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1.  Diet and Physical Activity for the Prevention of Noncommunicable Diseases in Low- and Middle-Income Countries: A Systematic Policy Review 
PLoS Medicine  2013;10(6):e1001465.
Carl Lachat and colleagues evaluate policies in low- and middle-income countries addressing salt and fat consumption, fruit and vegetable intake, and physical activity, key risk factors for non-communicable diseases.
Please see later in the article for the Editors' Summary
Background
Diet-related noncommunicable diseases (NCDs) are increasing rapidly in low- and middle-income countries (LMICs) and constitute a leading cause of mortality. Although a call for global action has been resonating for years, the progress in national policy development in LMICs has not been assessed. This review of strategies to prevent NCDs in LMICs provides a benchmark against which policy response can be tracked over time.
Methods and Findings
We reviewed how government policies in LMICs outline actions that address salt consumption, fat consumption, fruit and vegetable intake, or physical activity. A structured content analysis of national nutrition, NCDs, and health policies published between 1 January 2004 and 1 January 2013 by 140 LMIC members of the World Health Organization (WHO) was carried out. We assessed availability of policies in 83% (116/140) of the countries. NCD strategies were found in 47% (54/116) of LMICs reviewed, but only a minority proposed actions to promote healthier diets and physical activity. The coverage of policies that specifically targeted at least one of the risk factors reviewed was lower in Africa, Europe, the Americas, and the Eastern Mediterranean compared to the other two World Health Organization regions, South-East Asia and Western Pacific. Of the countries reviewed, only 12% (14/116) proposed a policy that addressed all four risk factors, and 25% (29/116) addressed only one of the risk factors reviewed. Strategies targeting the private sector were less frequently encountered than strategies targeting the general public or policy makers.
Conclusions
This review indicates the disconnection between the burden of NCDs and national policy responses in LMICs. Policy makers urgently need to develop comprehensive and multi-stakeholder policies to improve dietary quality and physical activity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Noncommunicable diseases (NCDs)—chronic medical conditions including cardiovascular diseases (heart disease and stroke), diabetes, cancer, and chronic respiratory diseases (chronic obstructive pulmonary disease and asthma)—are responsible for two-thirds of the world's deaths. Nearly 80% of NCD deaths, close to 30 million per year, occur in low- and middle-income countries (LMICs), where they are also rising most rapidly. Diet and lifestyle (including smoking, lack of exercise, and harmful alcohol consumption) influence a person's risk of developing an NCD and of dying from it. Because they can be modified, these risk factors have been at the center of strategies to combat NCDs. In 2004, the World Health Organization (WHO) adopted the Global Strategy on Diet, Physical Activity and Health. For diet, it recommended that individuals achieve energy balance and a healthy weight; limit energy intake from total fats and shift fat consumption away from saturated fats to unsaturated fats and towards the elimination of trans-fatty acids; increase consumption of fruits, vegetables, legumes, whole grains, and nuts; limit the intake of free sugars; and limit salt consumption from all sources and ensure that salt is iodized. For physical activity, it recommended at least 30 minutes of regular, moderate-intensity physical activity on most days throughout a person's life.
Why Was This Study Done?
By signing onto the Global Strategy in 2004, WHO member countries agreed to implement it with high priority. A first step of implementation is usually the development of local policies. Consequently, one of the four objectives of the WHO Global Strategy is “to encourage the development, strengthening and implementation of global, regional, national and community policies and action plans to improve diets and increase physical activity.” Along the same lines, in 2011 the United Nations held a high-level meeting in which the need to accelerate the policy response to the NCD epidemic was emphasized. This study was done to assess the existing national policies on NCD prevention in LMICs. Specifically, the researchers examined how well those policies matched the WHO recommendations for intake of salt, fat, and fruits and vegetables, as well as the recommendations for physical activity.
What Did the Researchers Do and Find?
The researchers searched the Internet (including websites of relevant ministries and departments) for all publicly available national policies related to diet, nutrition, NCDs, and health from all 140 WHO member countries classified as LMICs by the World Bank in 2011. For countries for which the search did not turn up policies, the researchers sent e-mail requests to the relevant national authorities, to the regional WHO offices, and to personal contacts. All documents dated from 1 January 2004 to 1 January 2013 that included national objectives and guidelines for action regarding diet, physical exercise, NCD prevention, or a combination of the three, were analyzed in detail.
Most of the policies obtained were not easy to find and access. For 24 countries, particularly in the Eastern Mediterranean, the researchers eventually gave up, unable to establish whether relevant national policies existed. Of the remaining 116 countries, 29 countries had no relevant policies, and another 30 had policies that failed to mention specifically any of the diet-related risk factors included in the analysis. Fifty-four of the 116 countries had NCD policies that addressed at least one of the risk factors. Thirty-six national policy documents contained strategies to increase fruit and vegetable intake, 20 addressed dietary fat consumption, 23 aimed to limit salt intake, and 35 had specific actions to promote physical activity. Only 14 countries, including Jamaica, the Philippines, Iran, and Mongolia, had policies that addressed all four risk factors. The policies of 27 countries mentioned only one of the four risk factors.
Policies primarily targeted consumers and government agencies and failed to address the roles of the business community or civil society. Consistent with this, most were missing plans, mechanisms, and incentives to drive collaborations between the different stakeholders.
What Do These Findings Mean?
More than eight years after the WHO Global Strategy was agreed upon, only a minority of the LMICs included in this analysis have comprehensive policies in place. Developing policies and making them widely accessible is a likely early step toward specific implementation and actions to prevent NCDs. These results therefore suggest that not enough emphasis is placed on NCD prevention in these countries through actions that have been proven to reduce known risk factors. That said, the more important question is what countries are actually doing to combat NCDs, something not directly addressed by this analysis.
In richer countries, NCDs have for decades been the leading cause of sickness and death, and the fact that public health strategies need to emphasize NCD prevention is now widely recognized. LMICs not only have more limited resources, they also continue to carry a large burden from infectious diseases. It is therefore not surprising that shifting resources towards NCD prevention is a difficult process, even if the human cost of these diseases is massive and increasing. That only about 3% of global health aid is aimed at NCD prevention does not help the situation.
The authors argue that one step toward improving the situation is better sharing of best practices and what works and what doesn't in policy development. They suggest that an open-access repository like one that exists for Europe could improve the situation. They offer to organize, host, and curate such a resource under the auspices of WHO, starting with the policies retrieved for this study, and they invite submission of additional policies and updates.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001465.
This study is further discussed in a PLOS Medicine Perspective by Stuckler and Basu
The WHO website on diet and physical activity contains links to various documents, including a diet and physical activity implementation toolbox that contains links to the 2004 Global Strategy document and a Framework to Monitor and Evaluate Implementation
There is a 2011 WHO primer on NCDs entitled Prioritizing a Preventable Epidemic
A recent PLOS Medicine editorial and call for papers addressing the global disparities in the burden from NCDs
A PLOS Blogs post entitled Politics and Global HealthAre We Missing the Obvious? and associated comments discuss the state of the fight against NCDs in early 2013
The NCD Alliance was founded by the Union for International Cancer Control, the International Diabetes Federation, the World Heart Federation, and the International Union Against Tuberculosis and Lung Disease; its mission is to combat the NCD epidemic by putting health at the center of all policies
The WHO European Database on Nutrition, Obesity and Physical Activity (NOPA) contains national and subnational surveillance data, policy documents, actions to implement policy, and examples of good practice in programs and interventions for the WHO European member states
doi:10.1371/journal.pmed.1001465
PMCID: PMC3679005  PMID: 23776415
2.  How countries cope with competing demands and expectations: perspectives of different stakeholders on priority setting and resource allocation for health in the era of HIV and AIDS 
BMC Public Health  2012;12:1071.
Background
Health systems have experienced unprecedented stress in recent years, and as yet no consensus has emerged as to how to deal with the multiple burden of disease in the context of HIV and AIDS and other competing health priorities. Priority setting is essential, yet this is a complex, multifaceted process. Drawing on a study conducted in five African countries, this paper explores different stakeholders′ perceptions of health priorities, how priorities are defined in practice, the process of resource allocation for HIV and Health and how different stakeholders perceive this.
Methods
A sub-analysis was conducted of selected data from a wider qualitative study that explored the interactions between health systems and HIV and AIDS responses in five sub-Saharan countries (Burkina Faso, the Democratic Republic of Congo, Ghana, Madagascar and Malawi). Key background documents were analysed and semi-structured interviews (n = 258) and focus group discussions (n = 45) were held with representatives of communities, health personnel, decision makers, civil society representatives and development partners at both national and district level.
Results
Health priorities were expressed either in terms of specific health problems and diseases or gaps in service delivery requiring a strengthening of the overall health system. In all five countries study respondents (with the exception of community members in Ghana) identified malaria and HIV as the two top health priorities. Community representatives were more likely to report concerns about accessibility of services and quality of care. National level respondents often referred to wider systemic challenges in relation to achieving the Millennium Development Goals (MDGs). Indeed, actual priority setting was heavily influenced by international agendas (e.g. MDGs) and by the ways in which development partners were supporting national strategic planning processes. At the same time, multi-stakeholder processes were increasingly used to identify priorities and inform sector-wide planning, whereby health service statistics were used to rank the burden of disease. However, many respondents remarked that health system challenges are not captured by such statistics.
In all countries funding for health was reported to fall short of requirements and a need for further priority setting to match actual resource availability was identified. Pooled health sector funds have been established to some extent, but development partners′ lack of flexibility in the allocation of funds according to country-generated priorities was identified as a major constraint.
Conclusions
Although we found consensus on health priorities across all levels in the study countries, current funding falls short of addressing these identified areas. The nature of external funding, as well as programme-specific investment, was found to distort priority setting. There are signs that existing interventions have had limited effects beyond meeting the needs of disease-specific programmes. A need for more comprehensive health system strengthening (HSS) was identified, which requires a strong vision as to what the term means, coupled with a clear strategy and commitment from national and international decision makers in order to achieve stated goals. Prospective studies and action research, accompanied by pilot programmes, are recommended as deliberate strategies for HSS.
doi:10.1186/1471-2458-12-1071
PMCID: PMC3549279  PMID: 23231820
HIV and AIDS; Health systems strengthening; Priority setting; Needs and priorities; Sector-wide approaches; Sub-Saharan Africa
3.  The Human Milk Protein-Lipid Complex HAMLET Sensitizes Bacterial Pathogens to Traditional Antimicrobial Agents 
PLoS ONE  2012;7(8):e43514.
The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend the lifetime of the current treatment arsenal.
doi:10.1371/journal.pone.0043514
PMCID: PMC3419703  PMID: 22905269
4.  Antibacterial Properties of an Oligo-Acyl-Lysyl Hexamer Targeting Gram-Negative Species 
Toward developing new tools for fighting resistance to antibiotics, we investigated the antibacterial properties of a new decanoyl-based oligo-acyl-lysyl (OAK) hexamer, aminododecanoyl-lysyl-[aminodecanoyl-lysyl]5 (α12-5α10). The OAK exhibited preferential activity against Gram-negative bacteria (GNB), as determined using 36 strains, including diverse species, with an MIC90 of 6.2 μM. The OAK's bactericidal mode of action was associated with rapid membrane depolarization and cell permeabilization, suggesting that the inner membrane was the primary target, whereas the observed binding affinity to lipoteichoic acid suggested that inefficacy against Gram-positive species resulted from a cell wall interaction preventing α12-5α10 from reaching internal targets. Interestingly, perturbation of the inner membrane structure and function was preserved at sub-MIC values. This prompted us to assess the OAK's effect on the proton motive force-dependent efflux pump AcrAB-TolC, implicated in the low sensitivity of GNB to various antibiotics, including erythromycin. We found that under sub-MIC conditions, wild-type Escherichia coli was significantly more sensitive to erythromycin (the MIC dropped by >10-fold), unlike its acr-deletion mutant. Collectively, the data suggest a useful approach for treating GNB infections through overcoming antibiotic efflux.
doi:10.1128/AAC.00511-12
PMCID: PMC3421859  PMID: 22751534
5.  The 'diagonal' approach to Global Fund financing: a cure for the broader malaise of health systems? 
Background
The potentially destructive polarisation between 'vertical' financing (aiming for disease-specific results) and 'horizontal' financing (aiming for improved health systems) of health services in developing countries has found its way to the pages of Foreign Affairs and the Financial Times. The opportunity offered by 'diagonal' financing (aiming for disease-specific results through improved health systems) seems to be obscured in this polarisation.
In April 2007, the board of the Global Fund to fight AIDS, Tuberculosis and Malaria agreed to consider comprehensive country health programmes for financing. The new International Health Partnership Plus, launched in September 2007, will help low-income countries to develop such programmes. The combination could lead the Global Fund to fight AIDS, Tuberculosis and Malaria to a much broader financing scope.
Discussion
This evolution might be critical for the future of AIDS treatment in low-income countries, yet it is proposed at a time when the Global Fund to fight AIDS, Tuberculosis and Malaria is starved for resources. It might be unable to meet the needs of much broader and more expensive proposals. Furthermore, it might lose some of its exceptional features in the process: its aim for international sustainability, rather than in-country sustainability, and its capacity to circumvent spending restrictions imposed by the International Monetary Fund.
Summary
The authors believe that a transformation of the Global Fund to fight AIDS, Tuberculosis and Malaria into a Global Health Fund is feasible, but only if accompanied by a substantial increase of donor commitments to the Global Fund. The transformation of the Global Fund into a 'diagonal' and ultimately perhaps 'horizontal' financing approach should happen gradually and carefully, and be accompanied by measures to safeguard its exceptional features.
doi:10.1186/1744-8603-4-6
PMCID: PMC2335098  PMID: 18364048
6.  Enhancing Exposure of HIV-1 Neutralization Epitopes through Mutations in gp41 
PLoS Medicine  2008;5(1):e9.
Background
The generation of broadly neutralizing antibodies is a priority in the design of vaccines against HIV-1. Unfortunately, most antibodies to HIV-1 are narrow in their specificity, and a basic understanding of how to develop antibodies with broad neutralizing activity is needed. Designing methods to target antibodies to conserved HIV-1 epitopes may allow for the generation of broadly neutralizing antibodies and aid the global fight against AIDS by providing new approaches to block HIV-1 infection. Using a naturally occurring HIV-1 Envelope (Env) variant as a template, we sought to identify features of Env that would enhance exposure of conserved HIV-1 epitopes.
Methods and Findings
Within a cohort study of high-risk women in Mombasa, Kenya, we previously identified a subtype A HIV-1 Env variant in one participant that was unusually sensitive to neutralization. Using site-directed mutagenesis, the unusual neutralization sensitivity of this variant was mapped to two amino acid mutations within conserved sites in the transmembrane subunit (gp41) of the HIV-1 Env protein. These two mutations, when introduced into a neutralization-resistant variant from the same participant, resulted in 3- to >360-fold enhanced neutralization by monoclonal antibodies specific for conserved regions of both gp41 and the Env surface subunit, gp120, >780-fold enhanced neutralization by soluble CD4, and >35-fold enhanced neutralization by the antibodies found within a pool of plasmas from unrelated individuals. Enhanced neutralization sensitivity was not explained by differences in Env infectivity, Env concentration, Env shedding, or apparent differences in fusion kinetics. Furthermore, introduction of these mutations into unrelated viral Env sequences, including those from both another subtype A variant and a subtype B variant, resulted in enhanced neutralization susceptibility to gp41- and gp120-specific antibodies, and to plasma antibodies. This enhanced neutralization sensitivity exceeded 1,000-fold in several cases.
Conclusions
Two amino acid mutations within gp41 were identified that expose multiple discontinuous neutralization epitopes on diverse HIV-1 Env proteins. These exposed epitopes were shielded on the unmodified viral Env proteins, and several of the exposed epitopes encompass desired target regions for protective antibodies. Env proteins containing these modifications could act as a scaffold for presentation of such conserved domains, and may aid in developing methods to target antibodies to such regions.
Julie Overbaugh and colleagues analyze an HIV strain with high susceptibility to antibody neutralization and identify two gp41 envelope mutations that confer this sensitivity by exposing multiple neutralization epitopes.
Editors' Summary
Background.
In 1984 when scientists identified human immunodeficiency virus (HIV)—the cause of acquired immunodeficiency syndrome (AIDS)—many experts believed that a vaccine against HIV infection would soon be developed. Nearly 25 years later, there is still no such vaccine and with about 2.5 million new HIV infections in 2007, an effective vaccine is urgently needed to contain the AIDS epidemic. Vaccines provide protection against infectious diseases by priming the immune system to deal quickly and effectively with viruses and other pathogens. Vaccines do this by exposing the immune system to an immunogen—a fragment or harmless version of the pathogen. The immune system mounts a response against the immunogen and also “learns” from this experience so that if it is ever challenged with a virulent version of the same pathogen, it can quickly contain the threat. Many vaccines work by stimulating an antibody response. Antibodies are proteins made by the immune system that bind to molecules called antigens on the surface of pathogens. Antibodies that inactivate the invader upon binding to it are called “neutralizing” antibodies.
Why Was This Study Done?
Several characteristics of HIV have hampered the development of an effective vaccine. An “envelope” protein consisting of two subunits called gp120 and gp41 covers the outside of HIV. Many regions of this protein change rapidly, so the antibody response stimulated by a vaccine containing the envelope protein of one HIV variant provides little protection against other variants. However, other regions of the protein rarely change, so a vaccine that stimulates the production of antibodies to these “conserved” regions is likely to provide protection against many HIV variants. That is, it will stimulate the production of broadly neutralizing antibodies. Unfortunately, it has been difficult to find HIV vaccines that do this, because these conserved regions are often hidden from the immune system by other parts of the envelope protein. In this study, the researchers investigate the envelope protein of an HIV-1 variant they have isolated that is highly susceptible to inactivation by antibodies specific for these conserved regions. Comparing the envelope protein of this sensitive virus to closely related envelope proteins that are resistant to neutralization could identify features that might, if included in an envelope protein immunogen, produce a vaccine capable of generating broadly neutralizing antibodies.
What Did the Researchers Do and Find?
The researchers isolated a subtype A HIV-1 variant from a newly infected woman in Kenya that was efficiently neutralized by monoclonal antibodies (antibodies made by cells that have been cloned in the laboratory). These antibodies were specific for several different conserved regions of gp41 and gp120. The isolate was also neutralized by antibodies in blood from HIV-1-infected people. The envelope protein of the sensitive variant was the same as that of a resistant variant isolated at the same time from the woman, except for four amino acid changes in conserved regions of gp41 (proteins are made from long strings of amino acids). Using a technique called site-directed mutagenesis, the researchers introduced these amino acid changes into envelope proteins made in the laboratory and determined that just two of these changes were responsible for the neutralization sensitivity of the HIV-1 variant. The introduction of these two changes into the neutralization resistant variant and into the unrelated envelope sequences of another subtype A (common in Africa) HIV-1 variant and a subtype B HIV-1 (common in Europe and the Western Hemisphere) variant increased the sensitivity of all these viruses to antibody neutralization.
What Do These Findings Mean?
These findings show that two amino acid changes in gp41 of a neutralization-sensitive HIV-1 variant are responsible for the sensitivity of this variant to several neutralizing antibodies. The finding that the inclusion of these changes in the envelope protein of neutralization-resistant HIV-1 variants greatly increases their sensitivity to neutralizing antibodies indicates that the normally shielded regions of the protein are somehow made accessible to antibody by these changes. One possibility is that the amino acid changes might modify the overall shape of the envelope protein, thus exposing multiple, normally hidden regions in the HIV-1 envelope protein to antibodies. Importantly, these findings open up the possibility that the inclusion of these modifications in envelope-based immunogens might improve the ability of vaccines to generate broadly neutralizing antibodies against HIV-1.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050009.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIVInSite has comprehensive information on all aspects of HIV/AIDS, including links to resources dealing with HIV vaccine development
Information is available from Avert, an international AIDS charity, on all aspects of HIV and AIDS, including HIV vaccines
The US Centers for Disease Control and prevention provides information on HIV/AIDS including information on its HIV vaccine unit (in English and some information in Spanish)
The AIDS Vaccine Clearinghouse provides clear information about HIV vaccine science, research and product development
The International AIDS Vaccine Initiative also provides straightforward information about the development of HIV vaccines
doi:10.1371/journal.pmed.0050009
PMCID: PMC2174964  PMID: 18177204
7.  Ready for a world without antibiotics? The Pensières Antibiotic Resistance Call to Action 
Resistance to antibiotics has increased dramatically over the past few years and has now reached a level that places future patients in real danger. Microorganisms such as Escherichia coli and Klebsiella pneumoniae, which are commensals and pathogens for humans and animals, have become increasingly resistant to third-generation cephalosporins. Moreover, in certain countries, they are also resistant to carbapenems and therefore susceptible only to tigecycline and colistin. Resistance is primarily attributed to the production of beta-lactamase genes located on mobile genetic elements, which facilitate their transfer between different species. In some rare cases, Gram-negative rods are resistant to virtually all known antibiotics. The causes are numerous, but the role of the overuse of antibiotics in both humans and animals is essential, as well as the transmission of these bacteria in both the hospital and the community, notably via the food chain, contaminated hands, and between animals and humans. In addition, there are very few new antibiotics in the pipeline, particularly for Gram-negative bacilli. The situation is slightly better for Gram-positive cocci as some potent and novel antibiotics have been made available in recent years. A strong and coordinated international programme is urgently needed. To meet this challenge, 70 internationally recognized experts met for a two-day meeting in June 2011 in Annecy (France) and endorsed a global call to action ("The Pensières Antibiotic Resistance Call to Action"). Bundles of measures that must be implemented simultaneously and worldwide are presented in this document. In particular, antibiotics, which represent a treasure for humanity, must be protected and considered as a special class of drugs.
doi:10.1186/2047-2994-1-11
PMCID: PMC3436635  PMID: 22958833
antibiotic resistance; antibiotic stewardship; infection control; hand hygiene; surveillance networks; care bundles; environment; regulations; human medicine; animal medicine
8.  Antibiotic resistance as a global threat: Evidence from China, Kuwait and the United States 
Background
Antimicrobial resistance is an under-appreciated threat to public health in nations around the globe. With globalization booming, it is important to understand international patterns of resistance. If countries already experience similar patterns of resistance, it may be too late to worry about international spread. If large countries or groups of countries that are likely to leap ahead in their integration with the rest of the world – China being the standout case – have high and distinctive patterns of resistance, then a coordinated response could substantially help to control the spread of resistance. The literature to date provides only limited evidence on these issues.
Methods
We study the recent patterns of antibiotic resistance in three geographically separated, and culturally and economically distinct countries – China, Kuwait and the United States – to gauge the range and depth of this global health threat, and its potential for growth as globalization expands. Our primary measures are the prevalence of resistance of specific bacteria to specific antibiotics. We also propose and illustrate methods for aggregating specific "bug-drug" data. We use these aggregate measures to summarize the resistance pattern for each country and to study the extent of correlation between countries' patterns of drug resistance.
Results
We find that China has the highest level of antibiotic resistance, followed by Kuwait and the U.S. In a study of resistance patterns of several most common bacteria in China in 1999 and 2001, the mean prevalence of resistance among hospital-acquired infections was as high as 41% (with a range from 23% to 77%) and that among community- acquired infections was 26% (with a range from 15% to 39%). China also has the most rapid growth rate of resistance (22% average growth in a study spanning 1994 to 2000). Kuwait is second (17% average growth in a period from 1999 to 2003), and the U.S. the lowest (6% from 1999 to 2002). Patterns of resistance across the three countries are not highly correlated; the most correlated were China and Kuwait, followed by Kuwait and the U.S., and the least correlated pair was China and the U.S.
Conclusion
Antimicrobial resistance is a serious and growing problem in all three countries. To date, there is not strong international convergence in the countries' resistance patterns. This finding may change with the greater international travel that will accompany globalization. Future research on the determinants of drug resistance patterns, and their international convergence or divergence, should be a priority.
doi:10.1186/1744-8603-2-6
PMCID: PMC1502134  PMID: 16603071
9.  A cross-country review of strategies of the German development cooperation to strengthen human resources 
Background
Recent years have seen growing awareness of the importance of human resources for health in health systems and with it an intensifying of the international and national policies in place to steer a response. This paper looks at how governments and donors in five countries – Cameroon, Indonesia, Malawi, Rwanda and Tanzania – have translated such policies into action. More detailed information with regard to initiatives of German development cooperation brings additional depth to the range and entry doors of human resources for health initiatives from the perspective of donor cooperation.
Methods
This qualitative study systematically presents different approaches and stages to human resources for health development in a cross-country comparison. An important reference to capture implementation at country level was grey literature such as policy documents and programme reports. In-depth interviews along a predefined grid with national and international stakeholders in the five countries provided information on issues related to human resources for health policy processes and implementation.
Results
All five countries have institutional entities in place and have drawn up national policies to address human resources for health. Only some of the countries have translated policies into strategies with defined targets and national programmes with budgets and operational plans. Traditional approaches of supporting training for individual health professionals continue to dominate. In some cases partners have played an advocacy and technical role to promote human resources for health development at the highest political levels, but usually they still focus on the provision of ad hoc training within their programmes, which may not be in line with national human resources for health development efforts or may even be counterproductive to them. Countries that face an emergency, such as Malawi, have intensified their efforts within a relatively short time and by using donor funding support also through new initiatives such as the Global Fund to Fight AIDS, Tuberculosis and Malaria.
Conclusion
The country case studies illustrate the range of initiatives that have surged in recent years and some main trends in terms of donor initiatives. Though attention and priority attributed to human resources for health is increasing, there is still a focus on single initiatives and programmes. This can be explained in part by the complexity of the issue, and in part by its need to be addressed through a long-term approach including public sector and salary reforms that go beyond the health sector.
doi:10.1186/1478-4491-7-46
PMCID: PMC2697154  PMID: 19500357
10.  Positioning women's and children's health in African union policy-making: a policy analysis 
Background
With limited time to achieve the Millennium Development Goals, progress towards improving women's and children's health needs to be accelerated. With Africa accounting for over half of the world's maternal and child deaths, the African Union (AU) has a critical role in prioritizing related policies and catalysing required investments and action. In this paper, the authors assess the evolution of African Union policies related to women's and children's health, and analyze how these policies are prioritized and framed.
Methods
The main method used in this policy analysis was a document review of all African Union policies developed from 1963 to 2010, focusing specifically on policies that explicitly mention health. The findings from this document review were discussed with key actors to identify policy implications.
Results
With over 220 policies in total, peace and security is the most common AU policy topic. Social affairs and other development issues became more prominent in the 1990s. The number of policies that mentioned health rose steadily over the years (with 1 policy mentioning health in 1963 to 7 in 2010).
This change was catalysed by factors such as: a favourable shift in AU priorities and systems towards development issues, spurred by the transition from the Organization of African Unity to the African Union; the mandate of the African Commission on Human and People's Rights; health-related advocacy initiatives, such as the Campaign for the Accelerated Reduction of Maternal Mortality in Africa (CARMMA); action and accountability requirements arising from international human rights treaties, the Millennium Development Goals (MDGs), and new health-funding mechanisms, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria.
Prioritization of women's and children's health issues in AU policies has been framed primarily by human rights, advocacy and accountability considerations, more by economic and health frames looking at investments and impact. AU policies related to reproductive, maternal, newborn and child health also use fewer policy frames than do AU policies related to HIV/AIDS, tuberculosis and malaria.
Conclusion
We suggest that more effective prioritization of women's and children's health in African Union policies would be supported by widening the range of policy frames used (notably health and economic) and strengthening the evidence base of all policy frames used. In addition, we suggest it would be beneficial if the partner groups advocating for women's and children's health were multi-stakeholder, and included, for instance, health care professionals, regional institutions, parliamentarians, the media, academia, NGOs, development partners and the public and private sectors.
doi:10.1186/1744-8603-8-3
PMCID: PMC3298467  PMID: 22340362
African Union; Millennium Development Goals (MDGs); policy-making; women's and children's health
11.  Promoting community participation in priority setting in district health systems: experiences from Mbarali district, Tanzania 
Global Health Action  2013;6:10.3402/gha.v6i0.22669.
Background
Community participation in priority setting in health systems has gained importance all over the world, particularly in resource-poor settings where governments have often failed to provide adequate public-sector services for their citizens. Incorporation of public views into priority setting is perceived as a means to restore trust, improve accountability, and secure cost-effective priorities within healthcare. However, few studies have reported empirical experiences of involving communities in priority setting in developing countries. The aim of this article is to provide the experience of implementing community participation and the challenges of promoting it in the context of resource-poor settings, weak organizations, and fragile democratic institutions.
Design
Key informant interviews were conducted with the Council Health Management Team (CHMT), community representatives, namely women, youth, elderly, disabled, and people living with HIV/AIDS, and other stakeholders who participated in the preparation of the district annual budget and health plans. Additionally, minutes from the Action Research Team and planning and priority-setting meeting reports were analyzed.
Results
A number of benefits were reported: better identification of community needs and priorities, increased knowledge of the community representatives about priority setting, increased transparency and accountability, promoted trust among health systems and communities, and perceived improved quality and accessibility of health services. However, lack of funds to support the work of the selected community representatives, limited time for deliberations, short notice for the meetings, and lack of feedback on the approved priorities constrained the performance of the community representatives. Furthermore, the findings show the importance of external facilitation and support in enabling health professionals and community representatives to arrive at effective working arrangement.
Conclusion
Community participation in priority setting in developing countries, characterized by weak democratic institutions and low public awareness, requires effective mobilization of both communities and health systems. In addition, this study confirms that community participation is an important element in strengthening health systems.
doi:10.3402/gha.v6i0.22669
PMCID: PMC3841300  PMID: 24280341
community participation; priority setting; district health systems; Tanzania
12.  Use of energy reserves in fighting hermit crabs. 
When animals engage in fights they face a series of decisions, which are based on the value of the contested resource and either their relative or their absolute fighting ability. Certain correlates of fighting ability or 'resource holding potential' such as body size are fixed but physiological correlates are expected to vary during the encounter. We examine the role of energy reserves in determining fight outcomes and parameters during 'shell fighting' in hermit crabs. During these fights, the two contestants perform very different roles of attacker and defender. We show that the balance of the total energy pool, in the form of glucose and glycogen, determines the ability of defenders to resist eviction from their shells. Low glucose in evicted defenders is not caused by depletion of energy reserves, rather mobilization of glycogen appears to be the result of a strategic decision about whether to resist effectively, based on the perceived fighting ability of the attacker. Attackers, however, always initiate the fight so such a decision for this role appears unlikely. In addition to influencing decisions and ability during fights, physiological correlates of fighting ability can in turn be influenced by strategic decisions.
PMCID: PMC1691600  PMID: 15101696
13.  Membrane-Active Action Mode of Polybia-CP, a Novel Antimicrobial Peptide Isolated from the Venom of Polybia paulista 
The extensive use of antibiotics in medicine, the food industry, and agriculture has resulted in the frequent emergence of multidrug-resistant bacteria, which creates an urgent need for new antibiotics. It is now widely recognized that antimicrobial peptides (AMPs) could play a promising role in fighting multidrug-resistant bacteria. Antimicrobial peptide polybia-CP was purified from the venom of the social wasp Polybia paulista. In this study, we synthesized polybia-CP and studied its action mode of antibacterial activity. Our results revealed that polybia-CP has potent antibacterial activity against both Gram-positive and Gram-negative bacteria. The results from both the real bacterial membrane and the in vitro model membrane showed that polybia-CP is membrane active and that its action target is the membrane of bacteria. It is difficult for bacteria to develop resistance to polybia-CP, which may thus offer a new strategy for defending against resistant bacteria in medicine and the food and farming industries.
doi:10.1128/AAC.05995-11
PMCID: PMC3370791  PMID: 22450985
14.  Evaluation of a learner-designed course for teaching health research skills in Ghana 
Background
In developing countries the ability to conduct locally-relevant health research and high quality education are key tools in the fight against poverty. The objective of our study was to evaluate the effectiveness of a novel UK accredited, learner-designed research skills course delivered in a teaching hospital in Ghana.
Methods
Study participants were 15 mixed speciality health professionals from Komfo Anokye Teaching Hospital, Kumasi, Ghana. Effectiveness measures included process, content and outcome indicators to evaluate changes in learners' confidence and competence in research, and assessment of the impact of the course on changing research-related thinking and behaviour. Results were verified using two independent methods.
Results
14/15 learners gained research competence assessed against UK Quality Assurance Agency criteria. After the course there was a 36% increase in the groups' positive responses to statements concerning confidence in research-related attitudes, intentions and actions. The greatest improvement (45% increase) was in learners' actions, which focused on strengthening institutional research capacity. 79% of paired before/after responses indicated positive changes in individual learners' research-related attitudes (n = 53), 81% in intention (n = 52) and 85% in action (n = 52). The course had increased learners' confidence to start and manage research, and enhanced life-long skills such as reflective practice and self-confidence. Doing their own research within the work environment, reflecting on personal research experiences and utilising peer support and pooled knowledge were critical elements that promoted learning.
Conclusion
Learners in Ghana were able to design and undertake a novel course that developed individual and institutional research capacity and met international standards. Learning by doing and a supportive peer community at work were critical elements in promoting learning in this environment where tutors were scarce. Our study provides a model for delivering and evaluating innovative educational interventions in developing countries to assess whether they meet external quality criteria and achieve their objectives.
doi:10.1186/1472-6920-7-18
PMCID: PMC1913503  PMID: 17596260
15.  Effect of Facilitation of Local Maternal-and-Newborn Stakeholder Groups on Neonatal Mortality: Cluster-Randomized Controlled Trial 
PLoS Medicine  2013;10(5):e1001445.
Lars Åke Persson and colleagues conduct a cluster randomised control in northern Vietnam to analyze the effect of the activity of local community-based maternal-and-newborn stakeholder groups on neonatal mortality.
Please see later in the article for the Editors' Summary
Background
Facilitation of local women's groups may reportedly reduce neonatal mortality. It is not known whether facilitation of groups composed of local health care staff and politicians can improve perinatal outcomes. We hypothesised that facilitation of local stakeholder groups would reduce neonatal mortality (primary outcome) and improve maternal, delivery, and newborn care indicators (secondary outcomes) in Quang Ninh province, Vietnam.
Methods and Findings
In a cluster-randomized design 44 communes were allocated to intervention and 46 to control. Laywomen facilitated monthly meetings during 3 years in groups composed of health care staff and key persons in the communes. A problem-solving approach was employed. Births and neonatal deaths were monitored, and interviews were performed in households of neonatal deaths and of randomly selected surviving infants. A latent period before effect is expected in this type of intervention, but this timeframe was not pre-specified. Neonatal mortality rate (NMR) from July 2008 to June 2011 was 16.5/1,000 (195 deaths per 11,818 live births) in the intervention communes and 18.4/1,000 (194 per 10,559 live births) in control communes (adjusted odds ratio [OR] 0.96 [95% CI 0.73–1.25]). There was a significant downward time trend of NMR in intervention communes (p = 0.003) but not in control communes (p = 0.184). No significant difference in NMR was observed during the first two years (July 2008 to June 2010) while the third year (July 2010 to June 2011) had significantly lower NMR in intervention arm: adjusted OR 0.51 (95% CI 0.30–0.89). Women in intervention communes more frequently attended antenatal care (adjusted OR 2.27 [95% CI 1.07–4.8]).
Conclusions
A randomized facilitation intervention with local stakeholder groups composed of primary care staff and local politicians working for three years with a perinatal problem-solving approach resulted in increased attendance to antenatal care and reduced neonatal mortality after a latent period.
Trial registration
Current Controlled Trials ISRCTN44599712
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Over the past few years, there has been enormous international effort to meet the target set by Millennium Development Goal 4 to reduce the under-five child mortality rate by two-thirds and to reduce the number of maternal deaths by three-quarters, respectively, from the 1990 level by 2015. There has been some encouraging progress and according to the latest figures from the World Health Organization, in 2011, just under 7 million children aged under 5 years died, a fall of almost 3 million from a decade ago. However, currently, 41% of all deaths among children under the age of 5 years occur around birth and the first 28 days of life (perinatal and neonatal mortality). Simple interventions can substantially reduce neonatal deaths and there have been several international, national, and local efforts to implement effective care packages to help reduce the number of neonatal deaths.
Why Was This Study Done?
In order for these interventions to be most effective, it is important that the local community becomes involved. Community mobilization, especially through local women's groups, can empower women to prioritize specific interventions to help improve their own health and that of their baby. An alternative strategy might be to mobilize people who already have responsibility to promote health and welfare in society, such as primary care staff, village health workers, and elected political representatives. However, it is unclear if the activities of such stakeholder groups result in improved neonatal survival. So in this study from northern Vietnam, the researchers analyzed the effect of the activity of local maternal-and-newborn stakeholder groups on neonatal mortality.
What Did the Researchers Do and Find?
Between 2008 and 2011, the researchers conducted a cluster-randomized controlled trial in 90 communes within the Quang Ninh province of northeast of Vietnam: 44 communes were allocated to intervention and 46 to the control. The local women's union facilitated recruitment to the intervention, local stakeholder groups (Maternal and Newborn Health Groups), which comprised primary care staff, village health workers, women's union representatives, and the person with responsibility for health in the commune. The groups' role was to identify and prioritize local perinatal health problems and implement actions to help overcome these problems.
Over the three-year period, the Maternal and Newborn Health Groups in the 44 intervention communes had 1,508 meetings. Every year 15–27 unique problems were identified and addressed 94–151 times. The problem-solving processes resulted in an annual number of 19–27 unique actions that were applied 297–649 times per year. The top priority problems and actions identified by these groups dealt with antenatal care attendance, post-natal visits, nutrition and rest during pregnancy, home deliveries, and breast feeding. Neonatal mortality in the intervention group did not change over the first two years but showed a significant improvement in the third year. The three leading causes of death were prematurity/low birth-weight (36%), intrapartum-related neonatal deaths (30%), and infections (15%). Stillbirth rates were 7.4 per 1,000 births in the intervention arm and 9.0 per 1,000 births in the control arm. There was one maternal death in the intervention communes and four in the control communes and there was a significant improvement in antenatal care attendance in the intervention arm. However, there were no significant differences between the intervention and control groups of other outcomes, including tetanus immunization, delivery preparedness, institutional delivery, temperature control at delivery, early initiation of breastfeeding, or home visit of a midwife during the first week after delivery.
What Do These Findings Mean?
These findings suggest that local stakeholder groups comprised of primary care staff and local politicians using a problem-solving approach may help to reduce the neonatal mortality rate after three years of implementation (although the time period for an expected reduction in neonatal mortality was not specified before the trial started) and may also increase the rate of antenatal care attendance. However, the intervention had no effect on other important outcomes such as the rate of institutional delivery and breast feeding. This study used a novel approach of community-based activity that was implemented into the public sector system at low cost. A further reduction in neonatal deaths around delivery might be achieved by neonatal resuscitation training and home visits to the mother and her baby.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001445.
The World Health Organization provides comprehensive statistics on neonatal mortality
The Healthy Newborn Network has information on community interventions to help reduce neonatal mortality from around the world
doi:10.1371/journal.pmed.1001445
PMCID: PMC3653802  PMID: 23690755
16.  Bites (mammalian) 
Clinical Evidence  2010;2010:0914.
Introduction
Mammalian bites are usually caused by dogs, cats, or humans, and are more prevalent in children (especially boys) than in adults. Animal bites are usually caused by the person's pet and, in children, frequently involve the face. Human bites tend to occur in children as a result of playing or fighting, while in adults they are usually the result of physical or sexual abuse. Mixed aerobe and anaerobe infection is the most common type of infection, and can occur in up to half of human bites.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent complications of mammalian bites? What are the effects of treatments for infected mammalian bites? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found five systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotic prophylaxis (human bites, non-human bites), antibiotics, debridement, decontamination, irrigation, primary wound closure, and tetanus vaccination (after mammalian bites).
Key Points
Mammalian bites are usually caused by dogs, cats, or humans, and are more prevalent in children (especially boys) than in adults. Animal bites are usually caused by the person's pet and, in children, frequently involve the face.Human bites tend to occur in children as a result of playing or fighting, while in adults they are usually the result of physical or sexual abuse.Physical and psychological trauma are the most common sequelae of a bite wound.Up to 18% of wounds may develop a bacterial infection with a mixture of aerobic and anaerobic organisms. Pasteurella species are pathogens of particular note.Methicillin-resistant Staphylococcus aureus (MRSA) is being increasingly reported in infections associated with domestic animal contact.
There is consensus that tetanus immunisation should be given routinely as part of wound care of mammalian bites, but we found no studies assessing the benefit of this strategy. Immunisation does not need to be performed if there is a record of tetanus immunisation having been given in the previous 5 years.
Antibiotics may prevent infection in high-risk bites to the hand, but we don't know if it is worth giving prophylactic antibiotics after other types of mammalian bites. High-risk bites are those with deep puncture or crushing, with much devitalised tissue, or those that are dirty.Bites that occurred less than 24 hours previously, or those with only simple epidermal stripping, scratches, and abrasions, are unlikely to benefit from antibiotic treatment.
There is consensus that wound debridement, irrigation, decontamination, and primary wound closure are beneficial in reducing infection, but we don't know this for sure.
There is consensus that antibiotics help cure infected bite wounds, although we found few studies. Selection of appropriate antibiotics depends on the likely mouth flora of the biting animal and the skin flora of the recipient, and can be based on samples of infected material examined by microscopy and culture.Antibiotics with activity against Pasteurella multocida should be selected for empirical treatment of infected bite wounds.There is consensus that rabies prophylaxis should be given after all animal bites in areas where rabies is known to exist, and after bat bites in all areas of the world.
PMCID: PMC3217732  PMID: 21418668
17.  Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 
Intensive Care Medicine  2007;34(1):17-60.
Objective
To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, “Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock,” published in 2004.
Design
Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding.
Methods
We used the GRADE system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation [1] indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost), or clearly do not. Weak recommendations [2] indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations.
Results
Key recommendations, listed by category, include: early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures prior to antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7–10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure ≥ 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for post-operative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7–9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B) targeting a blood glucose < 150 mg/dL after initial stabilization ( 2C ); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper GI bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D).
Recommendations specific to pediatric severe sepsis include: greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); a recommendation against the use of recombinant activated protein C in children (1B).
Conclusion
There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.
doi:10.1007/s00134-007-0934-2
PMCID: PMC2249616  PMID: 18058085
Sepsis; Severe sepsis; Septic shock; Sepsis syndrome; Infection; GRADE; Guidelines; Evidence-based medicine; Surviving Sepsis Campaign; Sepsis bundles
18.  Where Do We Go from Here? Prevalence of Trachoma Three Years after Stopping Mass Distribution of Antibiotics in the Regions of Kayes and Koulikoro, Mali 
Objectives
A national survey in 1997 demonstrated that trachoma was endemic in Mali. Interventions to control trachoma including mass drug administration (MDA) with azithromycin were launched in the regions of Kayes and Koulikoro in 2003. MDA was discontinued after three annual rounds in 2006, and an impact survey conducted. We resurveyed all districts in Kayes and Koulikoro in 2009 to reassess trachoma prevalence and determine intervention objectives for the future. In this paper we present findings from both the 2006 and 2009 surveys.
Methods
Population-based cluster surveys were conducted in each of the nine districts in Koulikoro in 2006 and 2009, whilst in Kayes, four of seven districts in 2006 and all seven districts in 2009 were surveyed. Household members present were examined for clinical signs of trachoma.
Results
Overall, 29,179 persons from 2,528 compounds, in 260 clusters were examined in 2006 and 32,918 from 7,533 households in 320 clusters in 2009. The prevalence of TF in children aged 1–9 years in Kayes and Koulikoro was 3.9% (95%CI 2.9–5.0%, range by district 1.2–5.4%) and 2.7% (95%CI 2.3–3.1%, range by district 0.1–5.0%) respectively in 2006. In 2009 TF prevalence was 7.26% (95%CI 6.2–8.2%, range by district 2.5–15.4%) in Kayes and 8.19% (95%CI 7.3–9.1%, range by district 1.7–17.2%) in Koulikoro among children of the same age group. TT in adults 15 years of age and older was 2.37% (95%CI 1.66–3.07%, range by district 0.30–3.54%) in 2006 and 1.37% (95%CI 1.02–1.72%, range by district 0.37–1.87%) in 2009 in Kayes and 1.75% (95%CI 1.31–2.23%, range by district 1.06–2.49%) in 2006 and 1.08% (95%CI 0.86–1.30%, range by district 0.34–1.78%) in 2009 in Koulikoro.
Conclusions
Using WHO guidelines for decision making, four districts, Bafoulabe in Kayes Region; and Banamba, Kolokani and Koulikoro in Koulikoro Region, still meet criteria for district-wide implementation of the full SAFE strategy as TF in children exceeds 10%. A community-by-community approach to trachoma control may now be required in the other twelve districts. Trichiasis surgery provision remains a need in all districts and should be enhanced in six districts in Kayes and five in Koulikoro where the prevalence exceeded 1.0% in adults. Since 1997 great progress has been observed in the fight against blinding trachoma; however, greater effort is required to meet the elimination target of 2015.
Author Summary
Trachoma, a blinding bacterial disease, is targeted for elimination by 2020. To achieve the elimination target, the World Health Organization (WHO) recommends member states implement the SAFE strategy; surgery, mass administration of antibiotics, promotion of hygiene and facial cleanliness and water and sanitation as environmental improvements. We present results from evaluation surveys conducted in 2006 and 2009 from the regions of Kayes and Koulikoro, Mali. Prevalence of active trachoma in 2006 was below baseline intervention thresholds in all surveyed districts and the national program stopped antibiotic distribution. The prevalence of trachoma in 2009 remained well below levels in 1998. However, in 8 of 13 districts compared, the prevalence of active trachoma was higher in 2009 than 2006. Three years of antibiotic intervention did not equate in all districts to a sustained reduction of active trachoma. No surveillance activities were implemented after stopping interventions. Surgical interventions may have reduced the burden of blinding trachoma but there is an ongoing need for surgeries specifically targeting affected women. Four districts meet the WHO criteria for resuming district-wide mass antibiotic distribution. A community-by-community approach to elimination may be needed in other districts. The promotion of facial cleanliness and good hygiene behavior should be reintroduced.
doi:10.1371/journal.pntd.0000734
PMCID: PMC2897896  PMID: 20625555
19.  Exploring New Biological Functions of Amyloids: Bacteria Cell Agglutination Mediated by Host Protein Aggregation 
PLoS Pathogens  2012;8(11):e1003005.
Antimicrobial proteins and peptides (AMPs) are important effectors of the innate immune system that play a vital role in the prevention of infections. Recent advances have highlighted the similarity between AMPs and amyloid proteins. Using the Eosinophil Cationic Protein as a model, we have rationalized the structure-activity relationships between amyloid aggregation and antimicrobial activity. Our results show how protein aggregation can induce bacteria agglutination and cell death. Using confocal and total internal reflection fluorescence microscopy we have tracked the formation in situ of protein amyloid-like aggregates at the bacteria surface and on membrane models. In both cases, fibrillar aggregates able to bind to amyloid diagnostic dyes were detected. Additionally, a single point mutation (Ile13 to Ala) can suppress the protein amyloid behavior, abolishing the agglutinating activity and impairing the antimicrobial action. The mutant is also defective in triggering both leakage and lipid vesicle aggregation. We conclude that ECP aggregation at the bacterial surface is essential for its cytotoxicity. Hence, we propose here a new prospective biological function for amyloid-like aggregates with potential biological relevance.
Author Summary
Microbial infections are reported among the worst human diseases and cause millions of deaths per year over the world. Antibiotics are used to treat infections and have saved more lives than any other drug in human history. However, due to extended use, many strains are becoming refractive to common antibiotics. In this light, new promising compounds, like antimicrobial proteins and peptides (AMPs) are being investigated. Some AMPs also show agglutinating activity; this is the ability to clump bacteria after treatment. This feature is particularly appealing because agglutinating peptides could be used to keep bacteria to the infection focus, helping microbe clearance by host immune cells. In this study, we propose a novel mechanism to explain agglutinating activity at a molecular level using Eosinophil Cationic Protein. We show that the agglutinating mechanism is driven by the protein amyloid-like aggregation at the bacteria cell surface. Accordingly, elimination of the amyloid behavior abolishes both the agglutinating and the antimicrobial activities. This study provides a new concept on how Nature could exploit amyloid-like aggregates to fight bacterial infections. Moreover, these results could also add new insights in understanding the relation between infection and inflammation with dementia and amyloid-related diseases like Alzheimer.
doi:10.1371/journal.ppat.1003005
PMCID: PMC3486885  PMID: 23133388
20.  Silver Enhances Antibiotic Activity Against Gram-negative Bacteria 
Science translational medicine  2013;5(190):190ra81.
A declining pipeline of clinically useful antibiotics has made it imperative to develop more effective antimicrobial therapies, particularly against difficult-to-treat Gram-negative pathogens. Silver has been used as an antimicrobial since antiquity, yet its mechanism of action remains unclear. Here, we show that silver disrupts multiple bacterial cellular processes, including disulfide bond formation, metabolism and iron homeostasis. These changes lead to increased production of reactive oxygen species (ROS) and increased membrane permeability of Gram-negative bacteria, that can potentiate the activity of a broad range of antibiotics against Gram-negative bacteria in different metabolic states, as well as restore antibiotic susceptibility to a resistant bacterial strain. We show both in vitro and in a mouse model of urinary tract infection that the ability of silver to induce oxidative stress can be harnessed to potentiate antibiotic activity. Additionally, we demonstrate in vitro and in two different mouse models of peritonitis that silver sensitizes Gram-negative bacteria to the Gram-positive specific antibiotic, vancomycin, thereby expanding the antibacterial spectrum of this drug. Finally, we used silver and antibiotic combinations in vitro to eradicate bacterial persister cells, and show both in vitro and in a mouse biofilm infection model, that silver can enhance antibacterial action against biofilms. This work shows that silver can be used to enhance the action of existing antibiotics against Gram-negative bacteria thus strengthening the antibiotic arsenal for fighting bacterial infections.
doi:10.1126/scitranslmed.3006276
PMCID: PMC3771099  PMID: 23785037
21.  A Network Inference Method for Large-Scale Unsupervised Identification of Novel Drug-Drug Interactions 
PLoS Computational Biology  2013;9(12):e1003374.
Characterizing interactions between drugs is important to avoid potentially harmful combinations, to reduce off-target effects of treatments and to fight antibiotic resistant pathogens, among others. Here we present a network inference algorithm to predict uncharacterized drug-drug interactions. Our algorithm takes, as its only input, sets of previously reported interactions, and does not require any pharmacological or biochemical information about the drugs, their targets or their mechanisms of action. Because the models we use are abstract, our approach can deal with adverse interactions, synergistic/antagonistic/suppressing interactions, or any other type of drug interaction. We show that our method is able to accurately predict interactions, both in exhaustive pairwise interaction data between small sets of drugs, and in large-scale databases. We also demonstrate that our algorithm can be used efficiently to discover interactions of new drugs as part of the drug discovery process.
Author Summary
Over one in four adults older than 57 in the US take five or more prescriptions at the same time; as many as 4% are at risk of a major adverse drug-drug interaction. Potentially beneficial effects of drug combinations, on the other hand, are also important. For example, combinations of drugs with synergistic effects increase the efficacy of treatments and reduce side effects; and suppressing interactions between drugs, in which one drug inhibits the action of the other, have been found to be effective in the fight against antibiotic-resistant pathogens. With thousands of drugs in the market, and hundreds or thousands being tested and developed, it is clear that we cannot rely only on experimental assays, or even mechanistic pharmacological models, to uncover new interactions. Here we present an algorithm that is able to predict such interactions. Our algorithm is parameter-free, unsupervised, and takes, as its only input, sets of previously reported interactions. We show that our method is able to accurately predict interactions, even in large-scale databases containing thousands of drugs, and that it can be used efficiently to discover interactions of new drugs as part of the drug discovery process.
doi:10.1371/journal.pcbi.1003374
PMCID: PMC3854677  PMID: 24339767
22.  The Fitness Cost of Antibiotic Resistance in Streptococcus pneumoniae: Insight from the Field 
PLoS ONE  2012;7(1):e29407.
Background
Laboratory studies have suggested that antibiotic resistance may result in decreased fitness in the bacteria that harbor it. Observational studies have supported this, but due to ethical and practical considerations, it is rare to have experimental control over antibiotic prescription rates.
Methods and Findings
We analyze data from a 54-month longitudinal trial that monitored pneumococcal drug resistance during and after biannual mass distribution of azithromycin for the elimination of the blinding eye disease, trachoma. Prescription of azithromycin and antibiotics that can create cross-resistance to it is rare in this part of the world. As a result, we were able to follow trends in resistance with minimal influence from unmeasured antibiotic use. Using these data, we fit a probabilistic disease transmission model that included two resistant strains, corresponding to the two dominant modes of resistance to macrolide antibiotics. We estimated the relative fitness of these two strains to be 0.86 (95% CI 0.80 to 0.90), and 0.88 (95% CI 0.82 to 0.93), relative to antibiotic-sensitive strains. We then used these estimates to predict that, within 5 years of the last antibiotic treatment, there would be a 95% chance of elimination of macrolide resistance by intra-species competition alone.
Conclusions
Although it is quite possible that the fitness cost of macrolide resistance is sufficient to ensure its eventual elimination in the absence of antibiotic selection, this process takes time, and prevention is likely the best policy in the fight against resistance.
doi:10.1371/journal.pone.0029407
PMCID: PMC3260144  PMID: 22272234
23.  Antibiotic consumption and antibiotic stewardship in Swedish hospitals 
Upsala Journal of Medical Sciences  2014;119(2):154-161.
Background
The aim of this paper was to describe and analyze the effect of antibiotic policy changes on antibiotic consumption in Swedish hospitals and to review antibiotic stewardship in Swedish hospitals.
Results
The main findings were: 1) Antibiotic consumption has significantly increased in Swedish hospitals over the last decade. The consumption of cephalosporins has decreased, whereas that of most other drugs including piperacillin-tazobactam, carbapenems, and penicillinase-sensitive and -resistant penicillins has increased and replaced cephalosporins. 2) Invasive infections caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae have increased, but the proportion of pathogens resistant to third-generation cephalosporins causing invasive infections is still very low in a European and international perspective. Furthermore, the following gaps in knowledge were identified: 1) lack of national, regional, and local data on the incidence of antibiotic resistance among bacteria causing hospital-acquired infections e.g. bloodstream infections and hospital-acquired pneumonia—data on which standard treatment guidelines should be based; 2) lack of data on the incidence of Clostridium difficile infections and the effect of change of antibiotic policies on the incidence of C. difficile infections and infections caused by antibiotic-resistant pathogens; and 3) lack of prospective surveillance programs regarding appropriate antibiotic treatment, including selection of optimal antimicrobial drug regimens, dosage, duration of therapy, and adverse ecological effects such as increases in C. difficile infections and emergence of antibiotic-resistant pathogens.
Conclusions
Evidence-based actions to improve antibiotic use and to slow down the problem of antibiotic resistance need to be strengthened. The effect of such actions should be analyzed, and standard treatment guidelines should be continuously updated at national, regional, and local levels.
doi:10.3109/03009734.2014.909911
PMCID: PMC4034553  PMID: 24724823
Antibiotic consumption; antibiotic resistance; antibiotic treatment guidelines
24.  Physiological and Technical-tactical Analysis in Brazilian Jiu-jitsu Competition 
Asian Journal of Sports Medicine  2013;4(2):137-143.
Purpose
The present study aims at investigating the physiological response and technical-tactical parameters in Brazilian jiu-jitsu competition.
Methods
The study included 35 male Brazilian jiu-jitsu athletes (adult category, body mass: 80.2 ± 13.0 kg), graded from white to brown belt, during combats fought at regional level. Twenty-two fights were analyzed in terms of technique and time structure. Blood glucose, lactate and maximal isometric grip strength were determined before and after the fights. The rate of perceived exertion was also assessed after the fight, using the 6-20 Borg rating. The fights were recorded and the following variables were determined: the exertion/pause ratio and subjective intensity of actions, categorized between low and high intensity.
Results
The results indicated that during Brazilian jiu-jitsu fights, the glycolytic pathway is only moderately activated (lactate before: 4.4 (4.0 – 4.6) mmol/L, after: 10.1 (8.0 – 11.3) mmol/L; glucose before: 112.4 ± 22.3 mg/dL, after: 130.5 ± 31.0 mg/dL). The exertion during the fight resulted in significant reductions in handgrip strength (right hand grip before: 45.9 ± 10.3 kgf, after: 40.1 ± 9.5 kgf; left hand grip before: 44.2 ± 11.1 kgf, after: 37.0 ± 10.2 kgf). The athletes rated the fight as hard: 15 (13 – 15). Effort/pause ratio was 6:1, while high-intensity actions lasted approximately 4 s, resulting in a low/high intensity? ratio of 8:1.
Conclusion
It is recommended that coaches direct the training loads to simulate the energy demand imposed by the competitive matches, activating moderately the glycolytic pathway. Moreover, the time structure of combats can be used to prescribe both physical and technical-tactical training.
PMCID: PMC3690734  PMID: 23802056
Combat Sports; Martial Arts; jiu-jitsu; Sports; Athletic Performance
25.  Ovarian Cancer Survivors’ Experiences of Self-Advocacy: A Focus Group Study 
Oncology nursing forum  2013;40(2):140-147.
Purpose/Objectives
To explore ovarian cancer survivors’ experiences of self-advocacy in symptom management.
Research Approach
Descriptive, qualitative.
Setting
A public café in an urban setting.
Participants
13 ovarian cancer survivors aged 26–69 years with a mean age of 51.31.
Methodologic Approach
Five focus groups were formed. Focus group discussions were audio recorded and transcribed verbatim. The content was analyzed using the constant comparison method with axial coding. In-depth interviews with 5 of the 13 participants occurred via telephone one to five months after each focus group meeting to clarify and expand on identified themes. Preliminary findings were shared with all participants for validation.
Findings
Two major themes emerged from the data: (a) knowing who I am and keeping my psyche intact, and (b) knowing what I need and fighting for it. Exemplar quotations illustrate the diverse dimensions of self-advocacy. In addition, a working female-centric definition of self-advocacy was attained.
Conclusions
Women have varying experiences with cancer- and treatment-related symptoms, but share a common process for recognizing and meeting their needs. Self-advocacy was defined as a process of learning one’s needs and priorities as a cancer survivor and negotiating with healthcare teams, social supports, and other survivors to meet these needs.
Interpretation
This phenomenologic process identified key dimensions and a preliminary definition of self-advocacy that nurses can recognize and support when patients seek and receive care consistent with their own needs and preferences.
Knowledge Translation
Self-advocacy among female cancer survivors is a process of recognizing one’s needs and priorities and fighting for them within their cancer care and life. Practitioners can support female cancer survivors through the process of self-advocacy by providing them with skills and resources in making informed choices for themselves.
doi:10.1188/13.ONF.A12-A19
PMCID: PMC4021021  PMID: 23454476

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