIN system would provide, and that are worth pointing to: 1. When looking up someone's publications, the fact that the last name of a given person can vary from one paper to another can be as much of a problem as that of multiple authors with the same name. For example, these variations include women who change their last name after getting married (or divorced), middle initials that are sometimes included or omitted, translations from non-Roman alphabets that result in variable spellings, and people with last names composed of several terms that can sometimes appear in databases as split or truncated. 2. Contrarily to M. Falagas, I do not see any good reason why a UAIN system could not be retroactive. It is clearly in every scientist's interest to facilitate the job of other people who want to look up their work. I therefore believe that authors could be asked to register for a UAIN, and to validate their list of publications themselves, retroactively. Even for the most productive scientists, this would take only a few minutes, and the fact that they had registered for a UAIN allowing users to trace their whole list of publications could then be indicated in the display of search results from the various bibliographic databases. I also do not see any reason for “hiding” this UAIN. I suggest that it could be designed to be quite simple to remember and to communicate to others, for example: the first four or five letters of the last name followed by the initial of the first name followed by the year of first scientific publication followed by an incremental number depending on order of registration (my UAIN would be JOLY-E-89-01). It would therefore be something quite comparable in length and spirit to a car's licence plate and, like UK licence plates, it would provide an interesting clue regarding the seniority of its bearer. 3. This type of UAIN would therefore provide a very simple way to assess a person's productivity. It would also provide a very useful means to assess the actual impact of their work in terms of citations, by discriminating between self-citation and citations by others. Today, most people are evaluated via the impact factor of the journals in which they have managed to publish their work, and not by the actual impact of the papers themselves. Although most scientists acknowledge that this is an extremely crude and unfair way of assessing the quality of someone's production, the impact factor lives on. By providing the simple means to track someone's bibliographic record and thus facilitate the evaluation of their productivity, I believe that the introduction of a UAIN system will not only help the scientific community to exploit bibliographic databases more efficiently, but also represent a major step towards getting rid of the despotic domination of the dreaded impact factors of journals as a means to evaluate the quality of scientific papers.

Recently, multi-regional clinical trials (MRCTs), which incorporate subjects from many countries/regions around the world under the same protocol, have been widely conducted by many global pharmaceutical companies. The objective of such trials is to accelerate the development process for a drug and shorten the drug's approval time in key markets. Several statistical methods have been purposed for the design and evaluation of MRCTs, as well as for assessing the consistency of treatment effects across all regions with one primary endpoint. However, in some therapeutic areas (e.g., Alzheimer's disease), the clinical efficacy of a new treatment may be characterized by a set of possibly correlated endpoints, known as multiple co-primary endpoints. In this paper, we focus on a specific region and establish three statistical criteria for evaluating consistency between the specific region and overall results in MRCTs with multiple co-primary endpoints. More specifically, two of those criteria are used to assess whether the treatment effect in the region of interest is as large as that of the other regions or of the regions overall, while the other criterion is used to assess the consistency of the treatment effect of the specific region achieving a pre-specified threshold. The sample size required for the region of interest can also be evaluated based on these three criteria.

Introduction We examined the design, analysis and reporting in multi-reader multi-case (MRMC) research studies using the area under the receiver-operating curve (ROC AUC) as a measure of diagnostic performance. Methods We performed a systematic literature review from 2005 to 2013 inclusive to identify a minimum 50 studies. Articles of diagnostic test accuracy in humans were identified via their citation of key methodological articles dealing with MRMC ROC AUC. Two researchers in consensus then extracted information from primary articles relating to study characteristics and design, methods for reporting study outcomes, model fitting, model assumptions, presentation of results, and interpretation of findings. Results were summarized and presented with a descriptive analysis. Results Sixty-four full papers were retrieved from 475 identified citations and ultimately 49 articles describing 51 studies were reviewed and extracted. Radiological imaging was the index test in all. Most studies focused on lesion detection vs. characterization and used less than 10 readers. Only 6 (12%) studies trained readers in advance to use the confidence scale used to build the ROC curve. Overall, description of confidence scores, the ROC curve and its analysis was often incomplete. For example, 21 (41%) studies presented no ROC curve and only 3 (6%) described the distribution of confidence scores. Of 30 studies presenting curves, only 4 (13%) presented the data points underlying the curve, thereby allowing assessment of extrapolation. The mean change in AUC was 0.05 (−0.05 to 0.28). Non-significant change in AUC was attributed to underpowering rather than the diagnostic test failing to improve diagnostic accuracy. Conclusions Data reporting in MRMC studies using ROC AUC as an outcome measure is frequently incomplete, hampering understanding of methods and the reliability of results and study conclusions. Authors using this analysis should be encouraged to provide a full description of their methods and results.

Network meta-analysis (NMA) – a statistical technique that allows comparison of multiple treatments in the same meta-analysis simultaneously – has become increasingly popular in the medical literature in recent years. The statistical methodology underpinning this technique and software tools for implementing the methods are evolving. Both commercial and freely available statistical software packages have been developed to facilitate the statistical computations using NMA with varying degrees of functionality and ease of use. This paper aims to introduce the reader to three R packages, namely, gemtc, pcnetmeta, and netmeta, which are freely available software tools implemented in R. Each automates the process of performing NMA so that users can perform the analysis with minimal computational effort. We present, compare and contrast the availability and functionality of different important features of NMA in these three packages so that clinical investigators and researchers can determine which R packages to implement depending on their analysis needs. Four summary tables detailing (i) data input and network plotting, (ii) modeling options, (iii) assumption checking and diagnostic testing, and (iv) inference and reporting tools, are provided, along with an analysis of a previously published dataset to illustrate the outputs available from each package. We demonstrate that each of the three packages provides a useful set of tools, and combined provide users with nearly all functionality that might be desired when conducting a NMA.

BACKGROUND:This paper presents findings from a qualitative investigation of ethical and participatory issues related to the conduct of biomedical HIV prevention trials among marginalized populations in Thailand. This research was deemed important to conduct, as several large-scale biomedical HIV prevention trials among marginalized populations had closed prematurely in other countries, and a better understanding of how to prevent similar trial closures from occurring in the future was desired. METHODS:In-depth key informant interviews were held in Bangkok and Chiang Mai, Thailand. Interviews were audio recorded, transcribed, translated and thematically analyzed. The Good Participatory Practice Guidelines for Biomedical HIV Prevention Trials (GPP) guided this work. RESULTS:Fourteen interviews were conducted: 10 with policymakers, academic and community-based researchers and trial staff and four with representatives of non-governmental organizations (NGOs). Suggested ways to improve ethical and participatory practice centered on standards of HIV prevention, informed consent, communication and human rights. In particular, the need to overcome language and literacy differences was identified. Key informants felt communication was the basis of ethical understanding and trust within biomedical HIV prevention trial contexts, and thus fundamental to trial participants' ability to exercise free will. DISCUSSION:Biomedical HIV prevention trials present opportunities for inclusive and productive ethical and participatory practice. Key informants suggested that efforts to improve practice could result in better relationships between research stakeholders and research investigative teams and by extension, better, more ethical participatory trials. This research took place in Thailand and its findings apply primarily to Thailand. However, given the universality of many ethical considerations, the results of this study can inform the improvement of ethical and participatory practice in other parts of the world where biomedical HIV prevention trials occur, and where clinical trials in marginalized populations continue.

Grade information has been considered in Yuan et al. (2007) wherein they proposed a Quasi-CRM method to incorporate the grade toxicity information in phase I trials. A potential problem with the Quasi-CRM model is that the choice of skeleton may dramatically vary the performance of the CRM model, which results in similar consequences for the Quasi-CRM model. In this paper, we propose a new model by utilizing bayesian model selection approach – Robust Quasi-CRM model – to tackle the above-mentioned pitfall with the Quasi-CRM model. The Robust Quasi-CRM model literally inherits the BMA-CRM model proposed by Yin and Yuan (2009) to consider a parallel of skeletons for Quasi-CRM. The superior performance of Robust Quasi-CRM model was demonstrated by extensive simulation studies. We conclude that the proposed method can be freely used in real practice.

When the individual outcomes within a composite outcome appear to have different treatment effects, either in magnitude or direction, researchers may question the validity or appropriateness of using this composite outcome as a basis for measuring overall treatment effect in a randomized controlled trial. The question remains as to how to distinguish random variation in estimated treatment effects from important heterogeneity within a composite outcome. This paper suggests there may be some utility in directly testing the assumption of homogeneity of treatment effect across the individual outcomes within a composite outcome. We describe a treatment heterogeneity test for composite outcomes based on a class of models used for the analysis of correlated data arising from the measurement of multiple outcomes for the same individuals. Such a test may be useful in planning a trial with a primary composite outcome and at trial end with final analysis and presentation. We demonstrate how to determine the statistical power to detect composite outcome treatment heterogeneity using the POISE Trial data. Then we describe how this test may be incorporated into a presentation of trial results with composite outcomes. We conclude that it may be informative for trialists to assess the consistency of treatment effects across the individual outcomes within a composite outcome using a formalized methodology and the suggested test represents one option.

BACKGROUND:Despite a well-recognised burden of disabling physical symptoms compounded by co-morbidities, psychological distress and social isolation, the needs of people with severe chronic obstructive pulmonary disease (COPD) are typically poorly addressed. AIM:To assess the effectiveness of interventions designed to deliver holistic care for people with severe COPD. METHODS:We searched 11 biomedical databases, three trial repositories (January 1990-March 2012; no language restrictions) and contacted international experts to locate published, unpublished and in-progress randomised controlled trials (RCTs), quasi-RCTs and controlled clinical trials (CCTs) that investigated holistic interventions to support patients with severe COPD in any healthcare context. The primary outcome was health-related quality of life (HRQoL). Quality assessment and data extraction followed Cochrane Collaboration methodology. We used a piloted data extraction sheet and undertook narrative synthesis. RESULTS:From 2,866 potentially relevant papers, we identified three trials: two RCTs (from United States and Australia), and one CCT (from Thailand): total 216 patients. Risk of bias was assessed as moderate in two studies and high in the third. All the interventions were led by nurses acting in a co-ordinating role (e.g. facilitating community support in Thailand, providing case-management in the USA, or co-ordinating inpatient care in Australia). HRQoL improved significantly in the Thai CCT compared to the (very limited) usual care (p

Background A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge. Methodology/Principal Findings NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected. Significance The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection. Trial Registration ClinicalTrials.gov NCT00392015

ObjectiveTo assess the cost effectiveness of giving tranexamic acid (TXA) to bleeding trauma patients in low, middle and high income settings.MethodsThe CRASH-2 trial showed that TXA administration reduces the risk of death in bleeding trauma patients with a small but statistically significant increase in non-intensive care stay. A Markov model was used to assess the cost effectiveness of TXA in Tanzania, India and the United Kingdom (UK). The health outcome was the number of life years gained (LYs). Two costs were considered: the cost of administering TXA and the cost of additional days in hospital. Cost data were obtained from hospitals, World Health Organization (WHO) database and UK reference costs. Cost-effectiveness was measured in international dollars ($) per LY. Both deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results to model assumptions.FindingsAdministering TXA to bleeding trauma patients within three hours of injury saved an estimated 372, 315 and 755 LYs per 1,000 trauma patients in Tanzania, India and the UK respectively. The cost of giving TXA to 1,000 patients was $17,483 in Tanzania, $19,550 in India and $30,830 in the UK. The incremental cost of giving TXA versus not giving TXA was $18,025 in Tanzania, $20,670 in India and $48,002 in the UK. The estimated incremental cost per LY gained of administering TXA is $48, $66 and $64 in Tanzania, India and the UK respectively.ConclusionEarly administration of TXA to bleeding trauma patients is likely to be highly cost effective in low, middle and high income settings.Trial registrationThis paper uses data collected by the CRASH 2 trial: Controlled-Trials.com ISRCTN86750102, Clinicaltrials.govNCT00375258 and South African Clinical Trial Register DOH-27-0607-1919.

Background Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia. Methods and Findings Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450) of hospital outpatients and 32% (12,171/37,800) of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887) in children under 1 y of age. Severe disease was present in 2,634 (22%) inpatients with malaria, with the risk greater among Pv (23% [675/2,937]) infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI) 1.08–1.32], p = 0.001), and greatest in patients with mixed infections (31% [389/1,273]); overall p < 0.0001. Severe anaemia (haemoglobin < 5 g/dl) was the major complication associated with Pv, accounting for 87% (589/675) of severe disease compared to 73% (1,144/1,570) of severe manifestations with Pf (p < 0.001). Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0%) patients with malaria died during admission: 2.2% (167/7,722) with Pf, 1.6% (46/2,916) with Pv, and 2.3% (29/1260) with mixed infections (p = 0.126). Conclusions In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where chloroquine resistance is increasing., Ric Price and colleagues present data from southern Papua, Indonesia, suggesting that malaria resulting from infection withPlasmodium vivax is associated with substantial morbidity and mortality., Editors' Summary Background. Malaria, a parasitic disease transmitted to people by mosquitoes, is common throughout the tropical and subtropical areas of the world. In sub-Saharan Africa, infections with Plasmodium falciparum cause most of the malaria-associated illness and death. Elsewhere, another related parasite—P. vivax—is often the commonest cause of malaria. Both parasites are injected into the human blood stream when an infected mosquito bites a person. From there, the parasites travel to the liver, where they multiply for 8–9 d and mature into a form of the parasite known as merozoites. These merozoites are released from the liver and invade red blood cells where they multiply rapidly for a couple of days before bursting out and infecting more red blood cells. This cyclical accumulation of parasites in the blood causes a recurring flu-like illness characterized by fevers, headaches, chills, and sweating. Malaria can be treated with antimalarial drugs but, if left untreated, infections with P. falciparum can cause anemia (by destroying red blood cells) and can damage the brain and other vital organs (by blocking the capillaries that supply these organs with blood), complications that can be fatal. Why Was This Study Done? Unlike falciparum malaria, vivax malaria is generally regarded as a benign or nonfatal disease even though there have been several reports recently of severe disease and deaths associated with vivax malaria. These reports do not indicate, however, whether P. vivax is responsible for a significant proportion of malarial deaths. Public health officials need to know this information because strains of P. vivax that are resistant to multiple antimalarial drugs are widespread in Indonesia and beginning to emerge elsewhere in Asia and South America. In this study, therefore, the researchers investigate the relative burden of vivax and falciparum malaria in Papua, Indonesia, a region where multidrug-resistant strains of both P. falciparum and P. vivax are common. What Did the Researchers Do and Find? The researchers examined data collected from all the patients attending the outpatient and inpatient departments of a hospital that serves a large area in the southern lowlands of Papua, Indonesia between January 2004 and December 2007. Among those inpatients in whom malaria had been confirmed by finding parasites in blood samples, two-thirds were infected with P. falciparum, a quarter with P. vivax, and the rest with a mixture of parasites. Nearly one in four patients infected with P. vivax developed severe malaria compared with roughly one in five patients infected with P. falciparum. However, about one in three patients infected with both parasites developed severe disease. Whichever parasite was responsible for the infection, the proportion of patients with severe disease was greatest among children below the age of five years. Severe anemia was the commonest complication associated with severe malaria caused by both P. vivax and P. falciparum (present in 87% and 73% of cases, respectively). Finally, one in 50 patients with malaria died; the risk of death was the same for patients infected with P. falciparum, P. vivax, or both parasites. What Do These Findings Mean? These findings provide important information about the burden of malaria associated with P. vivax infection. They show that in a region where multidrug-resistant strains of both P. falciparum and P. vivax are common, P. vivax infection (as well as P. falciparum infection) is associated with severe and fatal malaria, particularly in young children. The findings also show that infection with a mixture of the two parasites is associated with a higher risk of severe disease than infection with either parasite alone. Most importantly, they show that similar proportions of patients infected with P. falciparum, P. vivax, or a mixture of parasites die. Further studies need to be done in other settings to confirm these findings and to learn more about the pattern of severe malaria associated with P. vivax (in particular, with multidrug-resistant strains). Nevertheless, these findings highlight the need to consider both P. vivax and P. falciparum when implementing measures designed to reduce the malaria burden in regions where these parasites coexist. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050128. A PLoS Medicine Research in Translation article by Stephen Rogerson further discusses this study and a related PLoS Medicine paper on vivax malaria in a community cohort from Papua New Guinea The MedlinePlus encyclopedia has a page on malaria (in English and Spanish) The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish) Vivaxmalaria provides information on topics related to P. vivax The Malaria Vaccine Initiative also provides a fact sheet on P. vivax malaria Information is available from the Roll Back Malaria Partnership on the global control of malaria

Background Severe malaria (SM) is classically associated with Plasmodium falciparum infection. Little information is available on the contribution of P. vivax to severe disease. There are some epidemiological indications that P. vivax or mixed infections protect against complications and deaths. A large morbidity surveillance conducted in an area where the four species coexist allowed us to estimate rates of SM among patients infected with one or several species. Methods and Findings This was a prospective cohort study conducted within the framework of the Malaria Vaccine Epidemiology and Evaluation Project. All presumptive malaria cases presenting at two rural health facilities over an 8-y period were investigated with history taking, clinical examination, and laboratory assessment. Case definition of SM was based on the World Health Organization (WHO) criteria adapted for the setting (i.e., clinical diagnosis of malaria associated with asexual blood stage parasitaemia and recent history of fits, or coma, or respiratory distress, or anaemia [haemoglobin < 5 g/dl]). Out of 17,201 presumptive malaria cases, 9,537 (55%) had a confirmed Plasmodium parasitaemia. Among those, 6.2% (95% confidence interval [CI] 5.7%–6.8%) fulfilled the case definition of SM, most of them in children, In a study carried out in Papua New Guinea, Blaise Genton and colleagues show thatPlasmodium vivax is associated with severe malaria., Editors' Summary Background. Malaria is a parasitic infection that is transmitted to people by infected mosquitoes. Four different parasites cause malaria—Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. Of these, P. vivax is the commonest and most widely distributed, whereas P. falciparum causes the most deaths. All these parasites enter their human host when an infected mosquito takes a blood meal. They then migrate to the liver where they replicate without causing any symptoms. Eight to nine days later, mature parasites are released from the liver cells and invade red blood cells. Here, they multiply rapidly before bursting out and infecting more red blood cells. The recurring flu-like symptoms of malaria are caused by this cyclical increase in parasitemia (parasites in the blood) and should be treated promptly with antimalarial drugs to prevent the development of potentially fatal complications. Infections with P. falciparum in particular can cause anemia by destroying the red blood cells and can damage vital organs (including the brain) by blocking the capillaries that supply them with blood. Why Was This Study Done? It is generally believed that P. vivax malaria is rarely fatal. There is even some evidence that infection with P. vivax alone (monoinfection) or with other malaria parasites (mixed infection) provides protection against malarial complications. Recently, however, there have been reports of severe disease and deaths associated with infection by P. vivax alone. Most of these reports do not indicate what proportion of severe malaria cases are caused by P. vivax infections, but if P. vivax is responsible for a significant proportion of malarial deaths, efforts to prevent these deaths will need to target P. vivax as well as P. falciparum. In this study, therefore, the researchers estimate the proportion of cases of severe malaria among patients infected with one or several Plasmodium species in Papua New Guinea, a country where all four species coexist. What Did the Researchers Do and Find? The researchers enrolled everyone attending two rural health facilities in the Wosera subdistrict of Papua New Guinea over an eight-year period with symptoms indicative of malaria but without symptoms of any other disease (presumptive malaria cases) into their prospective cohort study. They asked each patient about their symptoms, did a standard physical examination, looked for parasites in their blood, and measured their hemoglobin levels to see whether they were anemic. Out of 17,201 presumptive malaria cases, 483 had severe malaria (defined as parasitemia plus a recent history of fits, coma, breathing problems, or anemia). Most of the patients with severe malaria were less than five years old—children have little immunity to Plasmodium parasites. In this age group, 11.7% of patients infected with P. falciparum, 8.8% of patients infected with P. vivax, and 17.3% of patients infected with both parasites had severe malaria. Patients with severe malaria caused by P. vivax presented with breathing difficulties more often than those infected with P. falciparum, whereas anemia was more common among patients with severe malaria caused by P. falciparum than by P. vivax. What Do These Findings Mean? The researchers use these results and data on the numbers of infections with each parasite to calculate that, in this rural region of Papua New Guinea, P. vivax is responsible for one-fifth of severe malaria cases, P. falciparum is responsible for three-quarters of cases, and the rest involve mixed P. falciparum/P. vivax infections. Put another way, these findings suggest that about one in ten children under the age of five years infected with either P. vivax or P. falciparum may develop severe malaria. These findings provide no evidence, however, that mixed infections are protective. Because the diagnosis of severe malaria was not confirmed by outcome data (deaths or permanent disability), additional, more detailed studies are needed to confirm these results. Nevertheless, these findings (and those reported separately in a related article published at the same time in PLoS Medicine) suggest that a significant proportion of the illness associated with malaria may be caused by P. vivax infections. Thus, efforts to reduce or eliminate the malarial burden must target P. vivax as well as P. falciparum in regions where these species coexist. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050127. A PLoSMedicine Research in Translation article by Stephen Rogerson further discusses this study and a related paper on vivax malaria infection in patients attending a regional hospital in Papua, Indonesia The MedlinePlus encyclopedia has a page on malaria (in English and Spanish) The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish) Information is available from the Roll Back Malaria Partnership on global control of malaria and on malaria in Papua New Guinea Vivaxmalaria provides information for the malaria research community on topics related to Plasmodiumvivax The Malaria Vaccine Initiative also provides a fact sheet on Plasmodiumvivax malaria

Summary Two views exist of medical science: one emphasises discovery and explanation, the other emphasises evaluation of interventions. This essay analyses in what respects these views differ, and how they lead to opposite research hierarchies, with randomisation on top for evaluation and at bottom for discovery and explanation. The two views also differ strongly in their thinking about the role of prior specification of a research hypothesis. Hence, the essay explores the controversies surrounding subgroup analyses and multiplicity of analyses in observational research. This exploration leads to a rethinking of the universally accepted hierarchy of strength of study designs, which has the randomised trial on top: this hierarchy may be confounded by the prior odds of the research hypothesis. Finally, the strong opinions that are sometimes displayed in pitting the two types of medical science against each other may be explained by a difference in “loss function”: the difference in penalty for being wrong. A longer, more detailed version of this paper is found in supplementary Text S1.