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1.  Mortality and Hospital Stay Associated with Resistant Staphylococcus aureus and Escherichia coli Bacteremia: Estimating the Burden of Antibiotic Resistance in Europe 
PLoS Medicine  2011;8(10):e1001104.
The authors calculate excess mortality, excess hospital stay, and related hospital expenditure associated with antibiotic-resistant bacterial bloodstream infections (Staphylococcus aureus and Escherichia coli) in Europe.
Background
The relative importance of human diseases is conventionally assessed by cause-specific mortality, morbidity, and economic impact. Current estimates for infections caused by antibiotic-resistant bacteria are not sufficiently supported by quantitative empirical data. This study determined the excess number of deaths, bed-days, and hospital costs associated with blood stream infections (BSIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) and third-generation cephalosporin-resistant Escherichia coli (G3CREC) in 31 countries that participated in the European Antimicrobial Resistance Surveillance System (EARSS).
Methods and Findings
The number of BSIs caused by MRSA and G3CREC was extrapolated from EARSS prevalence data and national health care statistics. Prospective cohort studies, carried out in hospitals participating in EARSS in 2007, provided the parameters for estimating the excess 30-d mortality and hospital stay associated with BSIs caused by either MRSA or G3CREC. Hospital expenditure was derived from a publicly available cost model. Trends established by EARSS were used to determine the trajectories for MRSA and G3CREC prevalence until 2015. In 2007, 27,711 episodes of MRSA BSIs were associated with 5,503 excess deaths and 255,683 excess hospital days in the participating countries, whereas 15,183 episodes of G3CREC BSIs were associated with 2,712 excess deaths and 120,065 extra hospital days. The total costs attributable to excess hospital stays for MRSA and G3CREC BSIs were 44.0 and 18.1 million Euros (63.1 and 29.7 million international dollars), respectively. Based on prevailing trends, the number of BSIs caused by G3CREC is likely to rapidly increase, outnumbering the number of MRSA BSIs in the near future.
Conclusions
Excess mortality associated with BSIs caused by MRSA and G3CREC is significant, and the prolongation of hospital stay imposes a considerable burden on health care systems. A foreseeable shift in the burden of antibiotic resistance from Gram-positive to Gram-negative infections will exacerbate this situation and is reason for concern.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Antimicrobial resistance—a consequence of the use and misuse of antimicrobial medicines—occurs when a microorganism becomes resistant (usually by mutation or acquiring a resistance gene) to an antimicrobial drug to which it was previously sensitive. Then standard treatments become ineffective, leading to persistent infections, which may spread to other people. With some notable exceptions such as TB, HIV, malaria, and gonorrhea, most of the disease burden attributable to antimicrobial resistance is caused by hospital-associated infections due to opportunistic bacterial pathogens. These bacteria often cause life-threatening or difficult-to-manage conditions such as deep tissue, wound, or bone infections, or infections of the lower respiratory tract, central nervous system, or blood stream. The two most frequent causes of blood stream infections encountered worldwide are Staphylococcus aureus and Escherichia coli.
Why Was This Study Done?
Although hospital-associated infections have gained much attention over the past decade, the overall effect of this growing phenomenon on human health and medical services has still to be adequately quantified. The researchers proposed to fill this information gap by estimating the impact—morbidity, mortality, and demands on health care services—of antibiotic resistance in Europe for two types of resistant organisms that are typically associated with resistance to multiple classes of antibiotics and can be regarded as surrogate markers for multi-drug resistance—methicillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli.
What Did the Researchers Do and Find?
Recently, the Burden of Resistance and Disease in European Nations project collected representative data on the clinical impact of antimicrobial resistance throughout Europe. Using and combining this information with 2007 prevalence data from the European Antibiotic Resistance Surveillance System, the researchers calculated the burden of disease associated with methicillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli blood stream infections. This burden of disease was expressed as excess number of deaths, excess number of days in hospital, and excess costs. Using statistical models, the researchers predicted trend-based resistance trajectories up to 2015 for the 31 participating countries in the European region.
The researchers included 1,293 hospitals from the 31 countries, typically covering 47% of all available acute care hospital beds in most countries, in their analysis. For S. aureus, the estimated number of blood stream infections totaled 108,434, of which 27,711 (25.6%) were methicillin-resistant. E. coli caused 163,476 blood stream infections, of which 15,183 (9.3%) were resistant to third-generation cephalosporins. An estimated 5,503 excess deaths were associated with blood stream infections caused by methicillin-resistant S. aureus (with the UK and France predicted to experience the highest excess mortality), and 2,712 excess deaths with blood stream infections caused by third-generation cephalosporin-resistant E. coli (predicted to be the highest in Turkey and the UK). The researchers also found that blood stream infections caused by both methicillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli contributed respective excesses of 255,683 and 120,065 extra bed-days, accounting for an estimated extra cost of 62.0 million Euros (92.8 million international dollars). In their trend analysis, the researchers found that 97,000 resistant blood stream infections and 17,000 associated deaths could be expected in 2015, along with increases in the lengths of hospital stays and costs. Importantly, the researchers estimated that in the near future, the burden of disease associated with third-generation cephalosporin-resistant E. coli is likely to surpass that associated with methicillin-resistant S. aureus.
What Do These Findings Mean?
These findings show that even though the blood stream infections studied represent only a fraction of the total burden of disease associated with antibiotic resistance, excess mortality associated with these infections caused by methicillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli is high, and the associated prolonged length of stays in hospital imposes a considerable burden on health care systems in Europe. Importantly, a possible shift in the burden of antibiotic resistance from Gram-positive to Gram-negative infections is concerning. Such forecasts suggest that despite anticipated gains in the control of methicillin-resistant S. aureus, the increasing number of infections caused by third-generation cephalosporin-resistant Gram-negative pathogens, such as E. coli, is likely to outweigh this achievement soon. This increasing burden will have a big impact on already stretched health systems.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001104.
The World Health Organization has a fact sheet on general antimicrobial resistance
The US Centers for Disease Control and Prevention webpage on antibiotic/antimicrobial resistance includes information on educational campaigns and resources
The European Centre for Disease Control provides data about the prevalence of resistance in Europe through an interactive database
doi:10.1371/journal.pmed.1001104
PMCID: PMC3191157  PMID: 22022233
2.  Funding of Research on Headache Disorders by the National Institutes of Health 
Headache  2009;49(2):162-169.
Introduction
Despite the high level of individual and societal burden resulting from headache disorders, the National Institutes of Health (NIH) has funded relatively little research on these disorders.
Objective
The objective of this study was to define current patterns of NIH funding of research on headache disorders.
Methods
The Computer Retrieval of Information on Scientific Projects (CRISP) database was searched using the terms “migraine” or “headache” or “trigeminovascular” and inclusive of the dates 1987 to November 2007. Titles and abstracts of the resulting projects were reviewed to identify headache research projects and to extract data. E-mails were sent to each of the principal investigators to identify investigators experienced in serving on NIH study sections. E-mails and membership directories were used to determine if principal investigators were members of the American Headache Society. Comparisons were made for levels of NIH funding for migraine, headache disorders, and ten other medical disorders relative to three measures of disease burden.
Results
111 headache research projects led by 93 different investigators were identified. Research project grants (R’s) accounted for 61 (55%) of the grants. Migraine was the most common headache type studied, being the focus in 77 (69.4%) of the projects. The National Institute of Neurological Disorders and Stroke (NINDS) was responsible for funding 66 (59.5%) of the projects. At least 30 (32.3%) of the principal investigators were American Headache Society members and 14 (15%) had served on NIH study sections.
Conclusions
A small number of research grants on headache disorders were funded by the NIH over the last two decades. By comparison to NIH funding of research on ten chronic medical conditions relative to disease burden, headache research funding should exceed $103 million annually.
doi:10.1111/j.1526-4610.2008.01323.x
PMCID: PMC3538853  PMID: 19222590
Funding; headache disorders; National Institute of Health
3.  The Chilling Effect: How Do Researchers React to Controversy? 
PLoS Medicine  2008;5(11):e222.
Background
Can political controversy have a “chilling effect” on the production of new science? This is a timely concern, given how often American politicians are accused of undermining science for political purposes. Yet little is known about how scientists react to these kinds of controversies.
Methods and Findings
Drawing on interview (n = 30) and survey data (n = 82), this study examines the reactions of scientists whose National Institutes of Health (NIH)-funded grants were implicated in a highly publicized political controversy. Critics charged that these grants were “a waste of taxpayer money.” The NIH defended each grant and no funding was rescinded. Nevertheless, this study finds that many of the scientists whose grants were criticized now engage in self-censorship. About half of the sample said that they now remove potentially controversial words from their grant and a quarter reported eliminating entire topics from their research agendas. Four researchers reportedly chose to move into more secure positions entirely, either outside academia or in jobs that guaranteed salaries. About 10% of the group reported that this controversy strengthened their commitment to complete their research and disseminate it widely.
Conclusions
These findings provide evidence that political controversies can shape what scientists choose to study. Debates about the politics of science usually focus on the direct suppression, distortion, and manipulation of scientific results. This study suggests that scholars must also examine how scientists may self-censor in response to political events.
Drawing on interview and survey data, Joanna Kempner's study finds that political controversies shape what many scientists choose not to study.
Editors' Summary
Background.
Scientific research is an expensive business and, inevitably, the organizations that fund this research—governments, charities, and industry—play an important role in determining the directions that this research takes. Funding bodies can have both positive and negative effects on the acquisition of scientific knowledge. They can pump money into topical areas such as the human genome project. Alternatively, by withholding funding, they can discourage some types of research. So, for example, US federal funds cannot be used to support many aspects of human stem cell research. “Self-censoring” by scientists can also have a negative effect on scientific progress. That is, some scientists may decide to avoid areas of research in which there are many regulatory requirements, political pressure, or in which there is substantial pressure from advocacy groups. A good example of this last type of self-censoring is the withdrawal of many scientists from research that involves certain animal models, like primates, because of animal rights activists.
Why Was This Study Done?
Some people think that political controversy might also encourage scientists to avoid some areas of scientific inquiry, but no studies have formally investigated this possibility. Could political arguments about the value of certain types of research influence the questions that scientists pursue? An argument of this sort occurred in the US in 2003 when Patrick Toomey, who was then a Republican Congressional Representative, argued that National Institutes of Health (NIH) grants supporting research into certain aspects of sexual behavior were “much less worthy of taxpayer funding” than research on “devastating diseases,” and proposed an amendment to the 2004 NIH appropriations bill (which regulates the research funded by NIH). The Amendment was rejected, but more than 200 NIH-funded grants, most of which examined behaviors that affect the spread of HIV/AIDS, were internally reviewed later that year; NIH defended each grant, so none were curtailed. In this study, Joanna Kempner investigates how the scientists whose US federal grants were targeted in this clash between politics and science responded to the political controversy.
What Did the Researchers Do and Find?
Kempner interviewed 30 of the 162 principal investigators (PIs) whose grants were reviewed. She asked them to describe their research, the grants that were reviewed, and their experience with NIH before, during, and after the controversy. She also asked them whether this experience had changed their research practice. She then used the information from these interviews to design a survey that she sent to all the PIs whose grants had been reviewed; 82 responded. About half of the scientists interviewed and/or surveyed reported that they now remove “red flag” words (for example, “AIDS” and “homosexual”) from the titles and abstracts of their grant applications. About one-fourth of the respondents no longer included controversial topics (for example, “abortion” and “emergency contraception”) in their research agendas, and four researchers had made major career changes as a result of the controversy. Finally, about 10% of respondents said that their experience had strengthened their commitment to see their research completed and its results published although even many of these scientists also engaged in some self-censorship.
What Do These Findings Mean?
These findings show that, even though no funding was withdrawn, self-censoring is now common among the scientists whose grants were targeted during this particular political controversy. Because this study included researchers in only one area of health research, its findings may not be generalizable to other areas of research. Furthermore, because only half of the PIs involved in the controversy responded to the survey, these findings may be affected by selection bias. That is, the scientists most anxious about the effects of political controversy on their research funding (and thus more likely to engage in self-censorship) may not have responded. Nevertheless, these findings suggest that the political environment might have a powerful effect on self-censorship by scientists and might dissuade some scientists from embarking on research projects that they would otherwise have pursued. Further research into what Kempner calls the “chilling effect” of political controversy on scientific research is now needed to ensure that a healthy balance can be struck between political involvement in scientific decision making and scientific progress.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050222.
The Consortium of Social Science Associations, an advocacy organization that provides a bridge between the academic research community and Washington policymakers, has more information about the political controversy initiated by Patrick Toomey
Some of Kempner's previous research on self-censorship by scientists is described in a 2005 National Geographic news article
doi:10.1371/journal.pmed.0050222
PMCID: PMC2586361  PMID: 19018657
4.  Systematic analysis of funding awarded for antimicrobial resistance research to institutions in the UK, 1997–2010 
Objectives
To assess the level of research funding awarded to UK institutions specifically for antimicrobial resistance-related research and how closely the topics funded relate to the clinical and public health burden of resistance.
Methods
Databases and web sites were systematically searched for information on how infectious disease research studies were funded for the period 1997–2010. Studies specifically related to antimicrobial resistance, including bacteriology, virology, mycology and parasitology research, were identified and categorized in terms of funding by pathogen and disease and by a research and development value chain describing the type of science.
Results
The overall dataset included 6165 studies receiving a total investment of £2.6 billion, of which £102 million was directed towards antimicrobial resistance research (5.5% of total studies, 3.9% of total spend). Of 337 resistance-related projects, 175 studies focused on bacteriology (40.2% of total resistance-related spending), 42 focused on antiviral resistance (17.2% of funding) and 51 focused on parasitology (27.4% of funding). Mean annual funding ranged from £1.9 million in 1997 to £22.1 million in 2009.
Conclusions
Despite the fact that the emergence of antimicrobial resistance threatens our future ability to treat many infections, the proportion of the UK infection-research spend targeting this important area is small. There are encouraging signs of increased investment in this area, but it is important that this is sustained and targeted at areas of projected greatest burden. Two areas of particular concern requiring more investment are tuberculosis and multidrug-resistant Gram-negative bacteria.
doi:10.1093/jac/dkt349
PMCID: PMC3886928  PMID: 24038777
antibiotics; antifungal; antiviral; antiparasitic
5.  The NIH-NIAID Schistosomiasis Resource Center 
A bench scientist studying schistosomiasis must make a large commitment to maintain the parasite's life cycle, which necessarily involves a mammalian (definitive) host and the appropriate species of snail (intermediate host). This is often a difficult and expensive commitment to make, especially in the face of ever-tightening funds for tropical disease research. In addition to funding concerns, investigators usually face additional problems in the allocation of sufficient lab space to this effort (especially for snail rearing) and the limited availability of personnel experienced with life cycle upkeep. These problems can be especially daunting for the new investigator entering the field. Over 40 years ago, the National Institutes of Health–National Institute of Allergy and Infectious Diseases (NIH-NIAID) had the foresight to establish a resource from which investigators could obtain various schistosome life stages without having to expend the effort and funds necessary to maintain the entire life cycle on their own. This centralized resource translated into cost savings to both NIH-NIAID and to principal investigators by freeing up personnel costs on grants and allowing investigators to divert more funds to targeted research goals. Many investigators, especially those new to the field of tropical medicine, are only vaguely, if at all, aware of the scope of materials and support provided by this resource. This review is intended to help remedy that situation. Following a short history of the contract, we will give a brief description of the schistosome species provided, provide an estimate of the impact the resource has had on the research community, and describe some new additions and potential benefits the resource center might have for the ever-changing research interests of investigators.
doi:10.1371/journal.pntd.0000267
PMCID: PMC2480520  PMID: 18665228
6.  Metrics associated with NIH funding: a high-level view 
Objective
To introduce the availability of grant-to-article linkage data associated with National Institutes of Health (NIH) grants and to perform a high-level analysis of the publication outputs and impacts associated with those grants.
Design
Articles were linked to the grants they acknowledge using the grant acknowledgment strings in PubMed using a parsing and matching process as embodied in the NIH Scientific Publication Information Retrieval & Evaluation System system. Additional data from PubMed and citation counts from Scopus were added to the linkage data. The data comprise 2 572 576 records from 1980 to 2009.
Results
The data show that synergies between NIH institutes are increasing over time; 29% of current articles acknowledge grants from multiple institutes. The median time lag to publication for a new grant is 3 years. Each grant contributes to approximately 1.7 articles per year, averaged over all grant types. Articles acknowledging US Public Health Service (PHS, which includes NIH) funding are cited twice as much as US-authored articles acknowledging no funding source. Articles acknowledging both PHS funding and a non-US government funding source receive on average 40% more citations that those acknowledging PHS funding sources alone.
Conclusion
The US PHS is effective at funding research with a higher-than-average impact. The data are amenable to further and much more detailed analysis.
doi:10.1136/amiajnl-2011-000213
PMCID: PMC3128410  PMID: 21527408
Bibliometric analysis; research evaluation; grants; citation impact; bibliometrics; citation analysis; input–output studies; text mining; science mapping; machine learning
7.  An Update: NIH Research Funding for Palliative Medicine 2006 to 2010 
Journal of Palliative Medicine  2013;16(2):125-129.
Abstract
Background
Palliative care clinical and educational programs are expanding to meet the needs of seriously ill patients and their families. Multiple reports call for an enhanced palliative care evidence base.
Objective
To examine current National Institutes of Health (NIH) funding of palliative medicine research and changes since our 2008 report.1
Methods
We sought to identify NIH funding of palliative medicine from 2006 to 2010 in two stages. First, we searched the NIH grants database RePorter2 for grants with key words “palliative care,” “end-of-life care,” “hospice,” and “end of life.” Second, we identified palliative care researchers likely to have secured NIH funding using three strategies: (1) We abstracted the first and last authors' names from original investigations published in major palliative medicine journals from 2008 to 2010; (2) we abstracted these names from a PubMed generated list of all original articles published in major medicine, nursing, and subspecialty journals using the above key words Medical Subject Headings (MESH) terms “palliative care,” “end-of-life care,” “hospice,” and “end of life;” and (3) we identified editorial board members of palliative medicine journals and key members of palliative medicine research initiatives. We crossmatched the pooled names against NIH grants funded from 2006 to 2010.
Results
The NIH RePorter search yielded 653 grants and the author search identified an additional 352 grants. Compared to 2001 to 2005, 589 (240%) more grants were NIH funded. The 391 grants categorized as relevant to palliative medicine represented 294 unique PIs, an increase of 185 (269%) NIH funded palliative medicine researchers. The NIH supported 21% of the 1253 original palliative medicine research articles identified. Compared to 2001 to 2005, the percentage of grants funded by institutes other than the National Cancer Institute (NCI), the National Institute for Nursing Research (NINR), and the National Institute of Aging (NIA) increased from 15% to 20% of all grants.
Conclusions
When compared to 2001–2005, more palliative medicine investigators received NIH funding; and research funding has improved. Nevertheless, additional initiatives to further support palliative care research are needed.
doi:10.1089/jpm.2012.0427
PMCID: PMC3607902  PMID: 23336358
8.  The NIH-NIAID Filariasis Research Reagent Resource Center 
Filarial worms cause a variety of tropical diseases in humans; however, they are difficult to study because they have complex life cycles that require arthropod intermediate hosts and mammalian definitive hosts. Research efforts in industrialized countries are further complicated by the fact that some filarial nematodes that cause disease in humans are restricted in host specificity to humans alone. This potentially makes the commitment to research difficult, expensive, and restrictive. Over 40 years ago, the United States National Institutes of Health–National Institute of Allergy and Infectious Diseases (NIH-NIAID) established a resource from which investigators could obtain various filarial parasite species and life cycle stages without having to expend the effort and funds necessary to maintain the entire life cycles in their own laboratories. This centralized resource (The Filariasis Research Reagent Resource Center, or FR3) translated into cost savings to both NIH-NIAID and to principal investigators by freeing up personnel costs on grants and allowing investigators to divert more funds to targeted research goals. Many investigators, especially those new to the field of tropical medicine, are unaware of the scope of materials and support provided by the FR3. This review is intended to provide a short history of the contract, brief descriptions of the fiilarial species and molecular resources provided, and an estimate of the impact the resource has had on the research community, and describes some new additions and potential benefits the resource center might have for the ever-changing research interests of investigators.
doi:10.1371/journal.pntd.0001261
PMCID: PMC3226539  PMID: 22140585
9.  Financial Anatomy of Biomedical Research, 2003 – 2008 
Context
With the exception of the American Recovery and Reinvestment Act, funding support for biomedical research in the United States has slowed after a decade of doubling. However, the extent and scope of slowing are largely unknown.
Objective
To quantify funding of biomedical research in the United States from 2003 to 2008.
Design
We used publicly available data to quantify funding from federal, state and local government, private, and industry sources. We used regression models to compare financial trends between 1994–2003 and 2003–2007 (the last year complete data were available). We also evaluated the number of new drug and device approvals by the US Food and Drug Administration (FDA) over the same time period.
Main Outcome Measures
Funding and growth rates by source. Number of FDA approvals.
Results
Biomedical research funding increased from $75.5 billion in 2003 to $101.1 billion in 2007. In 2008 funding from the National Institutes of Health (NIH) and industry totaled $88.8 billion. In 2007 funding from these sources, adjusted for inflation, was $90.2 billion. Adjusted for inflation, funding from 2003 to 2007 increased by 14% for a compound annual growth rate of 3.4%. By comparison, funding from 1994 to 2003 increased at an annual rate of 7.8% (P<0.001). In 2007, industry (58%) was the largest funder followed by the federal government (33%). The modest increase in funding was not accompanied by an increase in approvals for drugs or devices. In 2007 the United States spent an estimated 4.5% of its total health expenditures on biomedical research and 0.1% on health services research.
Conclusions
After a decade of doubling, the rate of increase in biomedical research funding slowed from 2003 to 2007, and after adjusting for inflation, the absolute level of funding from NIH and industry appears to have decreased by 2% in 2008.
doi:10.1001/jama.2009.1987
PMCID: PMC3118092  PMID: 20068207
10.  Analysis of the ‘reformpool’-activity in Austria: is the challenge met? 
Aim
The purpose of our study is to analyse the activities initiated by the foundation of the reformpools on the regional level. We wanted to see not only what projects have emerged from these funds, but also how the incentives of this special way of funding influence the activity and what overall impact can be expected on health services delivery in the future.
Context
In Austria, all expenses in the outpatient sector are borne by the statutory health insurance. But in the inpatient sector, SHI just co-finances about 45% of all costs incurred by patients, with the rest contributed by the federal, regional and municipal level. This, however, leads to a number of problems in today's epidemiological situation with patients in need of many different interventions in the course of their chronic disease.
Originally with the aim of finding solutions to these interface problems between inpatient and outpatient care, the healthcare reform 2005 instated the instrument of the reformpool. The reformpool unites funds from social health insurance and regions to finance projects that develop new ways of health services delivery across the sectors. In the course of recent reforms, it became explicitly possible to sponsor projects of integrated care, which had de facto already been the case before.
Theory
The reform pool has various disincentives or wrong incentives compared to e.g. the German ‘Anschubfinanzierung’ for IC-contracts, which was probably a role-model for the Austrian reformpool, because of the underlying differences in the healthcare system and the distinct differences in the regulation. For example, the ‘Anschubfinanzierung’ in Germany withdraws money from the available funds for contract physicians to finance IC-projects, whereas in Austria, their fees are fixed. So in Austria, there is no incentive to retrieve money by participating in such projects. For the stakeholders supplying the pool, mainly the sickness funds and the regions, many projects inflict additional costs on the one or on the other in the future. So as both parties have to agree on projects, there is a strong basic disincentive to grant funds in the present. If a project is in both their interest because it is reducing costs, the care providers might not be interested to participate, as this would diminish their revenues in the future. What is more, the federal control over the (region-based) funds and projects is poor, which might lead to duplication of efforts and missing scale-efficiency in some regions.
Methods and data
For our analysis, we conducted a survey with a standardised questionnaire sent to the management of the regional health funds, which are responsible for the reformpool funds. The questionnaire was checked by experts of the federal association of social security institutions. We also conducted an on-site visit of the reformpool-manager, a programme which can be used to evaluate the reformpool-projects. In addition, we used all available evaluation reports of projects to assess the situation of evaluation of the projects. Furthermore, we used financial data from the regional health funds, the federal association of social security institutions, from the ministry of health and the regional health funds to assess the usage of the reformpool.
(Preliminary) Results
The qualitative results are mixed. Some projects are promising with regard to improvements of the current situation and are well evaluated. Many projects neglect the requirement of the reformpool to be such as to yield a monetary benefit for the system but only focus on improving service delivery. Some evaluations are not well operationalised and thus, arguments why these projects should be transformed to ordinarily financed services will be lacking. The reformpool activity set on very slowly, with only one project already started in 2005, the first possible year. In 2007 we see the highest number (23) of new projects granted and the highest monetary volume, €11 Mio total for 21 of them 1, with activity subsiding in 2008 (6 projects with a volume of € 2.5 Mio total for 5 of them 1) and most certainly in 2009 (with diminishing tax revenues and health insurance contributions) with only one project granted in the first quarter of the year. Of all funds (theoretically) available, only about 16% have been put to use in a reformpool project per year, with high variation (e.g. in the region of Styria over 30%, in Tyrol only 1.5%).
(Preliminary) Conclusions
From our study we can tell that the instrument of reformpool was not devised well concerning its incentive structure, and the interest to conduct such projects is diminishing. Stricter control of the requirements by the federal level, more pronounced requirements, a dedication of the funds to projects instead of a virtual budget and more cooperation between regions could improve the effectiveness of the instrument. Conflicts of interest: The project was funded by the federal association of social security institutions. All authors are researchers at the IHS and hold no commercial interests in the subject. Additional information: Founded by the economist Oskar Morgenstern and the sociologist Paul Lazarsfeld, the IHS (Institute for Advanced Studies) is a non-profit post-graduate teaching and research facility in the fields of economics, sociology and politology, and one of the two Austrian institutes preparing the official economic forecast for Austria. For more than a decade, it has been one of the major research facilities in the fields of health economics and health policy in Austria.
PMCID: PMC2807071
evidence-based guidelines; quality of care
11.  Comparing Cutaneous Research Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases with 2010 Global Burden of Disease Results 
PLoS ONE  2014;9(7):e102122.
Importance
Disease burden data helps guide research prioritization.
Objective
To determine the extent to which grants issued by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) reflect disease burden, measured by disability-adjusted life years (DALYs) from Global Burden of Disease (GBD) 2010 project.
Design
Two investigators independently assessed 15 skin conditions studied by GBD 2010 in the NIAMS database for grants issued in 2013. The 15 skin diseases were matched to their respective DALYs from GBD 2010.
Setting
The United States NIAMS database and GBD 2010 skin condition disability data.
Main Outcome(s) and Measure(s)
Relationship of NIAMS grant database topic funding with percent total GBD 2010 DALY and DALY rank for 15 skin conditions.
Results
During fiscal year 2013, 1,443 NIAMS grants were issued at a total value of $424 million. Of these grants, 17.7% covered skin topics. Of the total skin disease funding, 82% (91 grants) were categorized as “general cutaneous research.” Psoriasis, leprosy, and “other skin and subcutaneous diseases” (ie; immunobullous disorders, vitiligo, and hidradenitis suppurativa) were over-represented when funding was compared with disability. Conversely, cellulitis, decubitus ulcer, urticaria, acne vulgaris, viral skin diseases, fungal skin diseases, scabies, and melanoma were under-represented. Conditions for which disability and funding appeared well-matched were dermatitis, squamous and basal cell carcinoma, pruritus, bacterial skin diseases, and alopecia areata.
Conclusions and Relevance
Degree of representation in NIAMS is partly correlated with DALY metrics. Grant funding was well-matched with disability metrics for five of the 15 studied skin diseases, while two skin diseases were over-represented and seven were under-represented. Global burden estimates provide increasingly transparent and important information for investigating and prioritizing national research funding allocations.
doi:10.1371/journal.pone.0102122
PMCID: PMC4086973  PMID: 25003335
12.  Outcomes of National Career Development Program that Promotes the Transition to Independent Scientist 
Academic Medicine  2011;86(9):1179-1184.
Purpose
The loss of new investigators from academic science is a “crisis” placing the future of biomedical science at risk. Failure to obtain independent funding contributes significantly to attrition from the NIH career path. The purpose of this paper is to describe the components and outcomes of the Advanced Research Institute (ARI) in Geriatric Mental Health, an NIMH grant-funded national program that targets successful transition of new investigators to independence.
Method
The authors first describe the program participants and key components. They then compare the record of federal grant funding, derived from the NIH Reporter database, of the first four cohorts (2004–2007; n=42) to those of all NIMH mentored career development (K) awardees funded 2001–2005 (n=404).
Results
As of January 2010, 45.2% of Scholars had achieved R01 funding. Nearly 70% obtained some NIH grant (not including K or small grants). Among all NIMH mentored K awardees, ARI Scholars were 2.36 (p=0.048) more likely to achieve an R01; outcomes were similar (OR=2.42, p= .045) when including R34s.
Conclusions
Based on objective outcomes, the Advanced Research Institute (ARI) in Geriatric Mental Health offers an effective model to promoting successful transition of new investigators to independence. While organized around a specific public health and scientific need, ARI’s components are generalizable to other fields. Further, the inclusion of biological, clinical and services researchers into a single program promotes translational science. Thus ARI is one tool to stemming attrition from the NIH career path and promoting the next generation of science.
doi:10.1097/ACM.0b013e3182254399
PMCID: PMC3162100  PMID: 21785315
13.  Enrollment of racial/ethnic minorities in NIAID-funded networks of HIV vaccine trials in the United States, 1988 to 2002. 
Public Health Reports  2005;120(5):543-548.
OBJECTIVE: The purpose of this study was to analyze enrollment of racial/ethnic minorities in Phase I and Phase II HIV vaccine trials in the U.S. conducted by National Institute of Allergy and Infectious Diseases (NIAID)-funded networks from 1988 to 2002. METHODS: A centralized database was searched for all NIAID-funded networks of HIV vaccine trial enrollment data in the U.S. from 1988 through 2002. The authors reviewed data from Phase I or Phase II preventive HIV vaccine trials that included HIV-1 uninfected participants at low to moderate or high risk for HIV infection based on self-reported risk behaviors. Of 66 identified trials, 55 (52 Phase I, 3 Phase II) met selection criteria and were used for analyses. Investigators extracted data on participant demographics using statistical software. RESULTS: A total of 3,731 volunteers enrolled in U.S. NIAID-funded network HIV vaccine trials from 1988 to 2002. Racial/ethnic minority participants represented 17% of the overall enrollment. By pooling data across all NIAID-funded networks from 1988 to 2002, the proportion of racial/ethnic minority participants was significantly greater (Fisher's exact test p-value < 0.001) in Phase II trials (278/1,061 or 26%) than in Phase I trials (347/2,670 or 13%). By generalized estimating equations, the proportion of minorities in Phase I trials increased over time (p = 0.017), indicating a significant increase in racial/ethnic minority participants from 1988 to 2002. CONCLUSIONS: There has been a gradual increase in racial/ethnic minority participation in NIAID-funded network HIV vaccine trials in the U.S. since 1988. In the light of recent efficacy trial results, it is essential to continue to increase the enrollment of diverse populations in HIV vaccine research.
PMCID: PMC1497755  PMID: 16224987
14.  Influenza Research Database: An integrated bioinformatics resource for influenza research and surveillance 
The recent experience with the emergence of the 2009 pandemic influenza A/H1N1 virus has highlighted the value of free and open access to influenza virus genome sequence data integrated with information about viral characteristics related to antiviral drug resistance and virulence. The Influenza Research Database (IRD, www.fludb.org) is a free, publicly accessible resource funded by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) through the Bioinformatics Resource Centers (BRC) program. The IRD provides a comprehensive, integrated database, and analysis resource for influenza sequence, surveillance, and research data. It also provides user-friendly interfaces for data retrieval and visualization, comparative genomics analysis, and personal log in-protected “workbench” spaces for saving data sets and analysis results. IRD integrates genomic, proteomic, immune epitope, and surveillance data from a variety of sources, including public databases, computational algorithms, external research groups, and the scientific literature. The goal of the IRD is to provide a resource that helps researchers identify root causes of virus pathogenicity and host range restriction, and facilitates the development of vaccines, diagnostics, and therapeutics.
doi:10.1111/j.1750-2659.2011.00331.x
PMCID: PMC3345175  PMID: 22260278
15.  International Funding for Malaria Control in Relation to Populations at Risk of Stable Plasmodium falciparum Transmission 
PLoS Medicine  2008;5(7):e142.
Background
The international financing of malaria control has increased significantly in the last ten years in parallel with calls to halve the malaria burden by the year 2015. The allocation of funds to countries should reflect the size of the populations at risk of infection, disease, and death. To examine this relationship, we compare an audit of international commitments with an objective assessment of national need: the population at risk of stable Plasmodium falciparum malaria transmission in 2007.
Methods and Findings
The national distributions of populations at risk of stable P. falciparum transmission were projected to the year 2007 for each of 87 P. falciparum–endemic countries. Systematic online- and literature-based searches were conducted to audit the international funding commitments made for malaria control by major donors between 2002 and 2007. These figures were used to generate annual malaria funding allocation (in US dollars) per capita population at risk of stable P. falciparum in 2007. Almost US$1 billion are distributed each year to the 1.4 billion people exposed to stable P. falciparum malaria risk. This is less than US$1 per person at risk per year. Forty percent of this total comes from the Global Fund to Fight AIDS, Tuberculosis and Malaria. Substantial regional and national variations in disbursements exist. While the distribution of funds is found to be broadly appropriate, specific high population density countries receive disproportionately less support to scale up malaria control. Additionally, an inadequacy of current financial commitments by the international community was found: under-funding could be from 50% to 450%, depending on which global assessment of the cost required to scale up malaria control is adopted.
Conclusions
Without further increases in funding and appropriate targeting of global malaria control investment it is unlikely that international goals to halve disease burdens by 2015 will be achieved. Moreover, the additional financing requirements to move from malaria control to malaria elimination have not yet been considered by the scientific or international community.
To reach global malaria control goals, Robert Snow and colleagues argue that more international funding is needed but that it must be targeted at specific countries most at risk.
Editors' Summary
Background.
Malaria is one of the most common infectious diseases in the world and one of the greatest global public health problems. The Plasmodium falciparum parasite causes approximately 500 million cases each year and over one million deaths. More than 40% of the world's population is at risk of malaria.
The Millennium Development Goals (MDGs), established by the United Nations in 2000, include a target in Goal 6: “to have halted by 2015 and begun to reverse the incidence of malaria and other major diseases.” Following the launch of the MDG and international initiatives like Roll Back Malaria, there has been an upsurge in support for malaria control. This effort has included the formation of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) and considerable funding from the US President's Malaria Initiative, the World Bank, the UK Department for International Development, USAID, and nongovernmental agencies and foundations like the Bill & Melinda Gates Foundation. But it is not yet clear how equitable or effective the financial commitments to malaria control have been.
Why Was This Study Done?
As part of the activities of the Malaria Atlas Project, the researchers had previously generated a global map of the limits of P. falciparum transmission. This map detailed areas where risk is moderate or high (stable transmission areas where malaria is endemic) and areas where the risk of transmission is low (unstable transmission areas where sporadic outbreaks of malaria may occur). Because the level of funding to control malaria should be proportionate to the size of the populations at risk, the researchers in this study appraised whether the areas of greatest need were receiving financial resources in proportion to this risk. That is, whether there is equity in how malaria funding is allocated.
What Did the Researchers Do and Find?
To assess the international financing of malaria control, the researchers conducted a audit of financial commitments to malaria control of the GFATM, national governments, and other donors for the period 2002 to 2007. To assess need, they estimated the population at risk of stable P. falciparum malaria transmission in 2007, building on their previous malaria map. Financial commitments were identified via online and literature searches, including the GFATM Web site, the World Malaria Report produced by WHO and UNICEF, and various other sources of financial information. Together these data allowed the authors to generate an estimate of the annual malaria funding allocation per capita population at risk of P. falciparum.
Of the 87 malaria-endemic countries, 76 received malaria funding commitments by the end of 2007. Overall, annual funding amounted to US$1 billion dollars, or less than US$1 per person at risk. Forty percent came from the GFATM, and the remaining from a mix of national government and external donors. The authors found great regional variation in the levels of funding. For example, looking at just the countries approved for GFATM funding, Myanmar was awarded an average annual per capita-at-risk amount of US$0.01 while Suriname was awarded US$147. With all financial commitments combined, ten countries had per capita annual support of more than US$4 per person, but 34 countries had less than US$1, including 16 where annual malaria support was less than US$0.5 per capita. These 16 countries represent 50% of the global population at risk and include seven of the poorest countries in Africa and two of the most densely populated stable endemic countries in the world (India and Indonesia).
What Do These Findings Mean?
The researchers find that the distribution of funds across the regions affected by malaria to be generally appropriate, with the Africa region and low-population-at-risk areas such as the Americas, the Caribbean, the Middle East, and Eastern Europe receiving proportionate annual malaria support. But they also identify large shortfalls, such as in the South East Asia and Western Pacific regions, which represents 47% of the global population at risk but received only 17% of GFATM and 24% of non-GFATM support. National government spending also falls short: for example, in Nigeria, where more than 100 million people are at risk of stable P. falciparum transmission, less than US$1 is invested per person per year. These findings illustrate how important it is to examine financial commitments against actual needs. Given the gaps between funding support and level of stable P. falciparum risk, the authors conclude that the goal to reduce the global burden of malaria by 2015 very likely will not be met with current commitments. They estimate that there remains a 50%–450% shortfall in funding needed to scale up malaria control worldwide.
Future research should assess the impact of these funding commitments and what additional resources will be needed if goals of malaria elimination are added to malaria control targets.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050142.
This study is discussed further in a PLoS Medicine Perspective by Anthony Kiszewski
The authors of this article have also published a global map of malaria risk; see Guerra, et al. (2008) PLoS Med 5(2) e38
Information is available from the Global Fund to Fight AIDS, Tuberculosis and Malaria
More information is available on global mapping of malaria risk from the Malaria Atlas Project
doi:10.1371/journal.pmed.0050142
PMCID: PMC2488181  PMID: 18651785
16.  NIH Disease Funding Levels and Burden of Disease 
PLoS ONE  2011;6(2):e16837.
Background
An analysis of NIH funding in 1996 found that the strongest predictor of funding, disability-adjusted life-years (DALYs), explained only 39% of the variance in funding. In 1998, Congress requested that the Institute of Medicine (IOM) evaluate priority-setting criteria for NIH funding; the IOM recommended greater consideration of disease burden. We examined whether the association between current burden and funding has changed since that time.
Methods
We analyzed public data on 2006 NIH funding for 29 common conditions. Measures of US disease burden in 2004 were obtained from the World Health Organization's Global Burden of Disease study and national databases. We assessed the relationship between disease burden and NIH funding dollars in univariate and multivariable log-linear models that evaluated all measures of disease burden. Sensitivity analyses examined associations with future US burden, current and future measures of world disease burden, and a newly standardized NIH accounting method.
Results
In univariate and multivariable analyses, disease-specific NIH funding levels increased with burden of disease measured in DALYs (p = 0.001), which accounted for 33% of funding level variation. No other factor predicted funding in multivariable models. Conditions receiving the most funding greater than expected based on disease burden were AIDS ($2474 M), diabetes mellitus ($390 M), and perinatal conditions ($297 M). Depression ($719 M), injuries ($691 M), and chronic obstructive pulmonary disease ($613 M) were the most underfunded. Results were similar using estimates of future US burden, current and future world disease burden, and alternate NIH accounting methods.
Conclusions
Current levels of NIH disease-specific research funding correlate modestly with US disease burden, and correlation has not improved in the last decade.
doi:10.1371/journal.pone.0016837
PMCID: PMC3044706  PMID: 21383981
17.  Malaria in selected non-Amazonian countries of Latin America 
Acta Tropica  2011;121(3):303-314.
Approximately 170 million inhabitants of the American continent live at risk of malaria transmission. Although the continent’s contribution to the global malaria burden is small, at least 1 to 1.2 million malaria cases are reported annually. Sixty per cent of the malaria cases occur in Brazil and the other 40% are distributed in 20 other countries of Central and South America. Plasmodium vivax is the predominant species (74.2 %) followed by P. falciparum (25.7 %) and P. malariae (0.1%), and no less than 10 Anopheles species have been identified as primary or secondary malaria vectors. Rapid deforestation and agricultural practices are directly related to increases in Anopheles species diversity and abundance, as well as in the number of malaria cases. Additionally, climate changes profoundly affect malaria transmission and are responsible for malaria epidemics in some regions of South America. Parasite drug resistance is increasing, but due to bio-geographic barriers there is extraordinary genetic differentiation of parasites with limited dispersion. Although the clinical spectrum ranges from uncomplicated to severe malaria cases, due to the generally low to middle transmission intensity, features such as severe anemia, cerebral malaria and other complications appear to be less frequent than in other endemic regions and asymptomatic infections are a common feature. Although the National Malaria Control Programs (NMCP) of different countries differ in their control activities these are all directed to reduce morbidity and mortality by using strategies like health promotion, vector control and impregnate bed nets among others. Recently, international initiatives such as the Malaria Control Program in Andean-country Border Regions (PAMAFRO) (implemented by the Andean Organism for Health (ORAS) and sponsored by The Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)) and The Amazon Network for the Surveillance of Antimalarial Drug Resistance (RAVREDA) (sponsored by the Pan American Health Organization/World Health Organization (PAHO/WHO) and several other partners), have made great investments for malaria control in the region. We describe here the current status of malaria in a non-Amazonian region comprising several countries of South and Central America participating in the Centro Latino Americano de Investigación en Malaria (CLAIM), an International Center of Excellence for Malaria Research (ICEMR) sponsored by the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID).
doi:10.1016/j.actatropica.2011.06.008
PMCID: PMC3237935  PMID: 21741349
malaria; Plasmodium falciparum; Plasmodium vivax; malaria elimination; epidemiology; Latin America
18.  Health Disparities Grants Funded by National Institute on Aging: Trends Between 2000 and 2010 
The Gerontologist  2012;52(6):748-758.
Purpose of the Study:
The present study examined the characteristics of health disparities grants funded by National Institute on Aging (NIA) from 2000 to 2010. Objectives were (a) to examine longitudinal trends in health disparities–related grants funded by NIA and (b) to identify moderators of these trends.
Design and Methods:
Our primary data source was the National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER) system. The RePORTER data were merged with data from the Carnegie Classification of Institutions of Higher Education. General linear models were used to examine the longitudinal trends and how these trends were associated with type of grant and institutional characteristics.
Results:
NIA funded 825 grants on health disparities between 2000 and 2010, expending approximately 330 million dollars. There was an overall linear increase over time in both the total number of grants and amount of funding, with an outlying spike during 2009. These trends were significantly influenced by several moderators including funding mechanism and type of institution.
Implications:
The findings highlight NIA’s current efforts to fund health disparities grants to reduce disparities among older adults. Gerontology researchers may find this information very useful for their future grant submissions.
doi:10.1093/geront/gns035
PMCID: PMC3495907  PMID: 22454392
Health disparities; National Institute on Aging (NIA); Funding; Grants; National Institutes of Health (NIH); Aging
19.  Funding and Forums for ELSI Research: Who (or What) is Setting the Agenda? 
AJOB primary research  2012;3(3):51-60.
Background
Discussion of the influence of money on bioethics research seems particularly salient in the context of research on the ethical, legal and social implications (ELSI) of human genomics, as this research may be financially supported by the ELSI Research Program. Empirical evidence regarding the funding of ELSI research and where such research is disseminated, in relation to the specific topics of the research and methods used, can help to further discussions regarding the appropriate influence of specific institutions and institutional contexts on ELSI and other bioethics research agendas.
Methods
We reviewed 642 ELSI publications (appearing between 2003–2008) for reported sources of funding, forum for dissemination, empirical and non-empirical methods, and topic of investigation.
Results
Most ELSI research is independent of direct grant-based funding sources; 66% reported no such sources of funding. The National Human Genome Research Institute (NHGRI) is the most dominant source of funding; 16% of publications acknowledged at least one source of NHGRI grant funding. Funding is acknowledged more frequently in empirical than non-empirical publications, and more frequently in publications in public health journals than in any other ELSI research dissemination forums. Dominant research topics vary by publication forum and by reported funding.
Conclusions
ELSI research is surprisingly independent of direct grant-based funding, yet correlations are apparent between this type of funding and publication placement, topics addressed, and methods used, implying a not insignificant influence on ELSI research agenda-setting. However, given the relatively low percentage of publications acknowledging external grant-based funding, as well as other significant correlations between publication placement and topics addressed, additional institutional contexts, perhaps related to professional advancement or valuation, may shape research agendas in ways that potentially exceed the direct influences of grant-based funding in this area. In some cases, grant-based funding may actually counter other potentially problematic institutional influences.
doi:10.1080/21507716.2012.678550
PMCID: PMC3413296  PMID: 22888470
Genomics [Ethics]; National Human Genome Research Institute (U.S.); Ethics, Professional
20.  PATRIC: The VBI PathoSystems Resource Integration Center 
Nucleic Acids Research  2006;35(Database issue):D401-D406.
The PathoSystems Resource Integration Center (PATRIC) is one of eight Bioinformatics Resource Centers (BRCs) funded by the National Institute of Allergy and Infection Diseases (NIAID) to create a data and analysis resource for selected NIAID priority pathogens, specifically proteobacteria of the genera Brucella, Rickettsia and Coxiella, and corona-, calici- and lyssaviruses and viruses associated with hepatitis A and E. The goal of the project is to provide a comprehensive bioinformatics resource for these pathogens, including consistently annotated genome, proteome and metabolic pathway data to facilitate research into counter-measures, including drugs, vaccines and diagnostics. The project's curation strategy has three prongs: ‘breadth first’ beginning with whole-genome and proteome curation using standardized protocols, a ‘targeted’ approach addressing the specific needs of researchers and an integrative strategy to leverage high-throughput experimental data (e.g. microarrays, proteomics) and literature. The PATRIC infrastructure consists of a relational database, analytical pipelines and a website which supports browsing, querying, data visualization and the ability to download raw and curated data in standard formats. At present, the site warehouses complete sequences for 17 bacterial and 332 viral genomes. The PATRIC website () will continually grow with the addition of data, analysis and functionality over the course of the project.
doi:10.1093/nar/gkl858
PMCID: PMC1669763  PMID: 17142235
21.  BEI Resources: Supporting antiviral research 
Antiviral research  2008;80(2):102-106.
The Biodefense and Emerging Infections Research Resources Repository (BEI Resources) provides unique, quality-assured reagents to the scientific community for use in basic research and product development involving biodefense and emerging infectious diseases. These include microorganisms (up to Biosafety Level-3) on the National Institute of Allergy and Infectious Diseases (NIAID) and Centers for Disease Control and Prevention (CDC) lists of Category A, B and C priority pathogens. In addition to live microorganisms, related products such as polyclonal antisera, monoclonal antibodies, isolated nucleic acid preparations, overlapping peptide arrays, purified proteins, and assay kits are also available. Many of these materials have direct or indirect applications in antiviral research. These reagents are available free of charge to all registered investigators, regardless of funding source or affiliation. Acquisition of new reagents for the repository is one of the critically necessary and challenging tasks for BEI Resources. Therefore, investigators are encouraged to deposit relevant items, so as to provide access to materials, relief from the burden of distribution, protection of intellectual property rights, and secure storage. In addition, BEI Resources has the capability of contracting for the preparation of specific reagents. If there is a resource needed to advance a specific research area, contact an NIAID program officer or use the “suggest a reagent” option on the BEI Resources homepage, www.beiresources.org.
doi:10.1016/j.antiviral.2008.07.003
PMCID: PMC2614313  PMID: 18675849
biodefense; emerging infectious disease; repository; reagents; culture collection; antiviral therapy
22.  Geographic Distribution of Staphylococcus aureus Causing Invasive Infections in Europe: A Molecular-Epidemiological Analysis 
PLoS Medicine  2010;7(1):e1000215.
Hajo Grundmann and colleagues describe the development of a new interactive mapping tool for analyzing the spatial distribution of invasive Staphylococcus aureus clones.
Background
Staphylococcus aureus is one of the most important human pathogens and methicillin-resistant variants (MRSAs) are a major cause of hospital and community-acquired infection. We aimed to map the geographic distribution of the dominant clones that cause invasive infections in Europe.
Methods and Findings
In each country, staphylococcal reference laboratories secured the participation of a sufficient number of hospital laboratories to achieve national geo-demographic representation. Participating laboratories collected successive methicillin-susceptible (MSSA) and MRSA isolates from patients with invasive S. aureus infection using an agreed protocol. All isolates were sent to the respective national reference laboratories and characterised by quality-controlled sequence typing of the variable region of the staphylococcal spa gene (spa typing), and data were uploaded to a central database. Relevant genetic and phenotypic information was assembled for interactive interrogation by a purpose-built Web-based mapping application. Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 countries collected 2,890 MSSA and MRSA isolates from patients with invasive S. aureus infection. A wide geographical distribution of spa types was found with some prevalent in all European countries. MSSA were more diverse than MRSA. Genetic diversity of MRSA differed considerably between countries with dominant MRSA spa types forming distinctive geographical clusters. We provide evidence that a network approach consisting of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of MRSA populations such as early signalling of emerging strains, cross border spread, and importation by travel.
Conclusions
In contrast to MSSA, MRSA spa types have a predominantly regional distribution in Europe. This finding is indicative of the selection and spread of a limited number of clones within health care networks, suggesting that control efforts aimed at interrupting the spread within and between health care institutions may not only be feasible but ultimately successful and should therefore be strongly encouraged.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The bacterium Staphylococcus aureus lives on the skin and in the nose of about a third of healthy people. Although S. aureus usually coexists peacefully with its human carriers, it is also an important disease-causing organism or pathogen. If it enters the body through a cut or during a surgical procedure, S. aureus can cause minor infections such as pimples and boils or more serious, life-threatening infections such as blood poisoning and pneumonia. Minor S. aureus infections can be treated without antibiotics—by draining a boil, for example. Invasive infections are usually treated with antibiotics. Unfortunately, many of the S. aureus clones (groups of bacteria that are all genetically related and descended from a single, common ancestor) that are now circulating are resistant to methicillin and several other antibiotics. Invasive methicillin-resistant S. aureus (MRSA) infections are a particular problem in hospitals and other health care facilities (so-called hospital-acquired MRSA infections), but they can also occur in otherwise healthy people who have not been admitted to a hospital (community-acquired MRSA infections).
Why Was This Study Done?
The severity and outcome of an S. aureus infection in an individual depends in part on the ability of the bacterial clone with which the individual is infected to cause disease—the clone's “virulence.” Public-health officials and infectious disease experts would like to know the geographic distribution of the virulent S. aureus clones that cause invasive infections, because this information should help them understand how these pathogens spread and thus how to control them. Different clones of S. aureus can be distinguished by “molecular typing,” the determination of clone-specific sequences of nucleotides in variable regions of the bacterial genome (the bacterium's blueprint; genomes consist of DNA, long chains of nucleotides). In this study, the researchers use molecular typing to map the geographic distribution of MRSA and methicillin-sensitive S. aureus (MSSA) clones causing invasive infections in Europe; a MRSA clone emerges when an MSSA clone acquires antibiotic resistance from another type of bacteria so it is useful to understand the geographic distribution of both MRSA and MSSA.
What Did the Researchers Do and Find?
Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 European countries collected almost 3,000 MRSA and MSSA isolates from patients with invasive S. aureus infections. The isolates were sent to the relevant national staphylococcal reference laboratory (SRL) where they were characterized by quality-controlled sequence typing of the variable region of a staphylococcal gene called spa (spa typing). The spa typing data were entered into a central database and then analyzed by a public, purpose-built Web-based mapping tool (SRL-Maps), which provides interactive access and easy-to-understand illustrations of the geographical distribution of S. aureus clones. Using this mapping tool, the researchers found that there was a wide geographical distribution of spa types across Europe with some types being common in all European countries. MSSA isolates were more diverse than MRSA isolates and the genetic diversity (variability) of MRSA differed considerably between countries. Most importantly, major MRSA spa types occurred in distinct geographical clusters.
What Do These Findings Mean?
These findings provide the first representative snapshot of the genetic population structure of S. aureus across Europe. Because the researchers used spa typing, which analyzes only a small region of one gene, and characterized only 3,000 isolates, analysis of other parts of the S. aureus genome in more isolates is now needed to build a complete portrait of the geographical abundance of the S. aureus clones that cause invasive infections in Europe. However, the finding that MRSA spa types occur mainly in geographical clusters has important implications for the control of MRSA, because it indicates that a limited number of clones are spreading within health care networks, which means that MRSA is mainly spread by patients who are repeatedly admitted to different hospitals. Control efforts aimed at interrupting this spread within and between health care institutions may be feasible and ultimately successful, suggest the researchers, and should be strongly encouraged. In addition, this study shows how, by sharing typing results on a Web-based platform, an international surveillance network can provide clinicians and infection control teams with crucial information about the dynamics of pathogens such as S. aureus, including early warnings about emerging virulent clones.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000215.
This study is further discussed in a PLoS Medicine Perspective by Franklin D. Lowy
The UK Health Protection Agency provides information about Staphylococcus aureus
The UK National Health Service Choices Web site has pages on staphylococcal infections and on MRSA
The US National Institute of Allergy and Infectious Disease has information about MRSA
The US Centers for Disease Control and Infection provides information about MRSA for the public and professionals
MedlinePlus provides links to further resources on staphylococcal infections and on MRSA (in English and Spanish)
SRL-Maps can be freely accessed
doi:10.1371/journal.pmed.1000215
PMCID: PMC2796391  PMID: 20084094
23.  Prevalence of antimicrobial resistance among bacterial pathogens isolated from cattle in different European countries: 2002–2004 
Background
The project "Antibiotic resistance in bacteria of animal origin – II" (ARBAO-II) was funded by the European Union (FAIR5-QLK2-2002-01146) for the period 2003–2005, with the aim to establish a continuous monitoring of antimicrobial susceptibility among veterinary laboratories in European countries based on validated and harmonised methodologies. Available summary data of the susceptibility testing of the bacterial pathogens from the different laboratories were collected.
Method
Antimicrobial susceptibility data for several bovine pathogens were obtained over a three year period (2002–2004). Each year the participating laboratories were requested to fill in excel-file templates with national summary data on the occurrence of antimicrobial resistance from different bacterial species.
A proficiency test (EQAS – external quality assurance system) for antimicrobial susceptibility testing was conducted each year to test the accuracy of antimicrobial susceptibility testing in the participating laboratories. The data from this testing demonstrated that for the species included in the EQAS the results are comparable between countries.
Results
Data from 25,241 isolates were collected from 13 European countries. For Staphylococcus aureus from bovine mastitis major differences were apparent in the occurrence of resistance between countries and between the different antimicrobial agents tested. The highest frequency of resistance was observed for penicillin. For Mannheimia haemolytica resistance to ampicillin, tetracycline and trimethoprim/sulphonamide were observed in France, the Netherlands and Portugal. All isolates of Pasteurella multocida isolated in Finland and most of those from Denmark, England (and Wales), Italy and Sweden were susceptible to the majority of the antimicrobials. Streptococcus dysgalactiae and Streptococcus uberis isolates from Sweden were fully susceptible. For the other countries some resistance was observed to tetracycline, gentamicin and erythromycin. More resistance and variation of the resistance levels between countries were observed for Escherichia coli compared to the other bacterial species investigated.
Conclusion
In general, isolates from Denmark, England (and Wales), the Netherlands, Norway, Sweden and Switzerland showed low frequencies of resistance, whereas many isolates from Belgium, France, Italy, Latvia and Spain were resistant to most antimicrobials tested. In the future, data on the prevalence of resistance should be used to develop guidelines for appropriate antimicrobial use in veterinary medicine.
doi:10.1186/1751-0147-50-28
PMCID: PMC2486267  PMID: 18611246
24.  Pathema: a clade-specific bioinformatics resource center for pathogen research 
Nucleic Acids Research  2009;38(Database issue):D408-D414.
Pathema (http://pathema.jcvi.org) is one of the eight Bioinformatics Resource Centers (BRCs) funded by the National Institute of Allergy and Infectious Disease (NIAID) designed to serve as a core resource for the bio-defense and infectious disease research community. Pathema strives to support basic research and accelerate scientific progress for understanding, detecting, diagnosing and treating an established set of six target NIAID Category A–C pathogens: Category A priority pathogens; Bacillus anthracis and Clostridium botulinum, and Category B priority pathogens; Burkholderia mallei, Burkholderia pseudomallei, Clostridium perfringens and Entamoeba histolytica. Each target pathogen is represented in one of four distinct clade-specific Pathema web resources and underlying databases developed to target the specific data and analysis needs of each scientific community. All publicly available complete genome projects of phylogenetically related organisms are also represented, providing a comprehensive collection of organisms for comparative analyses. Pathema facilitates the scientific exploration of genomic and related data through its integration with web-based analysis tools, customized to obtain, display, and compute results relevant to ongoing pathogen research. Pathema serves the bio-defense and infectious disease research community by disseminating data resulting from pathogen genome sequencing projects and providing access to the results of inter-genomic comparisons for these organisms.
doi:10.1093/nar/gkp850
PMCID: PMC2808925  PMID: 19843611
25.  International Monetary Fund Programs and Tuberculosis Outcomes in Post-Communist Countries 
PLoS Medicine  2008;5(7):e143.
Background
Previous studies have indicated that International Monetary Fund (IMF) economic programs have influenced health-care infrastructure in recipient countries. The post-communist Eastern European and former Soviet Union countries experienced relatively similar political and economic changes over the past two decades, and participated in IMF programs of varying size and duration. We empirically examine how IMF programs related to changes in tuberculosis incidence, prevalence, and mortality rates among these countries.
Methods and Findings
We performed multivariate regression of two decades of tuberculosis incidence, prevalence, and mortality data against variables potentially influencing tuberculosis program outcomes in 21 post-communist countries for which comparative data are available. After correcting for confounding variables, as well as potential detection, selection, and ecological biases, we observed that participating in an IMF program was associated with increased tuberculosis incidence, prevalence, and mortality rates by 13.9%, 13.2%, and 16.6%, respectively. Each additional year of participation in an IMF program was associated with increased tuberculosis mortality rates by 4.1%, and each 1% increase in IMF lending was associated with increased tuberculosis mortality rates by 0.9%. On the other hand, we estimated a decrease in tuberculosis mortality rates of 30.7% (95% confidence interval, 18.3% to 49.5%) associated with exiting the IMF programs. IMF lending did not appear to be a response to worsened health outcomes; rather, it appeared to be a precipitant of such outcomes (Granger- and Sims-causality tests), even after controlling for potential political, socioeconomic, demographic, and health-related confounders. In contrast, non-IMF lending programs were connected with decreased tuberculosis mortality rates (−7.6%, 95% confidence interval, −1.0% to −14.1%). The associations observed between tuberculosis mortality and IMF programs were similar to those observed when evaluating the impact of IMF programs on tuberculosis incidence and prevalence. While IMF programs were connected with large reductions in generalized government expenditures, tuberculosis program coverage, and the number of physicians per capita, non-IMF lending programs were not significantly associated with these variables.
Conclusions
IMF economic reform programs are associated with significantly worsened tuberculosis incidence, prevalence, and mortality rates in post-communist Eastern European and former Soviet countries, independent of other political, socioeconomic, demographic, and health changes in these countries. Future research should attempt to examine how IMF programs may have related to other non-tuberculosis–related health outcomes.
David Stuckler and colleagues show that, in Eastern European and former Soviet Union countries, participation in International Monetary Fund economic programs have been associated with higher mortality rates from tuberculosis.
Editors' Summary
Background.
Tuberculosis—a contagious, bacterial infection—has killed large numbers of people throughout human history. Over the last century improvements in public health began to reduce the incidence (the number of new cases in the population in a given time), prevalence (the number of infected people), and mortality rate (number of people dying each year) of tuberculosis in several countries. Many authorities thought that tuberculosis had become a disease of the past. It has become increasingly clear, however, that regions impacted by health and economic changes since the 1980s have continued to face a high and sometimes increasing burden of tuberculosis. In order to boost funding and resources for combating the global tuberculosis problem, the United Nations has set a target of halting and reversing increases in global tuberculosis incidence by 2015 as one of its Millennium Development Goals. Yet one region of the world—Eastern Europe and the former Soviet Union—is not on track to achieve this goal.
Why Was This Study Done?
To achieve these targets, the World Health Organization (WHO) and tuberculosis physicians' groups promote the expansion of detection and treatment efforts against tuberculosis. But these efforts depend on the maintenance of good health infrastructure to fund and support health-care workers, clinics, and hospitals. In countries with significant financial limitations, the development and maintenance of these health system resources are often dependent upon international donations and financial lending. The International Monetary Fund (IMF) is a major source of capital for resource-deprived countries, but it is unclear whether its economic reform programs have positive or negative effects on health and health infrastructures in recipient countries. There are indications, for example, that recipient countries sometimes reduce their public-health spending to meet the economic targets set by the IMF as conditions for its loans. In this study, the researchers examine the relationship between participating in IMF lending programs of varying sizes and durations by 21 post-communist Central and Eastern European and former Soviet Union countries and changes in tuberculosis incidence, prevalence, and mortality in these countries during the past two decades.
What Did the Researchers Do and Find?
To examine how participation in IMF lending programs affected tuberculosis control in these countries, the researchers developed a series of statistical models that take into account other variables (for example, directly observed therapy programs, HIV rates, military conflict, and urbanization) that might have affected tuberculosis control. Participation in an IMF program, they report, was associated with increases in tuberculosis incidence, prevalence, and mortality rate of about 15%, which corresponds to hundreds of thousands of new cases and deaths in this region. Each additional year of participation increased tuberculosis mortality rates by 4.1%; increases in the size of the IMF loan also corresponded to greater tuberculosis mortality rates. Conversely, when countries left IMF programs, tuberculosis mortality rates dropped by roughly one-third. The authors' further statistical tests indicated that IMF lending was not a positive response to worsened tuberculosis control but precipitated this adverse outcome and that lending from non-IMF sources of funding was associated with decreases in tuberculosis mortality rates. Consistent with these results, IMF (but not non-IMF) programs were associated with reductions in government expenditures, tuberculosis program coverage, and the number of doctors per capita in each country. These findings associated with mortality were also found when analyzing tuberculosis incidence and prevalence data.
What Do These Findings Mean?
These findings indicate that IMF economic programs are associated with significantly worsened tuberculosis control in post-communist Central and Eastern European and former Soviet Union countries, independent of other political, health, and economic changes in these countries. Further research is needed to discover exactly which aspects of the IMF programs were associated with the adverse effects on tuberculosis control reported here and to see whether IMF loans have similar effects on tuberculosis control in other countries or on other non–tuberculosis-related health outcomes. For now, these results challenge the proposition that the forms of economic development promoted by the IMF necessarily improve public health. In particular, they put the onus on the IMF to critically evaluate the direct and indirect effects of its economic programs on public health.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050143.
This study is further discussed in a PLoS Medicine Perspective by Murray and King
The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis, including a brief history of the disease
The US Centers for Disease Control and Prevention provide several fact sheets and other information resources about tuberculosis
The World Health Organization provides information (in several languages) on efforts to reduce the global burden of tuberculosis, including information on the Stop TB Strategy and the 2008 report on global tuberculosis control—surveillance, planning, financing
Detailed information about the International Monetary Fund is available on its Web site
An article that asks “Does the IMF constrain health spending in poor countries?” (with a link to a response from the IMF) is provided by the Center for Global Development
doi:10.1371/journal.pmed.0050143
PMCID: PMC2488179  PMID: 18651786

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