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Summary There is increasing concern that most current published research fi ndings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientifi c fi eld. In this framework, a research fi nding is less likely to be true when the studies conducted in a fi eld are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater fl exibility in designs, defi nitions, outcomes, and analytical modes; when there is greater fi nancial and other interest and prejudice; and when more teams are involved in a scientifi c fi eld in chase of statistical signifi cance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientifi c fi elds, claimed research fi ndings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research. It can be proven that most claimed research fi ndings are false.

A recent surge of interest in data sharing and data access has swept through the scientific community (e.g., [ 1]). Scientists recognize that free access to data is synergistic for fostering major advances. Concerns about standards of sharing are particularly acute with respect to large-scale DNA sequence and microarray data. Although some types of data have shallow histories or unclear protocols for how one would share them, DNA sequences have been deposited to the joint databases of GenBank, EMBL, and the DNA Databank of Japan [ 2, 3, 4] for over a decade, and many journals have policies requiring such submission before a paper can be accepted. For simplicity, we refer to these databases jointly as “GenBank.” However, policies are only as good as their adherence and enforcement, and one should consider the effectiveness of past policies before launching new ones. Given its long history, an ideal case study is the deposit of sequences reported in published work into GenBank. We know from personal experience that authors of published papers reporting DNA sequences sometimes intentionally fail to deposit their sequences to GenBank and refuse to release them upon request. Is this a rare exception, or do many papers make it past coauthors, associate editors, editors, reviewers, and journal staff without providing the purportedly required data accession numbers? We examined the frequency with which published studies failed to submit their DNA sequences to GenBank. We searched six journals that have explicit policies requiring the submission of DNA sequences ( Table 1). The previous six months (through February, 2006) of issues or most recent 30 papers presenting DNA sequence data were sought, though we examined a year of issues of one journal to test a longer-term trend (see below). Studies presenting only confirmatory sequence or sequences that would not be found in nature (e.g., transgenes) were not counted. We searched for GenBank entries using locus and species names, authors of the article, etc., thus executing a search that would mimic any scientist's approach. Table 1 Submission of DNA Sequences from Published Studies to GenBank No journal had complete compliance with its requirement for all DNA sequences to have been submitted to GenBank ( Table 1). Between 3% and 20% of papers in these journals did not include GenBank accession numbers, and between 3% and 15% of studies never submitted their DNA sequences at all. We also identified several papers with errors in the supplied accession numbers, but these errors were not counted. Table 1 also notes “special cases” that we considered less egregious violations of the journal rules. In these cases, the DNA sequences were noted in the paper itself, either as supplementary materials or by noting identity to published sequences. The observation that some papers have sequences submitted to GenBank despite not providing accession numbers suggests that common reasons may be forgetfulness of the authors coupled with the lack of consistent policing at the journals. An author forgets to deposit the sequences, but then remembers (or is reminded) after the paper is published and submits them at that time. If this “oops effect” is common, we expect that the publication dates of the papers completely lacking GenBank submissions should be later on average than the publication dates of papers only missing accession numbers. We test this prediction with our observations from the journal Molecular Biology and Evolution, for which our survey spans a longer time period. Consistent with the prediction, we find a marginally significant difference in publication month ( t = 2.2, p = 0.08) in the expected direction between papers for which sequences were never submitted to GenBank and those for which sequences were submitted but accession numbers were not printed. Our study concludes that the majority of papers provide their DNA sequences to GenBank. However, from the perspective of the journal, it is understandable how some papers get into print without providing sequence accession numbers. Paper submissions are closely checked for content by reviewers and associate editors, and they do not see it as their duty to police these policies—they merely evaluate the science and presentation. In contrast, the staff at many journals are often not scientists and not trained to recognize when and how these should be presented. Hence, although the staff may be asked to police this policy, it is understandable that they may miss several cases. Although the failure to submit DNA sequences to GenBank appears rare, we must consider the consequences to an author if he/she intentionally publishes a paper without providing access to the data. There are two possibilities of how enforcement by the journal could be achieved. The author could be “flagged” such that future submissions to the journal would be declined until the DNA sequences have been released. This is a rather aggressive stance, and journals are unlikely to adopt it. We suggest an easy alternative. In the 21st century, many writers access publications online. We propose that, in cases where an author has not released DNA sequences, the author be given one month notice, at which point, if accession numbers are not provided, the publication is removed from the journal Web site until compliance is reached. One cannot take back the printed issue, but having the publication removed from the journal website would prevent anyone from accessing it online. This approach would focus the consequences to the deviant publication. The databases of GenBank, EMBL, and the DNA Databank of Japan [ 2, 3, 4] serve as a model for data sharing from which the entire scientific community can learn. Although they sometimes get bad publicity for errors in DNA sequence submissions (e.g., see [ 5]), the positive impact they have had on all areas of biology is enormous. Let us look to the future and hope that new proposed forms of data sharing (e.g., [ 1]) are even more successful.

The article on influenza in tropical regions by Viboud and colleagues outlines an alarming global burden of influenza, with an estimated one million annual deaths worldwide [ 1]. We would like to give an example of the immense potential of Taiwan to assist developing world communities in fighting against emerging infectious diseases in the near future. Taiwan (area 36,000 km 2; population 23 million), officially known as the Republic of China, is located on the Tropic of Cancer. Taiwan lost its United Nation membership in 1971 to its rival, the People's Republic of China, but maintains official diplomatic relations with 25 countries and de facto relations with many nations. Taiwan has one of the highest levels of life expectancy in Asia, and it has eradicated infectious diseases such as the bubonic plague in 1948, smallpox in 1955, rabies in 1959, malaria in 1965, and polio in 2000. Taiwan became the first country in the world to implement a hepatitis B immunization program. Taiwan also initiated active vaccination programs against diptheria, pertussis, and tetanus in 1955, Japanese encephalitis in 1969, measles in 1978, hepatitis B in 1984, rubella in 1986, hepatitis A in 1995, and influenza in 1998. Valuable lessons may be learned from Taiwan's experience in public health and its response to disease outbreaks and crises. Taiwan provides a modern, world-class health-care system to its people [ 2]. According to Taiwan Department of Health's statistics, the average life expectancy in 1951 was 53.38 years, and it increased to 73.35 years for men and 79.05 years for women in 2003. The Centre for Disease Control in Taiwan was established in 1999 to consolidate disease control resources. When an epidemic of enterovirus took the lives of 78 people in 1998, Taiwan responded by setting up disease surveillance [ 3]. To fight influenza, Taiwan embarked on a free influenza immunization program aiming to increase the coverage rate to 80% for those above the age of 65. There has been an increase in immunization of the elderly from 59.9% in 2002 to 68.4% in 2003, with medical care providers and disease control staff immunization up to 91.3%. Taiwan is committed to retaining vaccination production capability in the event of an emergency. The government is supporting a plan for the domestic production of influenza vaccines over the next few years as a part of Taiwan's readiness for an avian flu epidemic. Taiwan is committed to work with the global medical community by contributing its resources and expertise. Unfortunately, it is not a member of the World Health Organization (WHO). It has therefore been excluded from the Global Outbreak Alert and Response Network (GOARN). During the time of the enterovirus outbreak, Taiwan did not get any assistance from the WHO but managed to combat the outbreak. The avian flu scare of 1997 was controlled in Hong Kong because of timely action, aided by the WHO. If Taiwan is to respond effectively to similar outbreaks of global epidemics in the future, it will certainly need the cooperation of the WHO. Although the WHO is a non-political agency, because of pressure from the People's Republic of China, which considers Taiwan as a renegade province, Taiwan has been marginalized. Regardless of this, Taiwan has contributed over US$180 million since 1995 in medical and humanitarian aid to 95 countries, and it plans to make further donations. Therefore, excluding Taiwan from the WHO's GOARN is counterproductive from both medical and ethical standpoints. Taiwan, through its own efforts, has managed to improve public health remarkably, despite having no assistance from the WHO. It certainly has the potential to assist developing nations in the fight against emerging disease outbreaks, so other countries can seek Taiwan's expertise to fight against infectious diseases in the near future.

The series of disease mongering articles in the April 2006 issue of PLoS Medicine overall seem to define the term as “widening the boundaries of illness” [ 1] by “taking a normal function and implying that there's something wrong with it and that it should be treated” [ 2]. While there is undoubtedly a strong case to be made for this sort of practice by pharmaceutical companies, perhaps we should also question ourselves on what we mean by “disease boundaries.” All of the conditions touched on by the disease mongering series (e.g., bipolar disease, attention deficit hyperactivity disorder, restless legs syndrome, and sexual dysfunctions) share the fact that they represent spectra of symptoms felt by virtually everyone, but which for some people can reach a point at which they become disturbing. However, since the benefit of treating these symptoms is ultimately dependent on their significance in a patient's life, it seems doubtful that anyone but the patient can adequately define the “boundaries” of illness for these conditions. The existence of these large “grey zones” between disease and normality (as well as the difficulty of doctors in dealing with them) might help to explain the increase in “lifestyle drug use” and self-prescription of psychiatric medication [ 3]. While these behaviors undoubtedly carry risks, they might well be an inevitable development in an age where information on anything (including drugs) is so widely available. Moreover, tampering with body chemistry is nothing new (alcohol, coffee, chocolate, and sunlight come to mind as examples), and it is hard to expect people will not do it because of pharmaceutical labels. Therefore, complain as we may, it is unlikely that this trend can be feasibly prevented. Therefore, if we want to prevent disease mongering, perhaps we should start by focusing on our own concept of “disease.” Maybe it is time we start to loosen the grip on our powers to define disease and start working less as diagnosing machines and more as decision facilitators for patients. It seems quite absurd to decide on a “concept” of erectile dysfunction or depression that can define who should be treated. On the contrary, our role should be to inform patients of the benefits and risks of treatment (or nontreatment) for their particular condition. This also means being comfortable with the fact that, no matter which criteria one uses to define disease, there will always be “normal” people who will want treatment as well as “sick” people who will refuse it. And in both cases they are probably entitled to do so, without necessarily receiving a diagnosis of “normal” or “sick.” Moreover, since the trend for self-prescription is not likely to be prevented, and since the pharmaceutical industry will surely try to capitalize on it, perhaps we should also worry about making nonprofit, unbiased scientific information more available to the public. Education on health matters is an important responsibility that traditionally has been overlooked by doctors in most countries. Now, if ever, seems to be the time to change that, because if physicians do not concentrate on it, drug companies will be happy to do it for them. It is obvious that medicine cannot abandon the concept of disease boundaries, since most of our medical knowledge and research is still based on it. Moreover, there are fields in which medical responsibility is sure to remain important in defining these boundaries (e.g., attribution of public funds, research studies, and treatment of children). But after reading so much on disease mongering, it seems to me that if we become a little more flexible in admitting that “disease boundaries” for many conditions are an oxymoron, perhaps the pharmaceutical industry will make less of a fuss in trying to convince people they are ill. My guess is that this would do everybody a favor.

Hotez et al. argue that achieving success in the global fight against HIV/AIDS, tuberculosis, and malaria may well require a concurrent attack on the neglected tropical diseases.

In PLoS Medicine, volume 2, issue 4: DOI: 10.1371/journal.pmed.0030185 The correct title for Figure 2 should be “Author's Graph of p-Value Function Based on Data in [28].” The correct title for Figure S1 should be “Episheet Showing Author's Relative Risk Calculation, Based on Data in [28].”

Exposure to alcohol during brain development may cause a neurological syndrome called fetal alcohol syndrome (FAS). Ethanol induces apoptotic neuronal death at specific developmental stages, particularly during the brain-growth spurt, which occurs from the beginning of third trimester of gestation and continues for several years after birth in humans, whilst occurring in the first two postnatal weeks in mice. Administration of a single dose of ethanol in 7-d postnatal (P7) mice triggers activation of caspase-3 and widespread apoptotic neuronal death in the forebrain, providing a possible explanation for the microencephaly observed in human FAS. The present study was aimed at determining whether nicotinamide may prevent ethanol-induced neurodegeneration.P7 mice were treated with a single dose of ethanol (5 g/kg), and nicotinamide was administered from 0 h to 8 h after ethanol exposure. The effects of nicotinamide on ethanol-induced activation of caspase-3 and release of cytochrome-c from the mitochondria were analyzed by Western blot (n = 4-7/group). Density of Fluoro-Jade B-positive cells and NeuN-positive cells was determined in the cingulated cortex, CA1 region of the hippocampus, and lateral dorsal nucleus of the thalamus (n = 5-6/group). Open field, plus maze, and fear conditioning tests were used to study the behavior in adult mice (n = 31-34/group). Nicotinamide reduced the activation of caspase-3 (85.14 +/- 4.1%) and the release of cytochrome-c (80.78 +/- 4.39%) in postnatal mouse forebrain, too. Nicotinamide prevented also the ethanol-induced increase of apoptosis. We demonstrated that ethanol-exposed mice showed impaired performance in the fear conditioning test and increased activity in the open field and in the plus maze. Administration of nicotinamide prevented all these behavioral abnormalities in ethanol-exposed mice.Our findings indicate that nicotinamide can prevent some of the deleterious effects of ethanol on the developing mouse brain when given shortly after ethanol exposure. These results suggest that nicotinamide, which has been used in humans for the treatment of diabetes and bullous pemphigoid, may hold promise as a preventive therapy of FAS.

Ethical issues are a growing concern for companies, in the wake of a series of corporate governance scandals and the accompanying sharp decline in societal and investor trust in firms. Some companies have responded to these concerns by creating internal ethics programs. In the aerospace sector, for example, companies have focused these efforts on ensuring compliance with government regulations, while in the energy sector, ethics initiatives have concentrated on environmental issues and corporate and social responsibility [ 1]. Companies in pharmaceutical, biotech, and bioagricultural industries must not only comply with a wide array of government regulations and balance the profit motive with social responsibility, but also must deal with the complex array of ethical issues raised by doing business in the biosciences. These complex issues include the production and sale of genetically modified foods; gene therapy experiments and embryonic stem cell research to produce new therapies; animal testing for pharmaceuticals; drug pricing at home and in developing countries; the potential misuse of personal genetic information; how to appropriately commercialize and profit from genetic and biological samples; and the creation of transgenic animals for drug production. Although a theoretical debate rages about whether bioethicists should consult to industry [ 2, 3], no one has systematically examined from the standpoint of bioscience companies themselves how they address these ethical issues and why they do so. In understanding the complex relationship between bioethics and industry, there is a need to obtain insight from the people closest to the phenomenon. Some researchers would like to discount the views of corporate managers, but to do so would inappropriately ignore a very legitimate viewpoint, and a good starting place to begin to understand the issues faced, and approaches taken, by companies. To address this gap, our research team sought to uncover how bioscience companies, from global corporations to small start-ups, address ethical challenges specific to bioscience firms. Using the case study method (see Box 1), we performed more than 100 in-depth, face-to-face interviews with top managers and executives at 13 bioscience companies to learn about bioindustry ethics from their perspective (see Table 1 for a list and description of the 13 companies). Of the 13 companies, the majority can be classified as biotechnology companies, engaged in developing medical products, tools, and bioagricultural or industrial products. We also chose to include some companies for comparison that are part of the biotech value chain: a few pharmaceutical companies that often partner with biotechnology firms, and a contract research organization that is a supplier to biotech firms; thus, we use the term bioscience rather than biotech. We invited 19 companies to take part in the project, and 13 agreed (four pharmaceutical, one biotech, and one bioagricultural company declined). Box 1. Research Methodology Qualitative case study methods were used for this research. Data Collection Data was collected over a two-year period, using a study design approved by the University of Toronto research ethics board. Our research team performed in-depth, open-ended interviews with managers and executives from 13 bioscience companies (more than 100 interviews in total). Media articles, press releases, and company documents were also analyzed to verify the data resulting from the interviews. Data Sources Data was drawn from (1) interview notes, (2) observations from company visits, and (3) written documents (produced by the company and by other sources). Data Analysis Case Studies. The three sources of data were analyzed for each company independently to produce 13 qualitative case studies describing ethical decision making in each company. These case studies were verified for accuracy and approved for publication by each firm. Cross-Case Comparison. To perform the comparison, the case studies and interview notes were coded on four themes: (1) What mechanisms are bioscience companies using to address their ethical issues? (2) How effective are their mechanisms? (3) Why have these bioscience companies decided to implement ethics mechanisms? (4) What ethical issues are these bioscience companies facing and addressing with the previously mentioned mechanisms? In qualitative research, this is known as axial coding. This coding process was performed first by one of our researchers and then verified for validity by other team members. Any discrepancies in results were discussed until consensus was reached. The results from Themes 1 and 2 are discussed in the text of this article, and Themes 3 and 4 are addressed in Box 3 and Table 2, respectively. Table 1 Description of Study Companies Ethical issues are a growing concern for companies. The companies were not approached because they were representative of the bioscience industry, but rather because we knew they had implemented interesting and varied mechanisms to address ethical decision making from which we felt the rest of the industry could learn. In our selection, we were also looking for variety in company size, type, and location. The individual company case studies have been published as a book, BioIndustry Ethics [ 4], and each case provides a detailed examination of the company, the ethical issues it faces, and the mechanisms the company is using to address these issues. What was not covered in the book (and is reported in this article) are the findings from a cross-case comparative analysis of the 13 case studies. The data were analyzed under four themes. The first theme, and focus of this article, examined what mechanisms are being used by these companies to address ethical issues. This theme produced a list of mechanisms that can help to address bioindustry ethics; these are highlighted in Box 2 and described below. The second theme of our analysis was an attempt to see how the companies evaluated the effectiveness of their ethics mechanisms. As will be discussed, this theme, although important, has only been incorporated by a few companies in our study, and only on a preliminary basis, illustrating that this area requires further research and development. Box 2. BioIndustry Ethics Mechanisms Ethical leadership Founder/CEO/management ethical leadership An ethics department External expertise External ethics consultant Ethics advisory boards Internal ethics mechanisms Hiring practices focused on ethics Employee performance evaluations Ethics education and forums for ethics discussion Ethical reinforcement techniques External ethics engagement Ethics mechanisms with partners and suppliers Transparent engagement mechanisms with stakeholders Transparency of science Influencing industry standards and regulations Strategic philanthropy Ethics evaluation and reporting mechanisms Although not discussed at length in this article, the third theme was to understand the reasons why these companies have decided to address ethical issues, and the fourth theme was to learn what ethical issues these companies are facing. The results from theme three produced a list of six reasons why these companies are addressing bioindustry ethics ( Box 3), and the ethical issues facing each firm from theme four are described in Table 2. Box 3. Why Are Bioscience Companies Addressing BioIndustry Ethics? Do the “right thing” Risk mitigation Public reputation Attract and keep the “right” employees Guidance in uncharted waters Promote good science Table 2 Ethical Issues Faced by Study Companies

PLoS Medicine now encourages translations in languages other than English; this decision can only be welcomed. German-speaking readers are pleased by the novelty of a PLoS title written in their language. The Editorial starts with the first line of the well-known German poem “Lorelei” by Heinrich Heine (1797–1856) [ 1]. This year commemorates the 150th anniversary of his death. Originating from Germany, Heine was an early European citizen and a mediator between cultures. After traveling through Europe for years, he settled down in Paris. There he wrote the “Lorelei” and other poems in German while his essays in French made German literature known to the francophone public. In Heine's time, the question which language would prevail in science was yet undecided. In the 19th and the early 20th centuries pivotal works in different disciplines were published in languages other than English, as evidenced in the biographies of the Nobel Prize laureates ( http://nobelprize.org). It seems that insufficient knowledge of the one foreign language did not impede an academic career at that time. Today, proficiency in English is a luxury for many users of scientific information, as pointed out in the Editorial. The same is true for the non-anglophone researchers, who invest time and money in English courses only to try to communicate with their anglophone peers on equal linguistic terms. Can scientific journals do more to overcome the existing language barriers in the meantime? Sure, they can allow the translation of their papers in other languages. But would they also trouble to employ smart machines or humans in order to translate a manuscript written in one of Heine's languages into English before sending it out for peer review? By the way, an English translation of the “Lorelei” is available at http://www.usd.edu/eric/deutsch/literatur/projekt/works/heine-lorelei.html.

A C1173T polymorphism in intron 1 of the VKORC1 gene has been claimed to determine the interindividual variability in the response to vitamin K antagonist therapy (VKA), but it is unknown whether it also influences bleeding risk. We aimed to confirm the relationship between C1173T status and phenprocoumon or acenocoumarol use, and to examine the risk of severe bleeding for the various genotypes.We studied this in a case-control study of 110 patients who bled during VKA therapy and 220 control patients free of bleeding under the same therapy. To achieve the same target INR, CT genotype and TT genotype control patients required less phenprocoumon (CC genotype 2.9 mg/d [95% confidence interval (CI): 2.6-3.2], CT genotype 2.6 mg/d [95% CI: 2.1-3.1], TT genotype 1.4 mg/d [95 % CI: 1.1-1.7]) or acenocoumarol (CC genotype 3.2 mg/d [95% CI: 2.9-3.5], CT genotype 2.3 mg/d [95% CI: 2.1-2.5], TT genotype 1.7 mg/d [95% CI: 1.3-2.1]) than CC genotype control patients. Compared with CC genotype individuals, carriers of at least one T allele had an increased risk of bleeding in the phenprocoumon users (crude odds ratio = 2.6, 95% CI: 1.2-5.7), but not in acenocoumarol users (crude odds ratio = 1.2, 95% CI: 0.6-2.3).These findings encourage taking further steps towards the evaluation of the use of VKORC1 genetic testing for bleeding prevention in individuals who receive VKA therapy.

Heidi Greulich and colleagues [ 1] have demonstrated the significance of insertion mutations in the epidermal growth factor receptor (EGFR) (exon 20) for tumorigenesis and responsiveness to tyrosine kinase inhibitors (TKIs) in lung cancers. They reported that different types of EGFR mutations conveyed different sensitivity to TKIs. Although several previous studies have suggested that tumors harboring mutations in the EGFR kinase domain were sensitive to TKIs such as gefitinib or erlotinib [ 2, 3], others had reported an association between the T790M mutation in exon 20 and the resistance to TKIs [ 4, 5]. As we learn more about the relationship between EGFR status (including gene copy number, mutation status, and mutation type) and drug sensitivity, decisions about treatment with TKIs for patients with non-small-cell lung cancer (NSCLC) become more complex. Previously, we reported HER2 mutational status, as well as EGFR and KRAS, in a large number of NSCLCs [ 6]. We found that 22% of tumors had EGFR kinase domain mutations (149 out of 671). Of these 149, 15 of them were insertion mutations in exon 20. The more common types of mutations—i.e., deletion in exon 19 (68 out of 149) and L858R in exon 21 (61 out of 149)—were more frequent in women and in “never smokers” (with p values of less than 0.001), whereas the exon 20 insertion mutations showed no bias for sex (seven in males versus eight in females) or smoking status (seven in smokers versus eight in never smokers). We have no data regarding TKI sensitivity for the 15 patients with insertion mutations to date, but based on the results from others and our own in vitro data, they may not benefit from the conventional TKIs, despite the fact that their tumors have EGFR kinase domain mutations. To maximize benefit to patients, we should determine the exact type of mutation for an individual tumor and determine whether it conveys sensitivity or resistance prior to TKI therapy. The development and clinical application of novel agents overcoming resistance should yield a more effective targeted therapy for tumors with all types of EGFR mutations.

Only two industrialized countries, the United States and New Zealand, allow direct-to-consumer advertising (DTCA) of prescription medicines, although New Zealand is planning a ban. The challenge for these governments is ensuring that DTCA is more beneficial than harmful. Proponents of DTCA argue that it helps to inform the public about available treatments and stimulates appropriate use of drugs for high-priority illnesses (such as statin use in people with ischemic heart disease). Critics argue that the information in the adverts is often biased and misleading, and that DTCA raises prescribing costs without net evidence of health benefits.

We agree with the thesis of Rosen et al. that despite initiatives such as the World Health Organizations "3 by 5" program rationing of HIV/AIDS antiretroviral therapy (ART) will be necessary in the majority of African countries. Difficult choices will need to be made and choices will be constrained due to the limited health infrastructure and lack of qualified health personnel in many African countries. Rosen et al. outlined a number of useful rationing systems and selection criteria. However some of the strategies they suggest are unfortunately not feasible in practice. For example targeting behavioral core groups (high-risk groups e.g. female sex workers) may well be impossible as it is not always possible to identify behavioral core groups. Furthermore once the prevalence of HIV becomes extremely high in the general population (as it already is in many African countries) the concept of a behavioral core group will be relatively meaningless. (excerpt)

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In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria.We measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falciparum malaria of varying severity hospitalised on the Thai-Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 x 10(11) (95% confidence interval [CI] 5.8 x 10(11) to 8.5 x 10(11)) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 x 10(12), 95% CI 1.3 x 10(12) to 2.3 x 10(12)) than in patients hospitalised without signs of severity (geometric mean 2.8 x 10(11), 95% CI 2.3 x 10(11) to 3.5 x 10(11); p0.001). Parasite burden was highest in patients who died (geometric mean 3.4 x 10(12), 95% CI 1.9 x 10(12) to 6.3 x 10(12); p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony-but in severe malaria is unrelated to stage of parasite development.Plasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes.

Medical education in South Asia is reinventing itself, to create doctors who can meet the needs of the local community.