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1.  International External Quality Assurance for Laboratory Diagnosis of Diphtheria ▿  
Journal of Clinical Microbiology  2009;47(12):4037-4042.
The diphtheria surveillance network (DIPNET) encompassing National Diphtheria Reference Centers from 25 European countries is a Dedicated Surveillance Network recognized by the European Commission. A key DIPNET objective is the quality assessment of microbiological procedures for diphtheria across the European Union and beyond. A detailed questionnaire on the level of reference laboratory services and an external quality assessment (EQA) panel comprising six simulated throat specimens were sent to 34 centers. Twenty-three centers are designated National Diphtheria Reference Centers, with the laboratory in the United Kingdom being the only WHO Collaborating Centre. A variety of screening and identification tests were used, including the cysteinase test (20/34 centers), pyrazinamidase test (17/34 centers), and commercial kits (25/34 centers). The classic Elek test for toxigenicity testing is mostly used (28/34 centers), with variations in serum sources and antitoxin concentrations. Many laboratories reported problems obtaining Elek reagents or media. Only six centers produced acceptable results for all six specimens. Overall, 21% of identification and 13% of toxigenicity reports were unacceptable. Many centers could not isolate the target organism, and most found difficulties with the specimens that contained Corynebacterium striatum as a commensal contaminant. Nineteen centers generated either false-positive or negative toxigenic results, which may have caused inappropriate medical management. The discrepancies in this diphtheria diagnostics EQA alarmingly reflect the urgent need to improve laboratory performance in diphtheria diagnostics in Europe, standardize feasible and robust microbiological methods, and build awareness among public health authorities. Therefore, DIPNET recommends that regular workshops and EQA distributions for diphtheria diagnostics should be supported and maintained.
doi:10.1128/JCM.00473-09
PMCID: PMC2786670  PMID: 19828749
2.  Toward a Global View of Alcohol, Tobacco, Cannabis, and Cocaine Use: Findings from the WHO World Mental Health Surveys 
PLoS Medicine  2008;5(7):e141.
Background
Alcohol, tobacco, and illegal drug use cause considerable morbidity and mortality, but good cross-national epidemiological data are limited. This paper describes such data from the first 17 countries participating in the World Health Organization's (WHO's) World Mental Health (WMH) Survey Initiative.
Methods and Findings
Household surveys with a combined sample size of 85,052 were carried out in the Americas (Colombia, Mexico, United States), Europe (Belgium, France, Germany, Italy, Netherlands, Spain, Ukraine), Middle East and Africa (Israel, Lebanon, Nigeria, South Africa), Asia (Japan, People's Republic of China), and Oceania (New Zealand). The WHO Composite International Diagnostic Interview (CIDI) was used to assess the prevalence and correlates of a wide variety of mental and substance disorders. This paper focuses on lifetime use and age of initiation of tobacco, alcohol, cannabis, and cocaine. Alcohol had been used by most in the Americas, Europe, Japan, and New Zealand, with smaller proportions in the Middle East, Africa, and China. Cannabis use in the US and New Zealand (both 42%) was far higher than in any other country. The US was also an outlier in cocaine use (16%). Males were more likely than females to have used drugs; and a sex–cohort interaction was observed, whereby not only were younger cohorts more likely to use all drugs, but the male–female gap was closing in more recent cohorts. The period of risk for drug initiation also appears to be lengthening longer into adulthood among more recent cohorts. Associations with sociodemographic variables were consistent across countries, as were the curves of incidence of lifetime use.
Conclusions
Globally, drug use is not distributed evenly and is not simply related to drug policy, since countries with stringent user-level illegal drug policies did not have lower levels of use than countries with liberal ones. Sex differences were consistently documented, but are decreasing in more recent cohorts, who also have higher levels of illegal drug use and extensions in the period of risk for initiation.
Louisa Degenhardt and colleagues report an international survey of 17 countries that finds clear differences in drug use across different regions of the world.
Editors' Summary
Background.
Understanding how much disability and death a particular disease causes (known as the “burden of disease”) is important. Knowing the burden of a disease in a country contributes to the development of healthier nations by directing strategies and policies against the disease. Researchers' understanding of the burden of diseases across different countries was piecemeal until the 1990 launch of a special World Health Organization (WHO) project, the Global Burden of Disease Project. In 2002, on the basis of updated information from this ongoing project, the WHO estimated that 91 million people were affected by alcohol use disorders and 15 million by drug use disorders.
Why Was This Study Done?
It is widely accepted that alcohol, tobacco, and illegal drug use are linked with a considerable amount of illness, disability, and death. However, there are few high-quality data quantifying the amount across different countries, especially in less-developed countries. The researchers therefore set out to collect basic patterns of alcohol, tobacco, cannabis, and cocaine use in different countries. They documented lifetime use of these substances in each county, focusing on young adults. They also wanted to examine the age of onset of use and whether the type of drugs used was affected by one's social and economic status.
What Did the Researchers Do and Find?
Data on drug use were available from 54,069 survey participants in 17 countries. The 17 countries were determined by the availability of collaborators and on funding for the survey. Trained lay interviewers carried out face-to-face interviews (except in France where the interviews were done over the telephone) using a standardized, structured diagnostic interview for psychiatric conditions. Participants were asked if they had ever used (a) alcohol, (b) tobacco (cigarettes, cigars or pipes), (c) cannabis (marijuana, hashish), or (d) cocaine. If they had used any of these drugs, they were asked about the age they started using each type of drug. The age of first tobacco smoking was not assessed in New Zealand, Japan, France, Germany, Belgium, The Netherlands, Italy, or Spain. The interviewers also recorded the participants' sex, age, years of education, marital status, employment, and household income.
The researchers found that in the Americas, Europe, Japan, and New Zealand, alcohol had been used by the vast majority of survey participants, compared to smaller proportions in the Middle East, Africa, and China. The global distribution of drug use is unevenly distributed with the US having the highest levels of both legal and illegal drug use among all countries surveyed. There are differences in both legal and illegal drug use among different socioeconomic groups. For example, males were more likely than females to have used all drug types; younger adults were more likely than older adults to have used all drugs examined; and higher income was related to drug use of all kinds. Marital status was found to be linked only to illegal drug use—the use of cocaine and cannabis is more likely in people who have never been married or were previously married. Drug use does not appear to be related to drug policy, as countries with more stringent policies (e.g., the US) did not have lower levels of illegal drug use than countries with more liberal policies (e.g., The Netherlands).
What Do These Findings Mean?
These findings present comprehensive and useful data on the patterns of drug use from national samples representing all regions of the world. The data will add to the understanding of the global burden of disease and should be useful to government and health organizations in developing policies to combat these problems. The study does have its limitations—for example, it surveyed only 17 of the world's countries, within these countries there were different rates of participation, and it is unclear whether people accurately report their drug use when interviewed. Nevertheless, the study did find clear differences in drug use across different regions of the world, with the US having among the highest levels of legal and illegal drug use of all the countries surveyed.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050141.
Facts and figures on alcohol are available from the World Health Organization, including information about the burden of disease worldwide as a result of alcohol
Information on the management of substance abuse is available from WHO
Information on the Global Burden of Disease Project is also available from WHO
Researchers from the University of New South Wales, Australia and the University of Queensland co-chair, sponsors the Global Burden of Disease Mental Disorders and Illicit Drug Use Expert Group, which examines illicit drug use and disorders
The UN World Drug Report is available from the UN Office on Drugs and Crime
The University of New South Wales also runs the Secretariat for the Reference Group to the United Nations on HIV and Injecting Drug Use
doi:10.1371/journal.pmed.0050141
PMCID: PMC2443200  PMID: 18597549
3.  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
4.  Benefits of a European Project on Diagnostics of Highly Pathogenic Agents and Assessment of Potential “Dual Use” Issues 
Quality assurance exercises and networking on the detection of highly infectious pathogens (QUANDHIP) is a joint action initiative set up in 2011 that has successfully unified the primary objectives of the European Network on Highly Pathogenic Bacteria (ENHPB) and of P4-laboratories (ENP4-Lab) both of which aimed to improve the efficiency, effectiveness, and response capabilities of laboratories directed at protecting the health of European citizens against high consequence bacteria and viruses of significant public health concern. Both networks have established a common collaborative consortium of 37 nationally and internationally recognized institutions with laboratory facilities from 22 European countries. The specific objectives and achievements include the initiation and establishment of a recognized and acceptable quality assurance scheme, including practical external quality assurance exercises, comprising living agents, that aims to improve laboratory performance, accuracy, and detection capabilities in support of patient management and public health responses; recognized training schemes for diagnostics and handling of highly pathogenic agents; international repositories comprising highly pathogenic bacteria and viruses for the development of standardized reference material; a standardized and transparent Biosafety and Biosecurity strategy protecting healthcare personnel and the community in dealing with high consequence pathogens; the design and organization of response capabilities dealing with cross-border events with highly infectious pathogens including the consideration of diagnostic capabilities of individual European laboratories. The project tackled several sensitive issues regarding Biosafety, Biosecurity and “dual use” concerns. The article will give an overview of the project outcomes and discuss the assessment of potential “dual use” issues.
doi:10.3389/fpubh.2014.00199
PMCID: PMC4227464  PMID: 25426479
EQAE in diagnostic; anthrax; tularemia; plague; melioidosis; glanders; brucellosis; dual use research of concern
5.  Intensified Tuberculosis Case Finding among Malnourished Children in Nutritional Rehabilitation Centres of Karnataka, India: Missed Opportunities 
PLoS ONE  2013;8(12):e84255.
Background
Severe acute malnutrition (SAM) is the most serious form of malnutrition affecting children under-five and is associated with many infectious diseases including Tuberculosis (TB). In India, nutritional rehabilitation centres (NRCs) have been recently established for the management of SAM including TB. The National TB Programme (NTP) in India has introduced a revised algorithm for diagnosing paediatric TB. We aimed to examine whether NRCs adhered to these guidelines in diagnosing TB among SAM children.
Methods
A cross-sectional study involving review of records of all SAM children identified by health workers during 2012 in six tehsils (sub-districts) with NRCs (population: 1.8 million) of Karnataka, India.
Results
Of 1927 identified SAM children, 1632 (85%) reached NRCs. Of them, 1173 (72%) were evaluated for TB and 19(2%) were diagnosed as TB. Of 1173, diagnostic algorithm was followed in 460 (37%). Among remaining 763 not evaluated as per algorithm, tuberculin skin test alone was conducted in 307 (41%), chest radiography alone in 99 (13%) and no investigations in 337 (45%). The yield of TB was higher among children evaluated as per algorithm (4%) as compared to those who were not (0.3%) (OR: 15.3 [95%CI: 3.5-66.3]). Several operational challenges including non-availability of a full-time paediatrician, non-functioning X-ray machine due to frequent power cuts, use of tuberculin with suboptimal strength and difficulties in adhering to a complex diagnostic algorithm were observed.
Conclusion
This study showed that TB screening in NRCs was sub-optimal in Karnataka. Some children did not reach the NRC, while many of those who did were either not or sub-optimally evaluated for TB. This study pointed to a number of operational issues that need to be addressed if this collaborative strategy is to identify more TB cases amongst malnourished children in India.
doi:10.1371/journal.pone.0084255
PMCID: PMC3865256  PMID: 24358350
6.  Accelerating the Development of 21st-Century Toxicology: Outcome of a Human Toxicology Project Consortium Workshop 
Toxicological Sciences  2011;125(2):327-334.
The U.S. National Research Council (NRC) report on “Toxicity Testing in the 21st century” calls for a fundamental shift in the way that chemicals are tested for human health effects and evaluated in risk assessments. The new approach would move toward in vitro methods, typically using human cells in a high-throughput context. The in vitro methods would be designed to detect significant perturbations to “toxicity pathways,” i.e., key biological pathways that, when sufficiently perturbed, lead to adverse health outcomes. To explore progress on the report’s implementation, the Human Toxicology Project Consortium hosted a workshop on 9–10 November 2010 in Washington, DC. The Consortium is a coalition of several corporations, a research institute, and a non-governmental organization dedicated to accelerating the implementation of 21st-century Toxicology as aligned with the NRC vision. The goal of the workshop was to identify practical and scientific ways to accelerate implementation of the NRC vision. The workshop format consisted of plenary presentations, breakout group discussions, and concluding commentaries. The program faculty was drawn from industry, academia, government, and public interest organizations. Most presentations summarized ongoing efforts to modernize toxicology testing and approaches, each with some overlap with the NRC vision. In light of these efforts, the workshop identified recommendations for accelerating implementation of the NRC vision, including greater strategic coordination and planning across projects (facilitated by a steering group), the development of projects that test the proof of concept for implementation of the NRC vision, and greater outreach and communication across stakeholder communities.
doi:10.1093/toxsci/kfr248
PMCID: PMC3262850  PMID: 21948868
toxicity testing in the 21st century; safety assessment; in vitro alternatives; National Research Council
7.  Xenotransplantation-associated infectious risk: a WHO consultation 
Xenotransplantation  2012;19(2):72-81.
Xenotransplantation carries the potential risk of the transmission of infection with the cells or tissues of the graft. The degree of risk is unknown in the absence of clinical trials. The clinical application of xenotransplantation has important implications for infectious disease surveillance, both at the national and international levels. Preclinical data indicate that infectious disease events associated with clinical xenotransplantation from swine, should they occur, will be rare; data in human trials are limited but have demonstrated no transmission of porcine microorganisms including porcine endogenous retrovirus. Xenotransplantation will necessitate the development of surveillance programs to detect known infectious agents and, potentially, previously unknown or unexpected pathogens. The development of surveillance and safety programs for clinical trials in xenotransplantation is guided by a “Precautionary Principle,” with the deployment of appropriate screening procedures and assays for source animals and xenograft recipients even in the absence of data suggesting infectious risk. All assays require training, standardization and validation, and sharing of laboratory methods and expertise to optimize the quality of the surveillance and diagnostic testing. Investigation of suspected xenogeneic infection events (xenosis, xenozoonosis) should be performed in collaboration with an expert data safety review panel and the appropriate public health and competent authorities. It should be considered an obligation of performance of xenotransplantation trials to report outcomes, including any infectious disease transmissions, in the scientific literature. Repositories of samples from source animals and from recipients prior to, and following xenograft transplantation are essential to the investigation of possible infectious disease events. Concerns over any potential hazards associated with xenotransplantation may overshadow potential benefits. Careful microbiological screening of source animals used as xenotransplant donors may enhance the safety of transplantation beyond that of allotransplant procedures. Xenogeneic tissues may be relatively resistant to infection by some human pathogens. Moreover, xenotransplantation may be made available at the time when patients require organ replacement on a clinical basis. Insights gained in studies of the microbiology and immunology of xenotransplantation will benefit transplant recipients in the future. This document summarizes approaches to disease surveillance in individual recipients of nonhuman tissues.
doi:10.1111/j.1399-3089.2012.00693.x
PMCID: PMC3768267  PMID: 22497509
Clinical assays; clinical trials; donor; derived infection; infectious disease; porcine endogenous retrovirus; safety; xenotransplantation
8.  Multidrug Resistance in Salmonella enterica Serotype Typhimurium from Humans in France (1993 to 2003) 
Journal of Clinical Microbiology  2006;44(3):700-708.
The aim of this study was to determine the distribution of the antimicrobial resistance phenotypes (R types), the phage types and XbaI-pulsed-field gel electrophoresis (PFGE) types, the genes coding for resistance to β-lactams and to quinolones, and the class 1 integrons among a representative sample of Salmonella enterica serotype Typhimurium isolates collected from humans in 2002 through the French National Reference Center for Salmonella (NRC-Salm) network. The trends in the evolution of antimicrobial resistance of serotype Typhimurium were reviewed by using NRC-Salm data from 1993, 1997, 2000, and 2003. In 2002, 3,998 isolates of serotype Typhimurium were registered at the NRC-Salm among 11,775 serotyped S. enterica isolates (34%). The most common multiple antibiotic resistance pattern was resistance to amoxicillin, chloramphenicol, streptomycin and spectinomycin, sulfonamides, and tetracycline (ACSSpSuTe R type), with 156 isolates (48.8%). One isolate resistant to extended-spectrum cephalosporins due to the production of TEM-52 extended-spectrum β-lactamase was detected (0.3%), and one multidrug-resistant isolate was highly resistant to ciprofloxacin (MIC > 32 mg/liter). We found that 57.2% of the isolates tested belonged to the DT104 clone. The main resistance pattern of DT104 isolates was R type ACSSpSuTe (83.2%). However, evolutionary changes have occurred within DT104, involving both loss (variants of Salmonella genomic island 1) and acquisition of genes for drug resistance to trimethoprim or to quinolones. PFGE profile X1 was the most prevalent (74.5%) among DT104 isolates, indicating the need to use a more discriminatory subtyping method for such isolates. Global data from the NRC-Salm suggested that DT104 was the main cause of multidrug resistance in serotype Typhimurium from humans from at least 1997 to 2003, with a roughly stable prevalence during this period.
doi:10.1128/JCM.44.3.700-708.2006
PMCID: PMC1393144  PMID: 16517842
9.  Harmonization of Pulsed-Field Gel Electrophoresis Protocols for Epidemiological Typing of Strains of Methicillin-Resistant Staphylococcus aureus: a Single Approach Developed by Consensus in 10 European Laboratories and Its Application for Tracing the Spread of Related Strains 
Journal of Clinical Microbiology  2003;41(4):1574-1585.
Pulsed-fieldgel electrophoresis (PFGE) is the most common genotypic method used in reference and clinical laboratories for typing methicillin-resistant Staphylococcus aureus (MRSA). Many different protocols have been developed in laboratories that have extensive experience with the technique and have established national databases. However, the comparabilities of the different European PFGE protocols for MRSA and of the various national MRSA clones themselves had not been addressed until now. This multinational European Union (EU) project has established for the first time a European database of representative epidemic MRSA (EMRSA) strains and has compared them by using a new “harmonized” PFGE protocol developed by a consensus approach that has demonstrated sufficient reproducibility to allow the successful comparison of pulsed-field gels between laboratories and the tracking of strains around the EU. In-house protocols from 10 laboratories in eight European countries were compared by each center with a “gold standard” or initial harmonized protocol in which many of the parameters had been standardized. The group found that it was not important to standardize some elements of the protocol, such as the type of agarose, DNA block preparation, and plug digestion. Other elements were shown to be critical, namely, a standard gel volume and concentration of agarose, the DNA concentration in the plug, the ionic strength and volume of running buffer used, the running temperature, the voltage, and the switching times of electrophoresis. A new harmonized protocol was agreed on, further modified in a pilot study in two laboratories, and finally tested by all others. Seven laboratories' gels were found to be of sufficiently good quality to allow comparison of the strains by using a computer software program, while two gels could not be analyzed because of inadequate destaining and DNA overloading. Good-quality gels and inclusion of an internal quality control strain are essential before attempting intercenter PFGE comparisons. A number of clonally related strains have been shown to be present in multiple countries throughout Europe. The well-known Iberian clone has been demonstrated in Belgium, Finland, France, Germany, and Spain (and from the wider HARMONY collection in Portugal, Slovenia, and Sweden). Strains from the United Kingdom (EMRSA-15 and -16) have been identified in several othercountries, and other clonally related strains have also been identified. This highlights the need for closer international collaboration to monitor the spread of current epidemic strains as well as the emergence of new ones.
doi:10.1128/JCM.41.4.1574-1585.2003
PMCID: PMC153895  PMID: 12682148
10.  Review of Institute of Medicine and National Research Council Recommendations for One Health Initiative 
Emerging Infectious Diseases  2013;19(12):1913-1917.
Human health is inextricably linked to the health of animals and the viability of ecosystems; this is a concept commonly known as One Health. Over the last 2 decades, the Institute of Medicine (IOM) and the National Research Council (NRC) have published consensus reports and workshop summaries addressing a variety of threats to animal, human, and ecosystem health. We reviewed a selection of these publications and identified recommendations from NRC and IOM/NRC consensus reports and from opinions expressed in workshop summaries that are relevant to implementation of the One Health paradigm shift. We grouped these recommendations and opinions into thematic categories to determine if sufficient attention has been given to various aspects of One Health. We conclude that although One Health themes have been included throughout numerous IOM and NRC publications, identified gaps remain that may warrant targeted studies related to the One Health approach.
doi:10.3201/eid1912.121659
PMCID: PMC3840875  PMID: 24274461
zoonoses; animal diseases; veterinary medicine; public health; environmental medicine; vectors; disease reservoirs; medicine; world health
11.  Pleurocidin-family cationic antimicrobial peptides are cytolytic for breast carcinoma cells and prevent growth of tumor xenografts 
Breast Cancer Research : BCR  2011;13(5):R102.
Introduction
Cationic antimicrobial peptides (CAPs) defend against microbial pathogens; however, certain CAPs also exhibit anticancer activity. The purpose of this investigation was to determine the effect of the pleurocidin-family CAPs, NRC-03 and NRC-07, on breast cancer cells.
Methods
MTT (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) and acid phosphatase cell-viability assays were used to assess NRC-03- and NRC-07-mediated killing of breast carcinoma cells. Erythrocyte lysis was determined with hemolysis assay. NRC-03 and NRC-07 binding to breast cancer cells and normal fibroblasts was assessed with fluorescence microscopy by using biotinylated-NRC-03 and -NRC-07. Lactate dehydrogenase-release assays and scanning electron microscopy were used to evaluate the effect of NRC-03 and NRC-07 on the cell membrane. Flow-cytometric analysis of 3,3'-dihexyloxacarbocyanine iodide- and dihydroethidium-stained breast cancer cells was used to evaluate the effects of NRC-03 and NRC-07 on mitochondrial membrane integrity and reactive oxygen species (ROS) production, respectively. Tumoricidal activity of NRC-03 and NRC-07 was evaluated in NOD SCID mice bearing breast cancer xenografts.
Results
NRC-03 and NRC-07 killed breast cancer cells, including drug-resistant variants, and human mammary epithelial cells but showed little or no lysis of human dermal fibroblasts, umbilical vein endothelial cells, or erythrocytes. Sublethal doses of NRC-03 and, to a lesser extent, NRC-07 significantly reduced the median effective concentration (EC50) of cisplatin for breast cancer cells. NRC-03 and NRC-07 bound to breast cancer cells but not fibroblasts, suggesting that killing required peptide binding to target cells. NRC-03- and NRC-07-mediated killing of breast cancer cells correlated with expression of several different anionic cell-surface molecules, suggesting that NRC-03 and NRC-07 bind to a variety of negatively-charged cell-surface molecules. NRC-03 and NRC-07 also caused significant and irreversible cell-membrane damage in breast cancer cells but not in fibroblasts. NRC-03- and NRC-07-mediated cell death involved, but did not require, mitochondrial membrane damage and ROS production. Importantly, intratumoral administration of NRC-03 and NRC-07 killed breast cancer cells grown as xenografts in NOD SCID mice.
Conclusions
These findings warrant the development of stable and targeted forms of NRC-03 and/or NRC-07 that might be used alone or in combination with conventional chemotherapeutic drugs for the treatment of breast cancer.
doi:10.1186/bcr3043
PMCID: PMC3262215  PMID: 22023734
12.  A Binational Model of Collaboration for Enhancing Cross-border ID Surveillance 
Objective
The purpose of this demonstration is to describe the cross-border collaborative processes used for the development of a transparent methodology to identify and prioritize zoonotic infectious disease agents in the California-Baja California border region.
Introduction
International borders present unique challenges for the surveillance of infectious disease. Border communities represent locations with vast differences in cultures and languages, governing institutions, healthcare access, and priorities for the collection and surveillance of disease data. Pathogens and the health and security risks they create do not respect geographical and political boundaries. However, the organizations responsible for the surveillance and control of these agents must function within the borders of their respective governments. One Border One Health (OBOH) is a binational, multidisciplinary initiative aimed at engaging partners in the US and Mexico to identify and implement methods for successful communication and collaboration to enhance health capacity and disease surveillance within the border region. The advancements of international initiatives such as OBOH will help to develop the types of multi-country networks necessary for the effective monitoring of disease patterns and risks.
Methods
One Border One Health Surveillance Committee participants represent multi-disciplinary professionals working together for the advancement of One Health principles in the California/Baja California border region. This showcase documents the identification and prioritization of zoonotic infectious disease agents along the US-Mexico border, by use of a transparent methodology which engaged public and private partners from both countries. Preliminary research and input from collaborators in government, academic, and private sectors in the US and Mexico allowed for review and discussion of current methodologies available for prioritizing infectious agents. The DISCONTOOLS Work Package 2 Prioritization Scoring Model was selected as the basis for scoring and weighting various zoonotic diseases of concern within border region. Subject matter experts were then asked to review and score an initial list of diseases, in order to produce a final ranked list of pathogens. The intent is that these prioritized pathogens will be used by government agencies to make informed decisions, integrating priorities from both nations with regards to infectious disease surveillance. This collaboration provides insight into the binational cooperation needed for the selection of diseases to be considered in a regional, integrated disease surveillance system. To the authors’ knowledge this is the first transparent scientific-based approach to pathogen prioritization in the US-Mexico border region.
Conclusions
OBOH is the first binational regional network of its kind along the US-Mexico border recognizing the interconnectivity between human, animal, and environmental health. Given the limited resources in the current economic climate, the use of regional integrated surveillance systems provide an opportunity to protect and improve border health and security by moving away from species-specific surveillance programs. The process showcased here for the transparent review and prioritization of pathogens along the California-Baja California border can be used as a model along the entire US-Mexico Border. The ultimate aim is to protect border communities through the creation of a binational, early warning surveillance system which would allow for actionable and timely interventions to limit emergence, mitigate spread, provide gap analysis, and enhance prevention and control for several emergent and re-emergent diseases. Ultimately, this will decrease negative health and environmental impacts while improving agricultural and economic outcomes in both nations. However, obstacles such as continued sustainability, identification of new multi-disciplinary collaborators, cooperation between government agencies, and identifying funding for advancement of integrated regional surveillance systems remain challenges.
PMCID: PMC3692861
One Health; disease surveillance; cross-border collaborative
13.  A Study to Evaluate the Effect of Nutritional Intervention Measures on Admitted Children in Selected Nutrition Rehabilitation Centers of Indore and Ujjain Divisions of the State of Madhya Pradesh (India) 
Background:
The state of Madhya Pradesh has 1.3 million severely malnourished children. Nutrition rehabilitation centers (NRCs) were started in the state to control severe malnutrition and decrease the prevalence of severe malnourished children to less than 1% among children aged 1–5 years.
Materials and Methods:
The present study was conducted from November 2008 to October 2009; 100 children admitted to seven different NRCs in Indore and Ujjain divisions of Madhya Pradesh were observed during their stay at NRCs and the follow-up period to analyze the effect of interventional measures on select anthropometric indicators. Mothers of the children were interviewed on health issues and therapeutic feeding practices at the NRCs using a predesigned and pretested interview schedule.
Results:
The study group consisted of 48 boys and 52 girls; 60% were between 13 and 36 months of age. 93 children were analyzed for anthropometric indicators following a dropout rate of 7%. A statistically significant difference was obtained between the weight of children at admission and discharge (t=14.552, P<0.001); difference of mid upper arm circumference (MUAC) at admission and discharge was statistically significant (t=9.548, P<0.001). The average weight gain during the stay at the centers was 9.25 ± 5.89 g/kg/day. Though the number of severe malnourished children decreased from 85 to 43 following the stay at NRCs (χ2 = 44.195, P<0.001); 48.78% of the children lost weight within 15 days of discharge from the NRCs. Dropout rates of 9.89%, 23.07%, 42.65%, and 61.76% for the study group were obtained during the follow-up period of 6 months for the four follow-up visits conducted 15 days, 1, 3, and 6 months after discharge. The mothers of the children lacked adequate information on health issues and composition and preparation of therapeutic diets at the centers.
Conclusion:
The NRCs were effective in improving the condition of admitted children, but the effects were not sustained following discharge due to high drop-out rate and lack of adequate parental awareness. There is an urgent need to link these centers with community-based models for follow-up and improve health education measures to maintain the gains achieved.
doi:10.4103/0970-0218.96096
PMCID: PMC3361793  PMID: 22654284
Nutrition rehabilitation centers; severe acute malnutrition; therapeutic feeds
14.  Declining trends in some sexually transmitted diseases in Belgium between 1983 and 1989. 
Genitourinary Medicine  1991;67(5):374-377.
OBJECTIVE--To examine trends in some sexually transmitted diseases in Belgium and to discuss them in the light of the European background. DESIGN--Analysis of the time trends of C trachomatis and N gonorrhoeae infections diagnosed by a network of microbiological laboratories, and of male urethritis diagnosed by a network of general practitioners. SETTING--Belgium. SUBJECTS--Reports of C trachomatis and N gonorrhoeae infections by a network of microbiological laboratories, and of male urethritis by a network of general practitioners, to the Institute of Hygiene and Epidemiology. RESULTS--Whereas an increase in the number of C trachomatis infections, more pronounced among women, was observed up to 1986, a small decrease has been observed afterwards in males. The mean number of chlamydial infections per laboratory and per year was 4.2 in 1983, 15.7 in 1986 and 13.9 in 1989. A decrease in the number of N gonorrhoeae infections, more pronounced among men, has been observed. The mean number of cases of gonorrhoea per laboratory and per year was 10.9 in 1983 and only 2.2 in 1989. The same declining trend has been observed in another surveillance programme of male urethritis, based on a network of general practitioners. The number of cases of male urethritis per 100 patient encounters went down from 0.06 in 1982-3 to 0.04 in 1988-9. CONCLUSION--The declining trend in Western Europe in incidence of gonococcal infections and of urethritis in men is also occurring in Belgium, but genital chlamydial infections remain an important public health problem.
PMCID: PMC1194735  PMID: 1743708
15.  Recommendations for Syndromic Surveillance Using Inpatient and Ambulatory EHR Data 
Objective
To develop national Stage 2 Meaningful Use (MUse) recommendations for syndromic surveillance using hospital inpatient and ambulatory clinical care electronic health record (EHR) data.
Introduction
MUse will make EHR data increasingly available for public health surveillance. For Stage 2, the Centers for Medicare & Medicaid Services (CMS) regulations will require hospitals and offer an option for eligible professionals to provide electronic syndromic surveillance data to public health. Together, these data can strengthen public health surveillance capabilities and population health outcomes (Figure 1).
To facilitate the adoption and effective use of these data to advance population health, public health priorities and system capabilities must shape standards for data exchange. Input from all stakeholders is critical to ensure the feasibility, practicality, and, hence, adoption of any recommendations and data use guidelines.
Methods
ISDS, in collaboration with the Division of Informatics Solutions and Operations at the Centers for Disease Control and Prevention (CDC), and HLN Consulting, convened a multi-stakeholder Work-group of clinicians, technologists, epidemiologists, and public health officials with expertise in syndromic surveillance. Recommended MUse guidelines were developed by performing an environmental scan of current practice and by using an iterative, expert and community input-driven process. The Workgroup developed initial guidelines and then solicited and received feedback from the stakeholder community via interview, e-mail, and structured surveys. Stakeholder feedback was analyzed using quantitative and qualitative methods and used to revise the recommendations.
Results
The MUse Workgroup defined electronic syndromic surveillance (ESS) characteristics. Specifically, data are characterized by their timeliness, sensitivity rather than specificity, population focus, limited personally identifiable information, and inclusion of all patient encounters within a specific healthcare setting (e.g., emergency department, inpatient, outpatient). Based on stakeholder input (n=125) and Workgroup expertise, the guidelines identify priority syndromic surveillance uses that can assist with: Monitoring population health;Informing public health services; andInforming interventions, health education, and policy by characterizing the burden of chronic disease and health disparities.
Similarly, the Workgroup identified data elements to support these uses in the hospital inpatient setting and possibly in the ambulatory care setting. They were aligned to previously identified emergency department and urgent care center data elements and Stage 1–2 clinical MUse objectives. Core data elements (required for certification) cover treating facility; patient demographics; subjective and objective clinical findings, including chief complaint, body mass index, smoking history, diagnoses; and outcomes. Other data elements were designated as extended (not required for certification) or future (for future consideration). The data elements and their specifications are subject to change based on applicable state and local laws and practices.
Based on their findings and recommended guidelines detailed in the report, the Workgroup also identified community activities and additional investments that would best support public health agencies in using EHR technology with syndromic surveillance methodologies.
Conclusions
The widespread adoption of EHRs, catalyzed by MUse, has the potential to improve population health. By identifying and describing potential ESS uses of new sources of EHR data and associated data elements with the greatest utility for public health, the recommendations set forth by the ISDS MUse Workgroup will serve to facilitate the adoption of MUse policy by both healthcare and public health agencies.
PMCID: PMC3692899
EHR; syndromic surveillance; Meaningful Use; inpatient; ambulatory
16.  Pneumococcal meningitis and vaccine effects in the era of conjugate vaccination: results of 20 years of nationwide surveillance in Germany 
Background
Long-term complications and a case mortality rate of 7.5% make meningitis caused by Streptococcus pneumoniae a serious clinical threat. In 2006, a general pneumococcal conjugate vaccination (PCV) recommendation was issued for all children under 2 years in Germany. Here, we investigate serotype changes in meningitis cases after this vaccine recommendation.
Methods
The German National Reference Center for Streptococci (NRCS) has conducted surveillance for invasive pneumococcal disease (IPD) in Germany since 1992. Pneumococcal isolates were serotyped by the Neufeld’s Quellung reaction and antibiotic susceptibility was tested using the broth microdilution method.
Results
Of 22,204 IPD isolates sent to the NRCS from July 1992 to June 2013, 3,086 were meningitis cases. Microbiological and statistical investigations were performed to characterize and quantify all meningitis cases, focusing on changes reflecting implementation of the national PCV recommendation. 1,766 isolates (57.2% of meningitis cases) were from adults (≥16 years) and 1,320 isolates (42.8%) originated from children (<16 years). Overall, the leading serotypes were 14 (9.7%), 7F (7.8%), 3 (6.9%), 19F (5.7%) and 23F (5.0%). Among children, serotypes 14 (16.2%), 7F (8.9%) and 19F (7.1%) were most common, whereas among adults, serotypes 3 (9.6%), 7F (6.9%), 22F (5.0%), 23F (4.9%) and 14 (4.8%) were most prevalent. After the introduction of general PCV7/10/13 vaccination a significant decrease for most vaccine serotypes was observed. Generally, the differences in antibiotic nonsusceptibility between children <16 years and adults ≥16 were low. For macrolides in the pre-PCV7 period, a significantly higher proportion of resistant isolates was found in children (25.1%), compared to the post-vaccination period (9.7%; p<0.0001).
Conclusions
Implementation of the pneumococcal conjugate vaccines broadly reduced vaccine-type meningitis cases. Changes in serotype prevalence must be continuously monitored to observe future trends concerning pneumococcal meningitis.
doi:10.1186/s12879-015-0787-1
PMCID: PMC4335684
Streptococcus pneumoniae; Meningitis; Serotypes; Vaccine coverage; Antibiotic susceptibility; Age
17.  Evaluating Drug Prices, Availability, Affordability, and Price Components: Implications for Access to Drugs in Malaysia 
PLoS Medicine  2007;4(3):e82.
Background
Malaysia's stable health care system is facing challenges with increasing medicine costs. To investigate these issues a survey was carried out to evaluate medicine prices, availability, affordability, and the structure of price components.
Methods and Findings
The methodology developed by the World Health Organization (WHO) and Health Action International (HAI) was used. Price and availability data for 48 medicines was collected from 20 public sector facilities, 32 private sector retail pharmacies and 20 dispensing doctors in four geographical regions of West Malaysia. Medicine prices were compared with international reference prices (IRPs) to obtain a median price ratio. The daily wage of the lowest paid unskilled government worker was used to gauge the affordability of medicines. Price component data were collected throughout the supply chain, and markups, taxes, and other distribution costs were identified. In private pharmacies, innovator brand (IB) prices were 16 times higher than the IRPs, while generics were 6.6 times higher. In dispensing doctor clinics, the figures were 15 times higher for innovator brands and 7.5 for generics. Dispensing doctors applied high markups of 50%–76% for IBs, and up to 316% for generics. Retail pharmacy markups were also high—25%–38% and 100%–140% for IBs and generics, respectively. In the public sector, where medicines are free, availability was low even for medicines on the National Essential Drugs List. For a month's treatment for peptic ulcer disease and hypertension people have to pay about a week's wages in the private sector.
Conclusions
The free market by definition does not control medicine prices, necessitating price monitoring and control mechanisms. Markups for generic products are greater than for IBs. Reducing the base price without controlling markups may increase profits for retailers and dispensing doctors without reducing the price paid by end users. To increase access and affordability, promotion of generic medicines and improved availability of medicines in the public sector are required.
Drug price and availability data were collected from West Malaysian public sector facilities, private sector retail pharmacies, and dispensing doctors. Mark-ups were higher on generic drugs than on innovator brands.
Editors' Summary
Background.
The World Health Organization has said that one-third of the people of the world cannot access the medicines they need. An important reason for this problem is that prices are often too high for people or government-funded health systems to afford. In developing countries, most people who need medicines have to pay for them out of their own pockets. Where the cost of drugs is covered by health systems, spending on medicines is a major part of the total healthcare budget. Governments use a variety of approaches to try to control the cost of drugs and make sure that essential medicines are affordable and not overpriced. According to the theory of “free market economics,” the costs of goods and services are determined by interactions between buyers and sellers and not by government intervention. However, free market economics does not work well at containing the costs of medicines, particularly new medicines, because new medicines are protected by patent law, which legally prevents others from making, using, or selling the medicine for a particular period of time. Therefore, without government intervention, there is nothing to help to push down prices.
Why Was This Study Done?
Malaysia is a middle-income country with a relatively effective public health system, but it is facing a rapid rise in drug costs. In Malaysia, medicine prices are determined by free-market economics, without any control by government. Government hospitals are expected to provide drugs free, but a substantial proportion of medicines are paid for by patients who buy them directly from private pharmacies or prescribing doctors. There is evidence that Malaysian patients have difficulties accessing the drugs they need and that cost is an important factor. Therefore, the researchers who wrote this paper wanted to examine the cost of different medicines in Malaysia, and their availability and affordability from different sources.
What Did the Researchers Do and Find?
In this research project, 48 drugs were studied, of which 28 were part of a “core list” identified by the World Health Organization as “essential drugs” on the basis of the global burden of disease. The remaining 20 reflected health care needs in Malaysia itself. The costs of each medicine were collected from government hospitals, private pharmacies, and dispensing doctors in four different regions of Malaysia. Data were collected for the “innovator brand” (made by the original patent holder) and for “generic” brands (an equivalent drug to the innovator brand, produced by a different company once the innovator brand no longer has an exclusive patent). The medicine prices were compared against international reference prices (IRP), which are the average prices offered by not-for-profit drug companies to developing countries. Finally, the researchers also compared the cost of the drugs with daily wages, in order to work out their “affordability.”
The researchers found that, irrespective of the source of medicines, prices were on average very much higher than the international reference price, ranging from 2.4 times the IRP for innovator brands accessed through public hospitals, to 16 times the IRP for innovator brands accessed through private pharmacies. The availability of medicines was also very poor, with only 25% of generic medicines available on average through the public sector. The affordability of many of the medicines studied was again very poor. For example, one month's supply of ranitidine (a drug for stomach ulcers) was equivalent to around three days' wages for a low-paid government worker, and one month's supply of fluoxetine (an antidepressant) would cost around 26 days' wages.
What Do These Findings Mean?
These results show that essential drugs are very expensive in Malaysia and are not universally available. Many people would not be able to pay for essential medicines. The cost of medicines in Malaysia seems to be much higher than in areas of India and Sri Lanka, although the researchers did not attempt to collect data in order to carry out an international comparison. It is possible that the high cost and low availability in Malaysia are the result of a lack of government regulation. Overall, the findings suggest that the government should set up mechanisms to prevent drug manufacturers from increasing prices too much and thus ensure greater access to essential medicines.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040082.
Read a related PLoS Medicine Perspective article by Suzanne Hill
Information is available from the World Health Organization on Improving Access to Medicines
Information on medicine prices is available from Health Action International
Wikipedia has an entry on Patent (a type of intellectual property that is normally used to prevent other companies from selling a newly invented medicine). (Wikipedia is an internet encyclopedia anyone can edit.)
The Drugs for Neglected Diseases Initiative is an international collaboration between public organizations that aims to develop drugs for people suffering from neglected diseases
doi:10.1371/journal.pmed.0040082
PMCID: PMC1831730  PMID: 17388660
18.  Implementation of a National Reference Laboratory for Buruli Ulcer Disease in Togo 
Background
In a previous study PCR analysis of clinical samples from suspected cases of Buruli ulcer disease (BUD) from Togo and external quality assurance (EQA) for local microscopy were conducted at an external reference laboratory in Germany. The relatively poor performance of local microscopy as well as effort and time associated with shipment of PCR samples necessitated the implementation of stringent EQA measures and availability of local laboratory capacity. This study describes the approach to implementation of a national BUD reference laboratory in Togo.
Methodology
Large scale outreach activities accompanied by regular training programs for health care professionals were conducted in the regions “Maritime” and “Central,” standard operating procedures defined all processes in participating laboratories (regional, national and external reference laboratories) as well as the interaction between laboratories and partners in the field. Microscopy was conducted at regional level and slides were subjected to EQA at national and external reference laboratories. For PCR analysis, sample pairs were collected and subjected to a dry-reagent-based IS2404-PCR (DRB-PCR) at national level and standard IS2404 PCR followed by IS2404 qPCR analysis of negative samples at the external reference laboratory.
Principal Findings
The inter-laboratory concordance rates for microscopy ranged from 89% to 94%; overall, microscopy confirmed 50% of all suspected BUD cases. The inter-laboratory concordance rate for PCR was 96% with an overall PCR case confirmation rate of 78%. Compared to a previous study, the rate of BUD patients with non-ulcerative lesions increased from 37% to 50%, the mean duration of disease before clinical diagnosis decreased significantly from 182.6 to 82.1 days among patients with ulcerative lesions, and the percentage of category III lesions decreased from 30.3% to 19.2%.
Conclusions
High inter-laboratory concordance rates as well as case confirmation rates of 50% (microscopy), 71% (PCR at national level), and 78% (including qPCR confirmation at external reference laboratory) suggest high standards of BUD diagnostics. The increase of non-ulcerative lesions, as well as the decrease in diagnostic delay and category III lesions, prove the effect of comprehensive EQA and training measures involving also procedures outside the laboratory.
Author Summary
Buruli ulcer disease (BUD), the third most common mycobacterial disease worldwide, is treated with standardized antimycobacterial therapy. According to WHO recommendations at least 50% of cases should be laboratory confirmed by polymerase chain reaction (PCR). In a previous study PCR analysis of clinical samples from suspected BUD cases from Togo and external quality assurance (EQA) for local microscopy were conducted at an external reference laboratory in Germany. The relatively poor performance of local microscopy as well as time and effort associated with shipment of clinical samples abroad necessitated the availability of a local BUD reference laboratory and the implementation of stringent EQA measures. All processes in the laboratories as well as in the field were defined by standard operating procedures, microscopy conducted at regional facilities was subjected to EQA at national and external reference level, and PCR samples were analyzed in parallel at national and external reference laboratories. Inter-laboratory concordance rates of >90% and case confirmation rates of 50% (microscopy) and >70% (PCR) respectively suggest high standards of BUD diagnostics. Furthermore, an increase of non-ulcerative lesions and a decrease in diagnostic delay and category III lesions reflect the impact of comprehensive EQA measures also involving procedures outside the laboratory on the quality of BUD control.
doi:10.1371/journal.pntd.0002011
PMCID: PMC3554568  PMID: 23359828
19.  Innoversity in knowledge-for-action and adaptation to climate change: the first steps of an ‘evidence-based climatic health’ transfrontier training program 
It has become increasingly clear to the international scientific community that climate change is real and has important consequences for human health. To meet these new challenges, the World Health Organization recommends reinforcing the adaptive capacity of health systems. One of the possible avenues in this respect is to promote awareness and knowledge translation in climatic health, at both the local and global scales. Within such perspective, two major themes have emerged in the field of public health research: 1) the development of advanced training adapted to ‘global environment’ change and to the specific needs of various groups of actors (doctors, nurses, public health practitioners, health care managers, public service managers, local communities, etc) and 2) the development of strategies for implementing research results and applying various types of evidence to the management of public health issues affected by climate change. Progress on these two fronts will depend on maximum innovation in transdisciplinary and transsectoral collaborations. The general purpose of this article is to present the program of a new research and learning chair designed for this double set of developmental objectives – a chair that emphasizes ‘innoversity’ (the dynamic relationship between innovation and diversity) and ‘transfrontier ecolearning for adaptive actions’. The Écoapprentissages, santé mentale et climat collaborative research chair (University of Montreal and Quebec National Public Health Institute) based in Montreal is a center for ‘transdisciplinary research’ on the transfrontier knowledge-for-action that can aid adaptation of the public health sector, the public mental health sector, and the public service sector to climate change, as well as a center for complex collaborations on evidence-based climatic health ‘training’. This program-focused article comprises two main sections. The first section presents the ‘general’ and ‘specific contexts’ in which the chair emerged. The ‘general context’ pertains to the health-related challenge of finding ways to integrate, transfer, and implement knowledge, a particularly pointed challenge in Canada. The ‘specific context’ refers to the emerging research field of adaptation of public health to climate change. In the second section, the characteristics of the research chair are more extensively detailed (the vision of ‘innoversity’ and ‘ transfrontier knowledge-for-action,’ the approach of shared responsibility and complex collaboration, objectives, and major axes of research). We conclude with a call for complex collaboration toward knowledge-for-action in public health services/mental health services/public services’ adaptation to climate change: this call is aimed at individual and institutional actors in the North and South/West and East concerned by these issues.
doi:10.2147/AMEP.S14027
PMCID: PMC3643138  PMID: 23745068
global changing environment; climatic health; adaptation to climate change; adaptive capacity; innoversity; diversity; complex collaboration; transdisciplinary knowledge-for-action; transfrontier training; andragogy; continuing education; ecocompetency; public health; mental health; health professional; public service manager; knowledge translation; implementation science; ecolearning; ecomanagement; eco-decision-making
20.  Strengthening systems for communicable disease surveillance: creating a laboratory network in Rwanda 
Background
The recent emergence of a novel strain of influenza virus with pandemic potential underscores the need for quality surveillance and laboratory services to contribute to the timely detection and confirmation of public health threats. To provide a framework for strengthening disease surveillance and response capacities in African countries, the World Health Organization Regional Headquarters for Africa (AFRO) developed Integrated Disease Surveillance and Response (IDSR) aimed at improving national surveillance and laboratory systems. IDSR emphasizes the linkage of information provided by public health laboratories to the selection of relevant, appropriate and effective public health responses to disease outbreaks.
Methods
We reviewed the development of Rwanda's National Reference Laboratory (NRL) to understand essential structures involved in creating a national public health laboratory network. We reviewed documents describing the NRL's organization and record of test results, conducted site visits, and interviewed health staff in the Ministry of Health and in partner agencies. Findings were developed by organizing thematic categories and grouping examples within them. We purposefully sought to identify success factors as well as challenges inherent in developing a national public health laboratory system.
Results
Among the identified success factors were: a structured governing framework for public health surveillance; political commitment to promote leadership for stronger laboratory capacities in Rwanda; defined roles and responsibilities for each level; coordinated approaches between technical and funding partners; collaboration with external laboratories; and use of performance results in advocacy with national stakeholders. Major challenges involved general infrastructure, human resources, and budgetary constraints.
Conclusions
Rwanda's experience with collaborative partnerships contributed to creation of a functional public health laboratory network.
doi:10.1186/1478-4505-9-27
PMCID: PMC3142247  PMID: 21702948
21.  Laboratory Confirmation of Buruli Ulcer Disease in Togo, 2007–2010 
Background
Since the early 1990s more than 1,800 patients with lesions suspicious for Buruli ulcer disease (BUD) have been reported from Togo. However, less than five percent of these were laboratory confirmed. Since 2007, the Togolese National Buruli Ulcer Control Program has been supported by the German Leprosy and Tuberculosis Relief Association (DAHW). Collaboration with the Department for Infectious Diseases and Tropical Medicine (DITM), University Hospital, Munich, Germany, allowed IS2404 PCR analysis of diagnostic samples from patients with suspected BUD during a study period of three years.
Methodology/Principal Findings
The DAHW integrated active BUD case finding in the existing network of TB/Leprosy Controllers and organized regular training and outreach activities to identify BUD cases at community level. Clinically suspected cases were referred to health facilities for diagnosis and treatment. Microscopy was carried out locally, external quality assurance (EQA) at DITM. Diagnostic samples from 202 patients with suspected BUD were shipped to DITM, 109 BUD patients (54%) were confirmed by PCR, 43 (29.9%) by microscopy. All patients originated from Maritime Region. EQA for microscopy resulted in 62% concordant results.
Conclusions/Significance
This study presents a retrospective analysis of the first cohort of clinically suspected BUD cases from Togo subjected to systematic laboratory analysis over a period of three years and confirms the prevalence of BUD in Maritime Region. Intensified training in the field of case finding and sample collection increased the PCR case confirmation rate from initially less than 50% to 70%. With a PCR case confirmation rate of 54% for the entire study period the WHO standards (case confirmation rate ≥50%) have been met. EQA for microscopy suggests the need for intensified supervision and training. In January 2011 the National Hygiene Institute, Lomé, has assumed the role of a National Reference Laboratory for PCR confirmation and microscopy.
Author Summary
Buruli ulcer disease (BUD) is an emerging disease particularly affecting children under the age of 15 years. Due to scarring and contractures BUD may lead to severe functional disability. Introduction of antimycobacterial treatment necessitated the laboratory confirmation of BUD, and WHO recommends confirmation of at least 50% of patients with suspected BUD by polymerase chain reaction (PCR). In Togo, cases have been reported since the early 1990s. However, less than five percent were laboratory confirmed. Since 2007, the German Leprosy and Tuberculosis Relief Organization (DAHW) has supported the Togolese National Buruli Ulcer Control Program in the area of training, treatment and laboratory confirmation of BUD. In close collaboration of DAHW and the Department for Infectious Diseases and Tropical Medicine, University Hospital, Munich (DITM), diagnostic samples from Togolese patients with suspected BUD were subjected to PCR. Out of 202 suspected BUD cases 109 BUD patients (54%) were PCR confirmed over a period of three years. Whereas the PCR case confirmation rate initially was below 50%, intensified training measures for health staff in the field of clinical diagnosis and collection of diagnostic samples ultimately resulted in 69% PCR confirmed cases. Our findings confirm the prevalence of BUD in Maritime Region.
doi:10.1371/journal.pntd.0001228
PMCID: PMC3139659  PMID: 21811641
22.  Perspectives of public health laboratories in emerging infectious diseases 
The world has experienced an increased incidence and transboundary spread of emerging infectious diseases over the last four decades. We divided emerging infectious diseases into four categories, with subcategories in categories 1 and 4. The categorization was based on the nature and characteristics of pathogens or infectious agents causing the emerging infections, which are directly related to the mechanisms and patterns of infectious disease emergence. The factors or combinations of factors contributing to the emergence of these pathogens vary within each category. We also classified public health laboratories into three types based on function, namely, research, reference and analytical diagnostic laboratories, with the last category being subclassified into primary (community-based) public health and clinical (medical) analytical diagnostic laboratories. The frontline/leading and/or supportive roles to be adopted by each type of public health laboratory for optimal performance to establish the correct etiological agents causing the diseases or outbreaks vary with respect to each category of emerging infectious diseases. We emphasize the need, especially for an outbreak investigation, to establish a harmonized and coordinated national public health laboratory system that integrates different categories of public health laboratories within a country and that is closely linked to the national public health delivery system and regional and international high-end laboratories.
doi:10.1038/emi.2013.34
PMCID: PMC3697305
emerging infectious disease; public health laboratory
23.  Do recent data from the Seychelles Islands alter the conclusions of the NRC Report on the toxicological effects of methylmercury? 
In 2000, the National Research Council (NRC), an arm of the National Academy of Sciences, released a report entitled, "Toxicological Effects of Methylmercury." The overall conclusion of that report was that, at levels of exposure in some fish- and marine mammal-consuming communities (including those in the Faroe Islands and New Zealand), subtle but significant adverse effects on neuropsychological development were occurring as a result of in utero exposure. Since the release of that report, there has been continuing discussion of the public health relevance of current levels of exposure to Methylmercury. Much of this discussion has been linked to the release of the most recent longitudinal update of the Seychelles Island study. It has recently been posited that these findings supercede those of the NRC committee, and that based on the Seychelles findings, there is little or no risk of adverse neurodevelopmental effects at current levels of exposure. In this commentary, members of the NRC committee address the conclusions from the NRC report in light of the recent Seychelles data. We conclude that no evidence has emerged since the publication of the NRC report that alters the findings of that report.
doi:10.1186/1476-069X-3-2
PMCID: PMC365028  PMID: 14754462
24.  Cost-Effectiveness Analysis of Pharmaceutical Treatment Options in the First-Line Management of Major Depressive Disorder in Belgium 
Pharmacoeconomics  2014;32(5):479-493.
Objective
The objective of this study was to assess the cost effectiveness of commonly used antidepressants as first-line treatment of major depressive disorder (MDD) in Belgium.
Methods
The model structure was based on a decision tree developed by the Swedish TLV (Tandvårds- och läkemedelsförmånsverket) and adapted to the Belgium healthcare setting, using primary local data on the patterns of treatment and following KCE [Federal Knowledge Center (Federaal Kenniscentrum voor de Gezondheidszorg)] recommendations. Comparators were escitalopram, citalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, and mirtazapine. In the model, patients not achieving remission or relapsing after remission on the assessed treatment moved to a second therapeutic step (titration, switch, add-on, or transfer to a specialist). In case of failure in the second step or following a suicide attempt, patients were assumed to be referred to secondary care. The time horizon was 1 year and the analysis was conducted from the National Institute for Health and Disability Insurance (NIHDI; national health insurance) and societal perspectives. Remission rates were obtained from the TLV network meta-analysis and risk of relapse, efficacy following therapeutic change, risk of suicide attempts and related death, utilities, costs (2012), and resources were derived from the published literature and expert opinion. The effect of uncertainty in model parameters was estimated through scenario analyses and a probabilistic sensitivity analysis (PSA).
Results
In the base-case analysis, escitalopram was identified as the optimal strategy: it dominated all other treatments except venlafaxine from the NIHDI perspective, against which it was cost effective with an incremental cost-effectiveness ratio of €6,352 per quality-adjusted life-year (QALY). Escitalopram also dominated all other treatments from the societal perspective. At a threshold of €30,000 per QALY and from the NIHDI perspective, the PSA showed that the probability of escitalopram being identified as the optimal strategy ranged from 61 % (vs. venlafaxine) to 100 % (vs. fluoxetine).
Conclusion
Escitalopram was associated with the highest probability of being the optimal treatment from the NIHDI and societal perspectives. This analysis, based on new Belgian clinical practice data and following KCE requirements, provides additional information that may be used to guide the choice of treatments in the management of MDD in Belgium.
Electronic supplementary material
The online version of this article (doi:10.1007/s40273-014-0138-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s40273-014-0138-x
PMCID: PMC4013445  PMID: 24554474
25.  Genotypic Identification of Fusarium Species from Ocular Sources: Comparison to Morphologic Classification and Antifungal Sensitivity Testing (An AOS Thesis) 
Purpose
Ocular infections caused by fungal organisms can cause significant ocular morbidity, particularly when diagnosis and treatment are delayed. Rapid and accurate identification of Fusarium species at the subgenus level using current diagnostic standards is timely and insensitive. The purpose of this study is to examine the usefulness of polymerase chain reaction (PCR) analysis of the internal transcribed spacer (ITS) regions (ITS1, 5.8S, and ITS2) in detecting and differentiating Fusarium species from isolates of ocular infections, and to assess the correlation between the genotypic and morphologic classification.
Methods
Fifty-eight isolates from 52 patients diagnosed with Fusarium ocular infections were retrieved from storage at the Bascom Palmer Eye Institute’s ocular microbiology laboratory. Morphologic classification was determined at both a general and a reference microbiology laboratory. DNA was extracted and purified, and the ITS region was amplified and sequenced. Following DNA sequences, alignment and phylogenetic analysis were done. Susceptibility to antifungal drugs was measured according to the Clinical and Laboratory Standards Institute reference method.
Results
Sequence analysis demonstrated 15 unique sequences among the 58 isolates. The grouping showed that the 58 isolates were distributed among 4 main species complexes. At the species level, morphologic classification correlated with genotypic classification in 25% and 97% of the isolates in a general microbiology and a reference mycology laboratory, respectively.
Conclusions
The sequence variation within the ITS provides a sufficient quantitative basis for the development of a molecular diagnostic approach to the Fusarium pathogens isolated from ocular infections. Morphology based on microscopic and macroscopic observations yields inconsistent results, particularly at nonreference laboratories, emphasizing the need for a more reproducible test with less user-dependent variability. Fusarium solani tends to be more resistant to certain antifungals (azoles).
PMCID: PMC2646427  PMID: 19277239

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