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Background: Most information on invasive Staphylococcus aureus infections comes from temperate countries. There are considerable knowledge gaps in epidemiology, treatment, drug resistance and outcome of invasive S. aureus infection in the tropics. Methods: A prospective, observational study of S. aureus bacteraemia was conducted in a 1000-bed regional hospital in northeast Thailand over 1 year. Detailed clinical data were collected and final outcomes determined at 12 weeks, and correlated with antimicrobial susceptibility profiles of infecting isolates. Principal findings: Ninety-eight patients with S. aureus bacteraemia were recruited. The range of clinical manifestations was similar to that reported from temperate countries. The prevalence of endocarditis was 14%. The disease burden was highest at both extremes of age, whilst mortality increased with age. The all-cause mortality rate was 52%, with a mortality attributable to S. aureus of 44%. Methicillin-resistant S. aureus (MRSA) was responsible for 28% of infections, all of which were healthcare-associated. Mortality rates for MRSA and methicillin-susceptible S. aureus (MSSA) were 67% (18/27) and 46 (33/71), respectively (p=0.11). MRSA isolates were multidrug resistant. Only vancomycin or fusidic acid would be suitable as empirical treatment options for suspected MRSA infection. Conclusions: S. aureus is a significant pathogen in northeast Thailand, with comparable clinical manifestations and a similar endocarditis prevalence but higher mortality than industrialised countries. S. aureus bacteraemia is frequently associated with exposure to healthcare settings with MRSA causing a considerable burden of disease. Further studies are required to define setting-specific strategies to reduce mortality from S. aureus bacteraemia, prevent MRSA transmission, and to define the burden of S. aureus disease and emergence of drug resistance throughout the developing world.

Previously we have shown that insertion of IS1301 in the sia/ctr intergenic region (IGR) of serogroup C Neisseria meningitidis (MenC) isolates from Spain confers increased resistance against complement-mediated killing. Here we investigate the significance of IS1301 in the same location in N. meningitidis isolates from the UK. PCR and sequencing was used to screen a collection of more than 1500 meningococcal carriage and disease isolates from the UK for the presence of IS1301 in the IGR. IS1301 was not identified in the IGR among vaccine failure strains but was frequently found in serogroup B isolates (MenB) from clonal complex 269 (cc269). Almost all IS1301 insertions in cc269 were associated with novel polymorphisms, and did not change capsule expression or resistance to human complement. After excluding sequence types (STs) distant from the central genotype within cc269, there was no significant difference for the presence of IS1301 in the IGR of carriage isolates compared to disease isolates. Isolates with insertion of IS1301 in the IGR are not responsible for MenC disease in UK vaccine failures. Novel polymorphisms associated with IS1301 in the IGR of UK MenB isolates do not lead to the resistance phenotype seen for IS1301 in the IGR of MenC isolates.

BACKGROUND: A substantial decline in malaria was reported to have occurred over several years until 2007 in the western part of The Gambia, encouraging consideration of future elimination in this previously highly endemic region. Scale up of interventions has since increased with support from the Global Fund and other donors. METHODOLOGY/PRINCIPAL FINDINGS: We continued to examine laboratory records at four health facilities previously studied and investigated six additional facilities for a 7 year period, adding data from 243,707 slide examinations, to determine trends throughout the country until the end of 2009. We actively detected infections in a community cohort of 800 children living in rural villages throughout the 2008 malaria season, and assayed serological changes in another rural population between 2006 and 2009. Proportions of malaria positive slides declined significantly at all of the 10 health facilities between 2003 (annual mean across all sites, 38.7%) and 2009 (annual mean, 7.9%). Statistical modelling of trends confirmed significant seasonality and decline over time at each facility. Slide positivity was lowest in 2009 at all sites, except two where lowest levels were observed in 2006. Mapping households of cases presenting at the latter sites in 2007-2009 indicated that these were not restricted to a few residual foci. Only 2.8% (22/800) of a rural cohort of children had a malaria episode in the 2008 season, and there was substantial serological decline between 2006 and 2009 in a separate rural area. CONCLUSIONS: Malaria has continued to decline in The Gambia, as indicated by a downward trend in slide positivity at health facilities, and unprecedented low incidence and seroprevalence in community surveys. We recommend intensification of control interventions for several years to further reduce incidence, prior to considering an elimination programme.

Background: Despite a substantial burden of non-bacteraemic methicillin resistant Staphylococcus aureus (MRSA) disease, most MRSA surveillance schemes are based on bacteraemias. Using bacteraemia as an outcome, trends at hospital level are difficult to discern, due to random variation. We investigated rates of nosocomial bacteraemic and non-bacteraemic MRSA infection as surveillance outcomes. Methods and Findings: We used microbiology and patient administration system data from an Oxford hospital to estimate monthly rates of first nosocomial MRSA bacteraemia, and nosocomial MRSA isolation from blood/respiratory/sterile site specimens (‘‘sterile sites’’) or all clinical samples (screens excluded) in all patients admitted from the community for at least 2 days between April 1998 and June 2006. During this period there were 441 nosocomial MRSA bacteraemias, 1464 MRSA isolations from sterile sites, and 3450 isolations from clinical specimens (8% blood, 15% sterile site, 10% respiratory, 59% surface swabs, 8% urine) in over 2.6 million patient-days. The ratio of bacteraemias to sterile site and all clinical isolations was similar over this period (around 3 and 8-fold lower respectively), during which rates of nosocomial MRSA bacteraemia increased by 27% per year to July 2003 before decreasing by 18% per year thereafter (heterogeneity p < 0.001). Trends in sterile site and all clinical isolations were similar. Notably, a change in rate of all clinical MRSA isolations in December 2002 could first be detected with conventional statistical significance by August 2003 (p = 0.03). In contrast, when monitoring MRSA bacteraemia, identification of probable changes in trend took longer, first achieving p < 0.05 in July 2004. Conclusions: MRSA isolation from all sites of suspected infection, including bacteraemic and non-bacteraemic isolation, is a potential new surveillance method for MRSA control. It occurs about 8 times more frequently than bacteraemia, allowing robust statistical determination of changing rates over substantially shorter times or smaller areas than using bacteraemia as an outcome.

Introduction With the creation of the Revised National TB Control Programme (RNTCP), tuberculosis services have become decentralized and more accessible. A 1997 study prior to RNTCP implementation reported that most chest symptomatics accessed first private health care facilities and a general dissatisfaction with government health facilities. The study was repeated post-RNTCP implementation to gain insight into the current care seeking behavior of chest symptomatics. Methodology A cross-sectional community-based study carried out between March-August 2008 in 4 sites (2 rural [R] and 2 urban [U]) from the same two districts of Chennai and Madurai, southern India, as in the 1997 study. Six hundred and forty chest symptomatics were identified (R 314; U 326), and detailed interviews were done for 606 (R311; U295). Results Prevalence of chest symptomatics in the urban and rural areas were 2.7% and 4.9% respectively (p

A postmortem study by Ted Cohen and colleagues reveals a huge toll of tuberculosis among patients dying in hospitals in KwaZulu-Natal, South Africa., Background Tuberculosis is the leading cause of death in South Africa by death notification, but accurate diagnosis of tuberculosis is challenging in this setting of high HIV prevalence. We conducted limited autopsies on young adults dying in a single public hospital in the province of KwaZulu-Natal between October 2008 and August 2009 in order to estimate the magnitude of deaths attributable to tuberculosis. Methods and Findings We studied a representative sample of 240 adult inpatients (aged 20–45 years) dying after admission to Edendale Hospital. Limited autopsies included collection of respiratory tract secretions and tissue by needle core biopsies of lung, liver, and spleen. Specimens were examined by fluorescent microscopy for acid-fast bacilli and cultured in liquid media; cultures positive for M. tuberculosis were tested for drug susceptibility to first- and second-line antibiotics. Ninety-four percent of our study cohort was HIV seropositive and 50% of decedents had culture-positive tuberculosis at the time of death. Fifty percent of the participants were on treatment for tuberculosis at the time of death and 58% of these treated individuals remained culture positive at the time of death. Of the 50% not receiving tuberculosis treatment, 42% were culture positive. Seventeen percent of all positive cultures were resistant to both isoniazid and rifampin (i.e., multidrug resistant); 16% of patients dying during the initiation phase of their first ever course of tuberculosis treatment were infected with multidrug-resistant bacilli. Conclusions Our findings reveal the immense toll of tuberculosis among HIV-positive individuals in KwaZulu-Natal. The majority of decedents who remained culture positive despite receiving tuberculosis treatment were infected with pan-susceptible M. tuberculosis, suggesting that the diagnosis of tuberculosis was made too late to alter the fatal course of the infection. There is also a significant burden of undetected multidrug-resistant tuberculosis among HIV-coinfected individuals dying in this setting. New public health approaches that improve early diagnosis of tuberculosis and accelerate the initiation of treatment are urgently needed in this setting. Please see later in the article for the Editors' Summary, Editors' Summary Background Every year, nearly 10 million people develop tuberculosis—a contagious bacterial infection that affects the lungs and other parts of the body—and nearly two million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, which spreads in airborne droplets when people with the disease cough or sneeze. Its characteristic symptoms are a persistent cough, weight loss, and night sweats. Diagnostic tests for tuberculosis include the microscopic examination of sputum samples (mucus brought up from the lungs by coughing) for M. tuberculosis bacilli, and mycobacterial culture (in which bacteriologists try to grow M. tuberculosis from sputum or tissue samples). Although tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months, global efforts to control tuberculosis are being thwarted by the emergence of strains of M. tuberculosis that are resistant to several antibiotics (multidrug and extensively drug-resistant tuberculosis) and by the HIV epidemic; people who are infected with HIV, the virus that causes AIDS, are particularly susceptible to tuberculosis because of their weakened immune system. Why Was This Study Done? In the past few years, tuberculosis has become the leading recorded cause of death in South Africa, a country where nearly a fifth of adults are infected with HIV. There are 122,000 recorded deaths from tuberculosis (including 94,000 deaths in HIV-positive people) in South Africa every year. However, because the accurate diagnosis of tuberculosis in HIV-positive people can be difficult—they are more likely to have sputum-negative tuberculosis than HIV-negative individuals—the true number of people dying because of tuberculosis is likely to be higher than the recorded number. Public-health experts in South Africa need an accurate picture of the tuberculosis deaths to help them improve tuberculosis control. In this postmortem study, the researchers determine the prevalence (the proportion of a population that has a disease) and drug sensitivity of tuberculosis among patients dying in a public hospital in KwaZulu-Natal, South Africa, to get a better estimate of how many people die because of tuberculosis in this setting. What Did the Researchers Do and Find? The researchers collected respiratory tract secretions and lung, liver, and spleen samples from 240 adults who died in the Edendale public hospital in KwaZulu-Natal over a 10-month period in 2008/9. They looked for M. tuberculosis bacilli in the samples, tried to culture M. tuberculosis from them, and tested any bacteria that grew for antibiotic sensitivity. They also collected information on current tuberculosis treatment status, previous tuberculosis treatment, and HIV status for each deceased patient (decedent) from medical records and from relatives. Ninety-four percent of the decedents were HIV positive and 50% had culture-positive tuberculosis at the time of death. Of the 50% of the decedents who were being treated for tuberculosis, 58% were culture positive at the time of death. A similar percentage (42%) of the decedents who were not being treated for tuberculosis were culture positive at the time of death. Seventeen percent of all the positive cultures were multidrug resistant and 16% of patients dying during their first course of tuberculosis treatment were infected with multidrug-resistant bacteria. Seventy percent of decedents who remained culture positive despite receiving tuberculosis treatment were infected with M. tuberculosis strains that were susceptible to all antibiotics. What Do These Findings Mean? These findings reveal the immense toll of tuberculosis among HIV-infected individuals in this hospital in KwaZulu-Natal. They show that many patients being treated for tuberculosis were culture positive at death despite being infected with antibiotic-sensitive M. tuberculosis, which suggests that diagnoses of tuberculosis are often made too late to alter the fatal course of infection. These findings also suggest that multidrug-resistant tuberculosis often goes undetected among HIV-infected individuals. Further studies are needed to confirm these findings elsewhere in South Africa and in other countries with a high HIV prevalence. Nevertheless, they suggest that public-health initiatives that improve the early diagnosis of tuberculosis, that introduce routine screening for tuberculosis among HIV-positive patients, and that accelerate the initiation of treatment for both tuberculosis and HIV might reduce the global death toll from tuberculosis. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000296. The World Health Organization provides information on all aspects of tuberculosis, including information on tuberculosis and HIV, on tuberculosis in South Africa, and on the Stop TB Partnership (some information is in several languages) The US Centers for Disease Control and Prevention has information about tuberculosis and on tuberculosis and HIV coinfection The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis Information is available from Avert, an international AIDS charity, on tuberculosis and HIV

Ricardo Soares Magalhães and colleagues used national cross-sectional household-based demographic health surveys to map the distribution of anemia risk in preschool children in Burkina Faso, Ghana, and Mali., Background Childhood anaemia is considered a severe public health problem in most countries of sub-Saharan Africa. We investigated the geographical distribution of prevalence of anaemia and mean haemoglobin concentration (Hb) in children aged 1–4 y (preschool children) in West Africa. The aim was to estimate the geographical risk profile of anaemia accounting for malnutrition, malaria, and helminth infections, the risk of anaemia attributable to these factors, and the number of anaemia cases in preschool children for 2011. Methods and Findings National cross-sectional household-based demographic health surveys were conducted in 7,147 children aged 1–4 y in Burkina Faso, Ghana, and Mali in 2003–2006. Bayesian geostatistical models were developed to predict the geographical distribution of mean Hb and anaemia risk, adjusting for the nutritional status of preschool children, the location of their residence, predicted Plasmodium falciparum parasite rate in the 2- to 10-y age group (Pf PR2–10), and predicted prevalence of Schistosoma haematobium and hookworm infections. In the four countries, prevalence of mild, moderate, and severe anaemia was 21%, 66%, and 13% in Burkina Faso; 28%, 65%, and 7% in Ghana, and 26%, 62%, and 12% in Mali. The mean Hb was lowest in Burkina Faso (89 g/l), in males (93 g/l), and for children 1–2 y (88 g/l). In West Africa, severe malnutrition, Pf PR2–10, and biological synergisms between S. haematobium and hookworm infections were significantly associated with anaemia risk; an estimated 36.8%, 14.9%, 3.7%, 4.2%, and 0.9% of anaemia cases could be averted by treating malnutrition, malaria, S. haematobium infections, hookworm infections, and S. haematobium/hookworm coinfections, respectively. A large spatial cluster of low mean Hb (95%) was predicted for an area shared by Burkina Faso and Mali. We estimate that in 2011, approximately 6.7 million children aged 1–4 y are anaemic in the three study countries. Conclusions By mapping the distribution of anaemia risk in preschool children adjusted for malnutrition and parasitic infections, we provide a means to identify the geographical limits of anaemia burden and the contribution that malnutrition and parasites make to anaemia. Spatial targeting of ancillary micronutrient supplementation and control of other anaemia causes, such as malaria and helminth infection, can contribute to efficiently reducing the burden of anaemia in preschool children in Africa. Please see later in the article for the Editors' Summary, Editors' Summary Background Global estimates for the time period 1993–2005 suggest that that worldwide, nearly 300 million children had anemia, that is, hemoglobin levels less than 110 g/l. In sub-Saharan Africa, two-thirds of all children were anemic, representing 83.5 million children. These statistics are important because anemia in infancy and childhood is associated with poor cognitive development, reduced growth, problems with immune function—and ultimately, decreased survival. Malnutrition (including micronutrient deficiency, especially of iron, vitamin A, vitamin C, and folate), undernutrition, and infectious diseases, particularly HIV, malaria, and helminth infections (caused by hookworm and Schistosoma haematobium—which causes urinary schistosomiasis), are major causes of anemia in children. Although iron supplementation can often correct anemia, in some circumstances, iron deficiency can protect against common infectious agents, and giving iron can, on occasion, increase the severity of infectious disease in some children. Focusing on the treatment and prevention of infectious diseases that cause anemia is therefore an important alternative strategy in the treatment of anemia. Why Was This Study Done? Control tools for targeting interventions for malaria and helminth infection in sub-Saharan Africa include modern spatial risk prediction methods that combine statistical models with geographical information systems (similar to those used in car navigation systems). However, to date no studies have used these tools to spatially predict the risk of anemia. Furthermore, the contribution that malnutrition and infections make to the overall anemia burden in Africa is largely unknown. In this study the researchers used these tools to predict the prevalence of anemia in three West African countries and to estimate the attributable risk of anemia due to malnutrition, malaria, and helminth infections. What Did the Researchers Do and Find? The researchers used geographically linked data from the most recent Demographic and Health Surveys (DHS) in Burkina Faso (2003), Ghana (2003), and Mali (2006), which included capillary blood sampling and testing and detailed anthropometric (height and weight) measurements. A total of 7,147 children aged 1–4 years (3,477 girls and 3,670 boys) in the three countries were included in the analysis. The researchers mapped DHS survey locations in the three study countries using DHS cluster coordinates in a geographic information system. Using data from the Malaria Atlas Project, the researchers extracted spatially predicted values of Plasmodium falciparum parasite rate for each DHS cluster using a geographical information system and used previously reported parasitological survey data of hookworm and S. haematobium infections to predict helminth infection risk across the region. Then the researchers developed spatial prediction models using Bayesian statistics to estimate of the population attributable fraction for specific predictors for anemia. Data from the DHS showed that the prevalence of mild, moderate, and severe anemia was 21%, 66%, and 13% in Burkina Faso; 28%, 65%, and 7% in Ghana, and 26%, 62%, and 12% in Mali. The prevalence of stunting, wasting, and being underweight in the study area was 87.8%, 89.7%, and 71.2%, respectively, and the mean P. falciparum parasite rate, and rates of S. haematobium infection, hookworm infection, and S. haematobium/hookworm coinfection for the study area were 52.0%, 26.8%, 8.2%, and 3.6%, respectively. The overall results indicate that in the three countries, approximately 6.7 million children aged 1–4 years have anemia. Severe malnutrition, P. falciparum infection, hookworm infection, S. haematobium infection, and hookworm/S. haematobium coinfection were responsible for an estimated 2.5 million, 1.0 million, 250,000, 285,000, and 61,000 anemia cases, respectively. Central Burkina Faso and southern Ghana had the highest number of anemic children. What Do These Findings Mean? These results add insight and detail to anemia prevalence and anemia severity within different geographical areas in three West African countries. The combination of anemia and mean hemoglobin predictive maps identifies communities in West Africa where preschool-age children are at increased risk of morbidity. The use of anemia maps has important practical implications for targeted control in these countries, such as guiding the efficient allocation of nutrient supplements and fortified foods, and enabling risk assessment of anemia due to different causes, which would in turn constitute an evidence base to calculate the best balance between interventions. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000438. This study is further discussed in a PLoS Medicine Perspective by Abdisalan Noor The WHO Web site has comprehensive information on the worldwide prevalence of anemia More information on Demographic Health Surveys is available More information on global predictions of malaria is available

Gerardo Chowell and colleagues address whether school closures and other social distancing strategies were successful in reducing pandemic flu transmission in Mexico by analyzing the age- and state-specific incidence of influenza morbidity and mortality in 32 Mexican states., Background Mexico's local and national authorities initiated an intense public health response during the early stages of the 2009 A/H1N1 pandemic. In this study we analyzed the epidemiological patterns of the pandemic during April–December 2009 in Mexico and evaluated the impact of nonmedical interventions, school cycles, and demographic factors on influenza transmission. Methods and Findings We used influenza surveillance data compiled by the Mexican Institute for Social Security, representing 40% of the population, to study patterns in influenza-like illness (ILIs) hospitalizations, deaths, and case-fatality rate by pandemic wave and geographical region. We also estimated the reproduction number (R) on the basis of the growth rate of daily cases, and used a transmission model to evaluate the effectiveness of mitigation strategies initiated during the spring pandemic wave. A total of 117,626 ILI cases were identified during April–December 2009, of which 30.6% were tested for influenza, and 23.3% were positive for the influenza A/H1N1 pandemic virus. A three-wave pandemic profile was identified, with an initial wave in April–May (Mexico City area), a second wave in June–July (southeastern states), and a geographically widespread third wave in August–December. The median age of laboratory confirmed ILI cases was ∼18 years overall and increased to ∼31 years during autumn (p, Editors' Summary Background From June 2009 to August 2010, the world was officially (according to specific World Health Organization [WHO] criteria—WHO phase 6 pandemic alert) in the grip of an Influenza A pandemic with a new strain of the H1N1 virus. The epidemic in Mexico, which had the second confirmed global case of H1N1 virus was first noted in early April 2009, when reports of respiratory hospitalizations and deaths among 62 young adults in Mexico alerted local health officials to the occurrence of atypical rates of respiratory illness. In line with its inter-institutional National Pandemic Influenza Preparedness and Response Plan, the Ministry of Health cancelled school attendance in the greater Mexico City area on April 24 and expanded these measures to the rest the country three days later. The Ministry of Health then implemented in Mexico City other “social distancing” strategies such as closing cinemas and restaurants and cancelling large public gatherings. Why Was This Study Done? School closures and other intense social distancing strategies can be very disruptive to the population, but as yet it is uncertain whether these measures were successful in reducing disease transmission. In addition, there have been no studies concentrating on recurrent pandemic waves in Mexico. So in this study the authors addressed these issues by analyzing the age- and state-specific incidence of influenza morbidity and mortality in 32 Mexican States and quantified the association between local influenza transmission rates, school cycles, and demographic factors. What Did the Researchers Do and Find? The researchers used the epidemiological surveillance system of the Mexican Institute for Social Security—a Mexican health system that covers private sector workers and their families, a group representative of the general population, that comprises roughly 40% of the Mexican population (107 million individuals), with a network of 1,099 primary health care units and 259 hospitals nationwide. Then the researchers compiled state- and age-specific time series of incident influenza-like illness and H1N1 influenza cases by day of symptom onset to analyze the geographic dissemination patterns of the pandemic across Mexico and defined three temporally distinct pandemic waves in 2009: spring (April 1–May 20), summer (May 21–August 1), and fall (August 2–December 31). The researchers then applied a mathematical model of influenza transmission to daily case data to assess the effectiveness of mandatory school closures and other social distancing measures implemented during April 24–May 11, in reducing influenza transmission rates. The Mexican Institute for Social Security reported a total of 117,626 people with influenza-like illness from April 1 to December 31, 2009, of which 36,044 were laboratory tested (30.6%) and 27,440 (23.3%) were confirmed with H1N1 influenza. During this period, 1,370 people with influenza-like illness died of which 585 (1.5 per 100,000) were confirmed to have H1N1 influenza. The median age of people with laboratory confirmed influenza like illness (H1N1) was 18 years overall but increased to 31 years during the autumn wave. The overall case-fatality ratio among people with influenza like illness was 1.2%, but highest (5.5%) among people over 60 years. The researchers found that the 18-day period of mandatory school closures and other social distancing measures implemented in the greater Mexico City area was associated with a substantial (29%–37%) reduction in influenza transmission in spring 2009 but increased in late May and early June in the southeast states, after mandatory school suspension resumed and before summer vacation started. State-specific pandemic waves began 2–5 weeks after school reopened for the fall term, coinciding with an age shift in influenza cases. What Do These Findings Mean? These findings show that the age distribution of pandemic influenza morbidity was greater in younger age groups, while the risk of severe disease was skewed towards older age groups, and that there were substantial geographical variation in pandemic patterns across Mexico, in part related to population size. But most importantly, these findings support the effectiveness of early mitigation efforts including mandatory school closures and cancellation of large public gatherings, reinforcing the importance of school cycles in the transmission of pandemic influenza. This analysis increases understanding of the age and transmission patterns of the Mexican 2009 influenza pandemic at various geographic scales, which is crucial for designing more efficient public health interventions against future influenza pandemics. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000436. The World Health Organization provides information about the global response to the 2009 H1N1 pandemic

Background Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It has been estimated that 10–20 million people are infected worldwide, but no successful treatment is available. Recently, the epidemiology of this virus was addressed in blood donors from Maputo, showing rates from 0.9 to 1.2%. However, the origin and impact of HTLV endemic in this population is unknown. Objective To assess the HTLV-1 molecular epidemiology in Mozambique and to investigate their relationship with HTLV-1 lineages circulating worldwide. Methods Blood donors and HIV patients were screened for HTLV antibodies by using enzyme immunoassay, followed by Western Blot. PCR and sequencing of HTLV-1 LTR region were applied and genetic HTLV-1 subtypes were assigned by the neighbor-joining method. The mean genetic distance of Mozambican HTLV-1 lineages among the genetic clusters were determined. Human mitochondrial (mt) DNA analysis was performed and individuals classified in mtDNA haplogroups. Results LTR HTLV-1 analysis demonstrated that all isolates belong to the Transcontinental subgroup of the Cosmopolitan subtype. Mozambican HTLV-1 sequences had a high inter-strain genetic distance, reflecting in three major clusters. One cluster is associated with the South Africa sequences, one is related with Middle East and India strains and the third is a specific Mozambican cluster. Interestingly, 83.3% of HIV/HTLV-1 co-infection was observed in the Mozambican cluster. The human mtDNA haplotypes revealed that all belong to the African macrohaplogroup L with frequencies representatives of the country. Conclusions The Mozambican HTLV-1 genetic diversity detected in this study reveals that although the strains belong to the most prevalent and worldwide distributed Transcontinental subgroup of the Cosmopolitan subtype, there is a high HTLV diversity that could be correlated with at least 3 different HTLV-1 introductions in the country. The significant rate of HTLV-1a/HIV-1C co-infection, particularly in the Mozambican cluster, has important implications for the controls programs of both viruses., Author Summary Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of Adult T-Cell Leukemia/Lymphoma (ATL), the Tropical Spastic Paraparesis/HTLV-1-associated Myelopathy (TSP/HAM) and other inflammatory diseases, including dermatitis, uveitis, and myositis. It is estimated that 2–8% of the infected persons will develop a HTLV-1-associated disease during their lifetimes, frequently TSP/HAM. Thus far, there is not a specific treatment to this progressive and chronic disease. HTLV-1 has means of three transmission: (i) from mother to child during prolonged breastfeeding, (ii) between sexual partners and (iii) through blood transfusion. HTLV-1 has been characterized in 7 subtypes and the geographical distribution and the clinical impact of this infection is not well known, mainly in African population. HTLV-1 is endemic in sub-Saharan Africa. Mozambique is a country of southeastern Africa where TSP/HAM cases were reported. Recently, our group estimated the HTLV prevalence among Mozambican blood donors as 0.9%. In this work we performed a genetic analysis of HTLV-1 in blood donors and HIV/HTLV co-infected patients from Maputo, Mozambique. Our results showed the presence of three HTLV-1 clusters within the Cosmopolitan/Transcontinental subtype/subgroup. The differential rates of HIV-1/HTLV-1 co-infection in the three HTLV-1 clusters demonstrated the dynamic of the two viruses and the need for implementation of control measures focusing on both retroviruses.

The evolution of drug resistant bacteria is a severe public health problem, both in hospitals and in the community. Currently, some countries aim at concentrating highly specialized services in large hospitals in order to improve patient outcomes. Emergent resistant strains often originate in health care facilities, but it is unknown to what extent hospital size affects resistance evolution and the resulting spillover of hospital-associated pathogens to the community. We used two published datasets from the US and Ireland to investigate the effects of hospital size and controlled for several confounders such as antimicrobial usage, sampling frequency, mortality, disinfection and length of stay. The proportion of patients acquiring both sensitive and resistant infections in a hospital strongly correlated with hospital size. Moreover, we observe the same pattern for both the percentage of resistant infections and the increase of hospital-acquired infections over time. One interpretation of this pattern is that chance effects in small hospitals impede the spread of drug-resistance. To investigate to what extent the size distribution of hospitals can directly affect the prevalence of antibiotic resistance, we use a stochastic epidemiological model describing the spread of drug resistance in a hospital setting as well as the interaction between one or several hospitals and the community. We show that the level of drug resistance typically increases with population size: In small hospitals chance effects cause large fluctuations in pathogen population size or even extinctions, both of which impede the acquisition and spread of drug resistance. Finally, we show that indirect transmission via environmental reservoirs can reduce the effect of hospital size because the slow turnover in the environment can prevent extinction of resistant strains. This implies that reducing environmental transmission is especially important in small hospitals, because such a reduction not only reduces overall transmission but might also facilitate the extinction of resistant strains. Overall, our study shows that the distribution of hospital sizes is a crucial factor for the spread of drug resistance., Author Summary The increasing spread of bacteria, which are resistant to antibiotics, is a serious threat to clinical care. Currently, several countries aim at concentrating highly specialized services in large hospitals in order to improve patient outcomes. However, empirical studies have shown that resistance levels correlate with hospital size. To illustrate this correlation, we analyze two published datasets from the US and Ireland and controlled for antimicrobial usage, disinfection and length of stay. The proportion of patients acquiring both sensitive and resistant infections in hospitals strongly correlated with hospital size. Moreover, we observe the same pattern for both the percentage of resistant infections and the temporal increase of hospital-acquired infections. To investigate to what extent hospital size can directly affect the prevalence of antibiotic resistance, we use mathematical models describing the epidemic spread of resistance in hospitals and the community. We find that small hospitals typically lead to considerably lower resistance levels than large hospitals. However, this beneficial effect of small hospital size may be reduced if bacteria are transmitted indirectly via the environment. Therefore, reducing environmental transmission might be particularly important in small hospitals. Overall, our findings suggest that the short-term benefits of larger hospitals may come at the price of increasing resistance in the long term.

Prospective evaluation of the effectiveness of the WHO-recommended standardized retreatment regimen for tuberculosis by Edward Jones-López and colleagues reveals an unacceptable proportion of unsuccessful outcomes., Background Each year, 10%–20% of patients with tuberculosis (TB) in low- and middle-income countries present with previously treated TB and are empirically started on a World Health Organization (WHO)-recommended standardized retreatment regimen. The effectiveness of this retreatment regimen has not been systematically evaluated. Methods and Findings From July 2003 to January 2007, we enrolled smear-positive, pulmonary TB patients into a prospective cohort to study treatment outcomes and mortality during and after treatment with the standardized retreatment regimen. Median time of follow-up was 21 months (interquartile range 12–33 months). A total of 29/148 (20%) HIV-uninfected and 37/140 (26%) HIV-infected patients had an unsuccessful treatment outcome. In a multiple logistic regression analysis to adjust for confounding, factors associated with an unsuccessful treatment outcome were poor adherence (adjusted odds ratio [aOR] associated with missing half or more of scheduled doses 2.39; 95% confidence interval (CI) 1.10–5.22), HIV infection (2.16; 1.01–4.61), age (aOR for 10-year increase 1.59; 1.13–2.25), and duration of TB symptoms (aOR for 1-month increase 1.12; 1.04–1.20). All patients with multidrug-resistant TB had an unsuccessful treatment outcome. HIV-infected individuals were more likely to die than HIV-uninfected individuals (p, Editors' Summary Background One-third of the world's population is currently infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), and 5%–10% of HIV-uninfected individuals will go on to develop disease and become infectious. The risk of progression from infection to disease in HIV infected is much higher. If left untreated, each person with active TB may infect 10 to 15 people every year, reinforcing the public health priority of controlling TB through adequate treatment. Patients with a previous history of TB treatment are a major concern for TB programs throughout the world because these patients are at a much higher risk of harboring a form of TB that is resistant to the drugs most frequently used, resulting in poorer treatment outcomes and significantly complicating current management strategies. More then 1 million people in over 90 countries need to be “re-treated” after failing, interrupting, or relapsing from previous TB treatment. Every year, 10%–20% of people with TB in low- and middle-income countries are started on a standardized five-drug retreatment regimen as recommended by the World Health Organization (WHO). Yet, unlike treatment regimens for newly diagnosed TB patients, the recommended retreatment regimen (also known as the category II regimen) has never been properly evaluated in randomized clinical trials or prospective cohort studies. Rather, this regimen was recommended by experts before the current situation of widespread drug-resistant TB and HIV infection. Why Was This Study Done? WHO surveillance data suggest that the retreatment regimen is successful in about 70% of patients, but retrospective studies that have evaluated the regimen's efficacy showed variable treatment responses with success rates ranging from 26% to 92%. However, these studies have generally only assessed outcomes at the completion of the retreatment regimen, and few have examined the risk of TB recurrence, especially in people who are also infected with HIV and so are more likely to experience TB recurrence—an issue of particular concern in sub-Saharan Africa. Therefore, in this study based in Kampala, Uganda, the researchers conducted a prospective cohort study to assess treatment and survival outcomes in patients previously treated for TB and to identify factors associated with poor outcomes. Given the overwhelming contribution of HIV infection to death, the researchers categorized their survival analysis by HIV status. What Did the Researchers Do and Find? The researchers recruited consecutive smear-positive TB patients who were admitted to Mulago Hospital, Kampala, Uganda, for the retreatment of TB with the standard retreatment regimen between July 2003 and January 2007. Eligible patients received daily directly observed therapy and after hospital discharge, were seen every month during their 8-month TB-retreatment course. Home health visitors assessed treatment adherence through treatment card review, monthly pill counts, and patient self-report. After the completion of the retreatment regimen, patients were evaluated for TB recurrence every 3 months for a median of 21 months. The researchers then used a statistical model to identify treatment outcomes and mortality HIV-uninfected and HIV-infected patients. The researchers found that 29/148 (20%) of HIV-uninfected and 37/140 (26%) of HIV-infected patients had an unsuccessful treatment outcome. Factors associated with an unsuccessful treatment outcome were poor adherence, HIV infection, increasing age, and duration of TB symptoms. All patients with multidrug resistant TB, a form of TB that is resistant to the two most important drugs used to treat TB, had an unsuccessful treatment outcome. In addition, HIV-infected subjects were more likely to die than HIV-uninfected subjects (p

Background: Screening at hospital admission for carriage of methicillin-resistant Staphylococcus aureus (MRSA) has been proposed as a strategy to reduce nosocomial infections. The objective of this study was to determine the long-term costs and health benefits of selective and universal screening for MRSA at hospital admission, using both PCR-based and chromogenic media-based tests in various settings.Methodology/Principal Findings: A simulation model of MRSA transmission was used to determine costs and effects over 15 years from a US healthcare perspective. We compared admission screening together with isolation of identified carriers against a baseline policy without screening or isolation. Strategies included selective screening of high risk patients or universal admission screening, with PCR-based or chromogenic media-based tests, in medium (5%) or high nosocomial prevalence (15%) settings. The costs of screening and isolation per averted MRSA infection were lowest using selective chromogenic-based screening in high and medium prevalence settings, at $4,100 and $10,300, respectively. Replacing the chromogenic-based test with a PCR-based test costs $13,000 and $36,200 per additional infection averted, and subsequent extension to universal screening with PCR would cost $131,000 and $232,700 per additional infection averted, in high and medium prevalence settings respectively. Assuming $17,645 benefit per infection averted, the most cost-saving strategies in high and medium prevalence settings were selective screening with PCR and selective screening with chromogenic, respectively.Conclusions/ Significance: Admission screening costs $4,100-$21,200 per infection averted, depending on strategy and setting. Including financial benefits from averted infections, screening could well be cost saving.

Background A five-year citywide control program based on regular application of temephos significantly reduced Aedes aegypti larval indices but failed to maintain them below target levels in Clorinda, northern Argentina. Incomplete surveillance coverage and reduced residuality of temephos were held as the main putative causes limiting effectiveness of control actions. Methodology The duration of temephos residual effects in household-owned water-holding tanks (the most productive container type and main target for control) was estimated prospectively in two trials. Temephos was applied using spoons or inside perforated small zip-lock bags. Water samples from the study tanks (including positive and negative controls) were collected weekly and subjected to larval mortality bioassays. Water turnover was estimated quantitatively by adding sodium chloride to the study tanks and measuring its dilution 48 hs later. Principal Findings The median duration of residual effects of temephos applied using spoons (2.4 weeks) was significantly lower than with zip-lock bags (3.4 weeks), and widely heterogeneous between tanks. Generalized estimating equations models showed that bioassay larval mortality was strongly affected by water type and type of temephos application depending on water type. Water type and water turnover were highly significantly associated. Tanks filled with piped water had high turnover rates and short-lasting residual effects, whereas tanks filled with rain water showed the opposite pattern. On average, larval infestations reappeared nine weeks post-treatment and seven weeks after estimated loss of residuality. Conclusions Temephos residuality in the field was much shorter and more variable than expected. The main factor limiting temephos residuality was fast water turnover, caused by householders' practice of refilling tanks overnight to counteract the intermittence of the local water supply. Limited field residuality of temephos accounts in part for the inability of the larval control program to further reduce infestation levels with a treatment cycle period of 3 or 4 months., Author Summary Dengue is currently the most important viral disease of humans transmitted by arthropods worldwide. Aedes aegypti, a human-biting mosquito dwelling in artificial domestic containers, is the main vector of dengue. Ae. aegypti larval control programs are frequently based on the application of the insecticide temephos. A five-year larval control program in northeastern Argentina significantly reduced infestations but could not maintain them below target levels, especially during summer. Identifying the underlying processes responsible for such shortcomings is important for improving dengue prevention strategies. Large water-holding containers were the most productive container type and the main targets for control. We found that the duration of temephos residual effects in household-owned large tanks was much shorter than expected and allowed early reinfestation post-treatment. The main factor limiting temephos residuality was fast water turnover, caused by householders' practice of refilling tanks overnight to counteract the intermittence of the local water supply.

Many pathogenic bacteria, fungi, and protozoa achieve chronic infection through an immune evasion strategy known as antigenic variation. In the human malaria parasite Plasmodium falciparum, this involves transcriptional switching among members of the var gene family, causing parasites with different antigenic and phenotypic characteristics to appear at different times within a population. Here we use a genome-wide approach to explore this process in vitro within a set of cloned parasite populations. Our analyses reveal a non-random, highly structured switch pathway where an initially dominant transcript switches via a set of switch-intermediates either to a new dominant transcript, or back to the original. We show that this specific pathway can arise through an evolutionary conflict in which the pathogen has to optimise between safeguarding its limited antigenic repertoire and remaining capable of establishing infections in non-naïve individuals. Our results thus demonstrate a crucial role for structured switching during the early phases of infections and provide a unifying theory of antigenic variation in P. falciparum malaria as a balanced process of parasite-intrinsic switching and immune-mediated selection., Author Summary The malaria parasite Plasmodium falciparum avoids recognition and clearance by the immune system by sequentially switching between members of the var multi-gene family which encode the immunodominant surface proteins PfEMP1. However, some mechanism must exist to prevent rapid exposure of the pathogen's entire antigenic repertoire as this would quickly terminate the infection. It has previously been shown that the immune system can play an important role in orchestrating the sequential display of variants once an infection is established; however this does not explain how repertoire exhaustion is avoided in the initial phases of infection before an immune response has been established. Here we show that P. falciparum has evolved a highly structured switching pattern to prevent repertoire exhaustion in the early stages of infection without compromising the ability to establish new infections among partially immune individuals.

Background Visceral Leishmaniasis (VL) is a vector-borne disease transmitted by Phlebotomus argentipes. To understand the VL seasonality, annual and monthly variations of VL incidence and its relationship to meteorological variables, the numbers of VL cases reported in Muzaffarpur district, Bihar, India from 1990 to 2008 were studied. Methods Annual VL incidence per 10,000 and the total number of annual VL cases reported at block Community Health Centres (CHC), Public Hospitals or Non-Governmental Organisations (NGO) and the number of VL cases per month from 2000 to 2008 as well as the monthly average of cases for 2000–08, 2000–04 and 2005–08 periods along with the monthly averages of temperature, rainfall and relative humidity were plotted. VL Standardised Incidence Ratios per block were computed for the periods of 1990–1993, 1994–1998, 1999–2004 and 2005–2008 and month wise from 2002 to 2008. A negative binomial regression model was used to evaluate the association between meteorological variables and the number of VL cases per month from 2000 to 2008. Results A total of 68,358 VL cases were reported in Muzaffarpur district from 1990 to 2008, ranging from 1,2481 in 1992 to 1,161 in 2001. The blocks with the highest number of cases shifted from East (1990–98) to West (1999–2008). Monthly averages of cases ranged from 149 to 309, highest peak in March–April and another one in July. Monthly VL incidence was associated positively to rainfall and negatively to relative humidity and the numbers of VL cases in the previous month. Interpretation The number of cases reported to the public health sector allowed the describing of the spatial distribution and temporal variations in the Muzaffarpur from 1990 to 2008. However, to assess the actual VL burden, as well as the efficacy of the control measures applied in the district, reporting from private practices and NGOs should be encouraged.

Background Disease incidence data are needed to guide decision-making for public health interventions. Although dengue is a reportable disease in Thailand and Cambodia, the degree that reported incidence underrecognizes true disease burden is unknown. We utilized dengue incidence calculated from laboratory-confirmed outpatient and inpatient cases in prospective cohort studies to estimate the magnitude of dengue underrecognition and to establish more accurate disease burden estimates for these countries. Methods and Findings Cohort studies were conducted among children aged 95,000 children in Thailand and >58,000 children in Cambodia were estimated to be hospitalized due to dengue. Conclusion Calculating MFs by comparing prospective cohort study data to locally-reported national surveillance data is one approach to more accurately assess disease burden. These data indicate that although dengue is regularly reported in many countries, national surveillance data significantly underrecognize the true burden of disease., Author Summary Dengue is a major public health problem especially in tropical and subtropical countries of Asia and Latin-America. An effective dengue vaccine is not yet available, but several vaccine candidates are currently being evaluated in clinical trials. Accurate country-level incidence data are crucial to assess the cost-effectiveness of such vaccines and will assist policy-makers in making vaccine introduction decisions. Existing national surveillance systems are often passive and are designed to monitor trends and to detect disease outbreaks. Our analyses of data from prospectively followed cohorts with laboratory confirmation of dengue cases show that, in Thailand and Cambodia, dengue incidence is underrecognized by more than 8-fold. The magnitude of the outpatient burden caused by dengue is not assessed or reflected by the national surveillance data. We estimate that a median of more than 340,000 symptomatic dengue virus infections occurred annually in children less than 15 years of age in Thailand in Cambodia between 2003 and 2007.

Using the Lives Saved Tool (LiST) Christa Fischer-Walker and colleagues estimate that scale-up of diarrhea prevention and treatment interventions over 5 years in 68 high child mortality countries could avert nearly 5 million deaths., Background Diarrhea remains a leading cause of mortality among young children in low- and middle-income countries. Although the evidence for individual diarrhea prevention and treatment interventions is solid, the effect a comprehensive scale-up effort would have on diarrhea mortality has not been estimated. Methods and Findings We use the Lives Saved Tool (LiST) to estimate the potential lives saved if two scale-up scenarios for key diarrhea interventions (oral rehydration salts [ORS], zinc, antibiotics for dysentery, rotavirus vaccine, vitamin A supplementation, basic water, sanitation, hygiene, and breastfeeding) were implemented in the 68 high child mortality countries. We also conduct a simple costing exercise to estimate cost per capita and total costs for each scale-up scenario. Under the ambitious (feasible improvement in coverage of all interventions) and universal (assumes near 100% coverage of all interventions) scale-up scenarios, we demonstrate that diarrhea mortality can be reduced by 78% and 92%, respectively. With universal coverage nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$84.8 billion would be required for the addition of all water and sanitation interventions. Conclusion Using currently available interventions, we demonstrate that with improved coverage, diarrheal deaths can be drastically reduced. If delivery strategy bottlenecks can be overcome and the international community can collectively deliver on the key strategies outlined in these scenarios, we will be one step closer to achieving success for the United Nations' Millennium Development Goal 4 (MDG4) by 2015. Please see later in the article for the Editors' Summary, Editors' Summary Background Diarrhea—passing three or more loose or liquid stools per day—kills about 1.5 million young children every year, mainly in low- and middle-income countries. It is the second leading cause of death in under-5-year olds and causes nearly one in five child deaths. Diarrhea, which can lead to life-threatening dehydration, is a common symptom of gastrointestinal infections. The viruses, bacteria and parasites that cause diarrhea spread through contaminated food or drinking water, and from person-to-person through poor hygiene and inadequate sanitation (unsafe disposal of human excreta). Interventions that prevent diarrhea include improvements in water supplies, sanitation and hygiene, the promotion of breastfeeding, vitamin A supplementation, and vaccination against rotavirus (a major cause of diarrhea). Treatments for diarrhea include oral rehydration salts (ORS), which prevent and treat dehydration, and zinc supplementation, which decreases the severity and duration of diarrhea, and antibiotics for dysentery. Why Was This Study Done? Deaths from diarrhea in young children have declined markedly over the past 30 years. However, if diarrhea deaths are not reduced further, it is unlikely that Millennium Development Goal 4 (MDG4; one of the goals agreed by world leaders in 2000 to reduce poverty)—the reduction of child mortality by two-thirds of the 1990 level by 2015—will be reached. In 2009, UNICEF and the World Health Organization (WHO) proposed a new diarrhea reduction plan. Although the effect of individual interventions in this plan is established, the likely effect of the whole package on diarrhea mortality has not been estimated. Such information would be useful for health policy planning. In this study, the researchers use the Lives Saved Tool (LiST) to estimate the potential lives saved by scale-up of diarrhea prevention and treatment interventions in 68 high child mortality countries that together account for 95% of child deaths. LiST is a child survival modeling tool that uses country-level under-5 death rates and cause of death profiles to model the effects of changes in health intervention package coverage on deaths among children. What Did the Researchers Do and Find? The researchers calculated 2010 (baseline) coverage values for seven prevention interventions (breastfeeding, vitamin A supplementation, hand washing with soap, improved sanitation, improved water source, better household water treatment, and rotavirus vaccination) and for three treatment interventions (ORS, zinc supplementation, and antibiotics for dysentery) from published data. They then used LiST to estimate the effect on diarrhea deaths of scaling up intervention coverage according to two scenarios. The “ambitious” scenario assumed a feasible increase in the coverage of all interventions from the baseline year to 2015 in 68 countries with high child mortality. The “universal” scenario assumed an increase to near 100% coverage for all the interventions. Diarrhea mortality was reduced by 78% and 92% by 2015 under the ambitious and universal scenarios, respectively. Over the 5 years of the scale-up, the universal scenario averted nearly 5 million deaths. The researchers also estimated that the additional costs in 2015 of personal prevention and treatment interventions would be US$0.80 per capita with universal coverage; the additional costs for these interventions and all sanitation and water interventions would be US$3.24 per capita. What Do These Findings Mean? These findings suggest that, with currently available interventions, it should be possible to reduce diarrhea deaths substantially at a reasonable cost. As with all computer models, the accuracy of these findings depends on the data and assumptions fed into the model, which does not, for example, account for the difficulties that may be encountered in scaling up intervention coverage in hard to reach populations. Similarly, the estimated costs associated with the two scenarios do not include the resources required to strengthen health systems in developing countries so that they are able to sustain high coverage levels of diarrhea prevention and treatment interventions. Nevertheless, these findings suggest that child mortality due to diarrhea could be significantly reduced by 2015 provided the international community acts collectively to deliver these interventions. Most importantly, the potential 1.4 million lives saved in that year would bring MDG4 a step closer simply by implementing existing low cost and effective interventions. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000428. The World Health Organization provides information on diarrhea (in several languages); its 2009 report with UNICEF Diarrhea: why children are still dying and what can be done, which includes the WHO/UNICEF treatment and prevention plan, can be downloaded from the Internet The children's charity UNICEF, which protects the rights of children and young people around the world, provides information on water, sanitation, and hygiene, and on diarrhea (in several languages) The United Nations Millennium Development Goals provides information on ongoing world efforts to reduce child mortality More details on LiST are available

Background The VL elimination strategy requires cost-effective tools for case detection and management. This intervention study tests the yield, feasibility and cost of 4 different active case detection (ACD) strategies (camp, index case, incentive and blanket approach) in VL endemic districts of India, Nepal and Bangladesh. Methodology/Principal Findings First, VL screening (fever more than 14 days, splenomegaly, rK39 test) was performed in camps. This was followed by house to house screening (blanket approach). An analysis of secondary VL cases in the neighborhood of index cases was simulated (index case approach). A second screening round was repeated 4–6 months later. In another sub-district in India and Nepal, health workers received incentives for detecting new VL cases over a 4 month period (incentive approach). This was followed by house screening for undetected cases. A total of 28 new VL cases were identified by blanket approach in the 1st screening round, and used as ACD gold standard. Of these, the camp approach identified 22 (sensitivity 78.6%), index case approach identified 12 (sensitivity – 42.9%), and incentive approach identified 23 new VL cases out of 29 cases detected by the house screening (sensitivity – 79.3%). The effort required to detect a new VL case varied (blanket approach – 1092 households, incentive approach – 978 households; index case approach – 788 households had to be screened). The cost per new case detected varied (camp approach $21 – $661; index case approach $149 – $200; incentive based approach $50 – $543; blanket screening $112 – $629). The 2nd screening round yielded 20 new VL cases. Sixty and nine new PKDL cases were detected in the first and second round respectively. Conclusions/Significance ACD in the VL elimination campaign has a high yield of new cases at programme costs which vary according to the screening method chosen. Countries need the right mix of approaches according to the epidemiological profile, affordability and organizational feasibility., Author Summary For the elimination of any infectious disease (i.e., reduction of the burden of a serious public health problem to a minor problem which can be managed by the general health services) the right mix of public health tools has to be identified for the early detection and successful treatment of new cases as well as effective vector control (in the case of vector borne diseases) at affordable costs. The paper provides a powerful example of evidence building for cost-effective early case detection in the visceral leishmaniasis elimination initiative of Bangladesh, India and Nepal. It compares the camp approach (mobile teams testing in chronic fever camps for spleen enlargement and rapid diagnostic tests) with the index case approach (screening for new cases in the neighbourhood of reported visceral leishmaniasis patients) and the incentive based approach (where basic health workers receive an allowance for detecting a new case) using subsequent house-to-house screening for the identification of the real number of un-detected cases. By applying a mix of different study methods and an itinerate research process to identify the most effective, feasible and affordable case detection method, under different environmental conditions, recommendations could be developed which help governments in shaping their visceral leishmaniasis elimination strategy.

BackgroundMany countries have amassed antiviral stockpiles for pandemic preparedness. Despite extensive trial data and modelling studies, it remains unclear how to make optimal use of antiviral stockpiles within the constraints of healthcare infrastructure. Modelling studies informed recommendations for liberal antiviral distribution in the pandemic phase, primarily to prevent infection, but failed to account for logistical constraints clearly evident during the 2009 H1N1 outbreaks. Here we identify optimal delivery strategies for antiviral interventions accounting for logistical constraints, and so determine how to improve a strategy's impact.Methods and findingsWe extend an existing SEIR model to incorporate finite diagnostic and antiviral distribution capacities. We evaluate the impact of using different diagnostic strategies to decide to whom antivirals are delivered. We then determine what additional capacity is required to achieve optimal impact. We identify the importance of sensitive and specific case ascertainment in the early phase of a pandemic response, when the proportion of false-positive presentations may be high. Once a substantial percentage of ILI presentations are caused by the pandemic strain, identification of cases for treatment on syndromic grounds alone results in a greater potential impact than a laboratory-dependent strategy. Our findings reinforce the need for a decentralised system capable of providing timely prophylaxis.ConclusionsWe address specific real-world issues that must be considered in order to improve pandemic preparedness policy in a practical and methodologically sound way. Provision of antivirals on the scale proposed for an effective response is infeasible using traditional public health outbreak management and contact tracing approaches. The results indicate to change the transmission dynamics of an influenza epidemic with an antiviral intervention, a decentralised system is required for contact identification and prophylaxis delivery, utilising a range of existing services and infrastructure in a "whole of society" response.

Background Visual analytics, a technique aiding data analysis and decision making, is a novel tool that allows for a better understanding of the context of complex systems. Public health professionals can greatly benefit from this technique since context is integral in disease monitoring and biosurveillance. We propose a graphical tool that can reveal the distribution of an outcome by time and age simultaneously. Methodology/Principal Findings We introduce and demonstrate multi-panel (MP) graphs applied in four different settings: U.S. national influenza-associated and salmonellosis-associated hospitalizations among the older adult population (≥65 years old), 1991–2004; confirmed salmonellosis cases reported to the Massachusetts Department of Public Health for the general population, 2004–2005; and asthma-associated hospital visits for children aged 0–18 at Milwaukee Children's Hospital of Wisconsin, 1997–2006. We illustrate trends and anomalies that otherwise would be obscured by traditional visualization techniques such as case pyramids and time-series plots. Conclusion/Significance MP graphs can weave together two vital dynamics—temporality and demographics—that play important roles in the distribution and spread of diseases, making these graphs a powerful tool for public health and disease biosurveillance efforts.

Background Human African Trypanosomiasis (HAT), also referred to as sleeping sickness, and African Animal Trypanosomaisis (AAT), known as nagana, are highly prevalent parasitic vector-borne diseases in sub-Saharan Africa. Humans acquire trypanosomiasis following the bite of a tsetse fly infected with the protozoa Trypanosoma brucei (T.b.) spp. –i.e., T.b. gambiense in West and Central Africa and T.b. rhodesiense in East and Southern Africa. Over the last decade HAT diagnostic capacity to estimate HAT prevalence has improved in active case-finding areas but enhanced passive surveillance programs are still lacking in much of rural sub-Saharan Africa. Methodology/Principal Findings This retrospective-cross-sectional study examined the use of national census data (1999) to estimate population vulnerability and disability in Kenya's 7 tsetse belts to assess the potential of HAT-acquired infection in those areas. A multilevel study design estimated the likelihood of disability in individuals, nested within households, nested within tsetse fly habitats of varying levels of poverty. Residents and recent migrants of working age were studied. Tsetse fly's impact on disability was conceptualised via two exposure pathways: directly from the bite of a pathogenic tsetse fly resulting in HAT infection or indirectly, as the potential for AAT takes land out of agricultural production and diseased livestock leads to livestock morbidity and mortality, contributing to nutritional deficiencies and poverty. Tsetse belts that were significantly associated with increased disability prevalence were identified and the direct and indirect exposure pathways were evaluated. Conclusions/Significance Incorporating reports on disability from the national census is a promising surveillance tool that may enhance future HAT surveillance programs in sub-Saharan Africa. The combined burdens of HAT and AAT and the opportunity costs of agricultural production in AAT areas are likely contributors to disability within tsetse-infested areas. Future research will assess changes in the spatial relationships between high tsetse infestation and human disability following the release of the Kenya 2009 census at the local level., Author Summary The tsetse fly's influence on human health occurs through direct and indirect exposure pathways. Directly, the fly is a vector for the disease human African trypanosomiasis (HAT), which it spreads to nearly 18,000 new victims each year. Indirectly, the fly is a vector for African Animal Trypanosomaisis (AAT) also known as nagana, which restricts agricultural production, limiting the availability of food and contributing to impoverished conditions across rural sub-Saharan Africa. This historical study used 1999 census data to determine the prevalence of disability among residents and migrants living within Kenya's 7 tsetse fly belts. The results showed that the HAT transmission cycle may differ for residents and migrants with mechanisms leading to exposures that are environmentally driven for residents and economically driven for migrants. The combined burdens of HAT and AAT and the opportunity costs of agricultural production in AAT areas are potential contributors to disability within these tsetse-infested areas. Incorporating reports on disability from the national census appears to be an important surveillance tool that would enhance future HAT surveillance programs in sub-Saharan Africa.

Mitigation of a severe influenza pandemic can be achieved using a range of interventions to reduce transmission. Interventions can reduce the impact of an outbreak and buy time until vaccines are developed, but they may have high social and economic costs. The non-linear effect on the epidemic dynamics means that suitable strategies crucially depend on the precise aim of the intervention. National pandemic influenza plans rarely contain clear statements of policy objectives or prioritization of potentially conflicting aims, such as minimizing mortality (depending on the severity of a pandemic) or peak prevalence or limiting the socio-economic burden of contact-reducing interventions. We use epidemiological models of influenza A to investigate how contact-reducing interventions and availability of antiviral drugs or pre-pandemic vaccines contribute to achieving particular policy objectives. Our analyses show that the ideal strategy depends on the aim of an intervention and that the achievement of one policy objective may preclude success with others, e.g., constraining peak demand for public health resources may lengthen the duration of the epidemic and hence its economic and social impact. Constraining total case numbers can be achieved by a range of strategies, whereas strategies which additionally constrain peak demand for services require a more sophisticated intervention. If, for example, there are multiple objectives which must be achieved prior to the availability of a pandemic vaccine (i.e., a time-limited intervention), our analysis shows that interventions should be implemented several weeks into the epidemic, not at the very start. This observation is shown to be robust across a range of constraints and for uncertainty in estimates of both R0 and the timing of vaccine availability. These analyses highlight the need for more precise statements of policy objectives and their assumed consequences when planning and implementing strategies to mitigate the impact of an influenza pandemic., Author Summary In the event of an influenza pandemic which has high mortality and the potential to spread rapidly, such as the 1918–19 pandemic, there are a number of non-pharmaceutical public health control options available to reduce transmission in the community and mitigate the effects of the pandemic. These include reducing social contacts by closing schools or postponing public events, and encouraging hand washing and the use of masks. These interventions will not only have a non-intuitive impact on the epidemic dynamics, but they will also have direct and indirect social and economic costs, which mean that governments will only want to use them for a limited amount of time. We use simulations to show that limited-time interventions that achieve one aim, e.g., contain the total number of cases below some maximum number of treatments available, are not the same as those that achieve another, e.g., minimize peak demand for health care services. If multiple aims are defined simultaneously, we often see that the optimal intervention need not commence immediately but can begin a few weeks into the epidemic. Our research demonstrates the importance of tailoring pandemic plans to defined policy targets with some flexibility to allow for uncertainty in the characteristics of the pandemic.

Background The three major soil-transmitted helminths (STH) Ascaris lumbricoides, Trichuris trichiura and Necator americanus/Ancylostoma duodenale are among the most widespread parasites worldwide. Despite the global expansion of preventive anthelmintic treatment, standard operating procedures to monitor anthelmintic drug efficacy are lacking. The objective of this study, therefore, was to define the efficacy of a single 400 milligram dose of albendazole (ALB) against these three STH using a standardized protocol. Methodology/Principal Findings Seven trials were undertaken among school children in Brazil, Cameroon, Cambodia, Ethiopia, India, Tanzania and Vietnam. Efficacy was assessed by the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR) using the McMaster egg counting technique to determine fecal egg counts (FEC). Overall, the highest CRs were observed for A. lumbricoides (98.2%) followed by hookworms (87.8%) and T. trichiura (46.6%). There was considerable variation in the CR for the three parasites across trials (country), by age or the pre-intervention FEC (pre-treatment). The latter is probably the most important as it had a considerable effect on the CR of all three STH. Therapeutic efficacies, as reflected by the FECRs, were very high for A. lumbricoides (99.5%) and hookworms (94.8%) but significantly lower for T. trichiura (50.8%), and were affected to different extents among the 3 species by the pre-intervention FEC counts and trial (country), but not by sex or age. Conclusions/Significance Our findings suggest that a FECR (based on arithmetic means) of >95% for A. lumbricoides and >90% for hookworms should be the expected minimum in all future surveys, and that therapeutic efficacy below this level following a single dose of ALB should be viewed with concern in light of potential drug resistance. A standard threshold for efficacy against T. trichiura has yet to be established, as a single-dose of ALB is unlikely to be satisfactory for this parasite. Trial Registration ClinicalTrials.gov NCT01087099, Author Summary Soil-transmitted helminths (roundworms, whipworms and hookworms) infect millions of children in (sub)tropical countries, resulting in malnutrition, growth stunting, intellectual retardation and cognitive deficits. Currently, there is a need to closely monitor anthelmintic drug efficacy and to develop standard operating procedures, as highlighted in a World Health Organization–World Bank meeting on “Monitoring of Drug Efficacy in Large Scale Treatment Programs for Human Helminthiasis” in Washington DC at the end of 2007. Therefore, we have evaluated the efficacy of a commonly used treatment against these parasitic infections in school children in Africa, Asia and South-America using a standardized protocol. In addition, different statistical approaches to analyzing the data were evaluated in order to develop standardized procedures for data analysis. The results demonstrate that the applied treatment was highly efficacious against round- and hookworms, but not against whipworms. However, there was large variation in efficacy across the different trials which warrants further attention. This study also provides new insights into the statistical analysis of efficacy data, which should be considered in future monitoring and evaluation studies of large scale anthelmintic treatment programs. Finally, our findings emphasize the need to update the World Health Organization recommended efficacy threshold for the treatment of STH.

Matthias Egger and colleagues present a nomogram and a web-based calculator to correct estimates of program-level mortality for loss to follow-up, for use in antiretroviral treatment programs., Background The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART. Methods and Findings We developed a nomogram to correct mortality estimates for loss to follow-up, based on the fact that mortality of all patients starting ART in a treatment programme is a weighted average of mortality among patients lost to follow-up and patients remaining in care. The nomogram gives a correction factor based on the percentage of patients lost to follow-up at a given point in time, and the estimated ratio of mortality between patients lost and not lost to follow-up. The mortality observed among patients retained in care is then multiplied by the correction factor to obtain an estimate of programme-level mortality that takes all deaths into account. A web calculator directly calculates the corrected, programme-level mortality with 95% confidence intervals (CIs). We applied the method to 11 ART programmes in sub-Saharan Africa. Patients retained in care had a mortality at 1 year of 1.4% to 12.0%; loss to follow-up ranged from 2.8% to 28.7%; and the correction factor from 1.2 to 8.0. The absolute difference between uncorrected and corrected mortality at 1 year ranged from 1.6% to 9.8%, and was above 5% in four programmes. The largest difference in mortality was in a programme with 28.7% of patients lost to follow-up at 1 year. Conclusions The amount of bias in mortality estimates can be large in ART programmes with substantial loss to follow-up. Programmes should routinely report mortality among patients retained in care and the proportion of patients lost. A simple nomogram can then be used to estimate mortality among all patients who started ART, for a range of plausible mortality rates among patients lost to follow-up. Please see later in the article for the Editors' Summary, Editors' Summary Background AIDS has killed more than 25 million people since 1981 and about 33 million people (30 million of them in low- and middle-income countries) are now infected with HIV, which causes AIDS. HIV destroys immune system cells, leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART) became available. For people living in affluent, developed countries, HIV/AIDS became a chronic condition, but for people living in low- and middle-income countries, ART was prohibitively expensive and HIV/AIDS remained a fatal illness. In 2003, this situation was declared a global health emergency and governments, international agencies, and funding bodies began to implement plans to increase ART coverage in developing countries. By the end of 2009, 5.25 million of the 14.6 million people in low- and middle-income countries who needed ART (36%) were receiving it. Why Was This Study Done? ART program managers in developing countries need to monitor the effectiveness of their programs to ensure that their limited resources are used wisely. In particular, they need accurate records of the death (mortality) rates in their programs. However, in resource-limited countries, many patients drop out of ART programs. In sub-Saharan Africa, for example, only about 60% of patients are retained in ART programs 2 years after starting therapy. In many programs, it is not known how many of the patients lost to follow-up subsequently die, but it is known that mortality is higher among these patients than among those who remain in care. Thus, in programs with high dropout rates and poor ascertainment of death in patients lost to follow-up, estimates of the mortality of all patients starting ART are underestimates. In this study, the researchers develop a simple nomogram (a graphical method for finding the value of a third variable from the values of two other variables) to correct estimates of program-level mortality for loss to follow-up. What Did the Researchers Do and Find? The researchers' nomogram uses the percentage of patients lost to follow and the estimated ratio of mortality between patients lost and not lost to follow-up to provide a correction factor that converts mortality among patients remaining in care to mortality among all the patients in a program. The researchers first applied their nomogram to the Academic Model Providing Access to Healthcare (AMPATH), a large ART program in Kenya. They used data collected by outreach teams to estimate mortality among the 40.5% of patients lost to follow-up at two AMPATH sites between 1 January 2005 and 31 January 2007. The uncorrected estimate of mortality over this period was 2.8%, whereas the corrected estimate obtained using the nomogram was 9.4%. The researchers then applied their nomogram to 11 other African ART programs. This time, the researchers used a statistical model to provide estimates of mortality among patients lost to follow-up. Mortality among patients retained in care was 1.4% to 12.0% at 1 year; loss to follow-up ranged from 2.8% to 28.7%. The nomogram provided a correction value for mortality among all patients in the ART program of 1.2 to 8.0, which resulted in absolute differences between uncorrected and corrected mortality of 1.6% to 9.8%. The largest absolute difference was in the program with the largest percentage of patients lost to follow-up. What Do These Findings Mean? These findings indicate that, in ART programs where a large percentage of patients are lost to follow-up, program-level mortality estimates based on the mortality among patients retained in the program can be substantial underestimates. This bias needs to be taken into account when comparing the effectiveness of different programs, so the researchers recommend that all programs routinely report mortality among patients retained in care and the proportion of patients lost to follow-up. The nomogram developed by the researchers can then be used to estimate mortality among all patients who started ART using a range of plausible mortality rates among patients lost to follow-up. To help program managers make use of the nomogram, the researchers provide a user-friendly web calculator based on the nomogram on the International epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa website. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000390. This study is further discussed in a PLoS Medicine Perspective by Gregory Bisson Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS HIV InSite has comprehensive information on all aspects of HIV/AIDS Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the HIV and AIDS in Africa, and on universal access to AIDS treatment (in English and Spanish) The World Health Organization provides information about universal access to AIDS treatment, including the 2010 progress report (in English, French and Spanish) The International epidemiologic Databases to Evaluate Aids (IeDEA) Southern Africa website provides access to a calculator for correcting overall program-specific mortality for loss to follow-up

Results from a European multicentre case-control study reported by Marta Valenciano and colleagues suggest good protection by the pandemic monovalent H1N1 vaccine against pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine on H1N1., Background A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1). Methods and Findings Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients, Editors' Summary Background Following the World Health Organization's declaration of pandemic phase six in June 2009, manufacturers developed vaccines against pandemic influenza A 2009 (pH1N1). On the basis of the scientific opinion of the European Medicines Agency, the European Commission initially granted marketing authorization to three pandemic vaccines for use in European countries. During the autumn of 2009, most European countries included the 2009–2010 seasonal influenza vaccine and the pandemic vaccine in their influenza vaccination programs. The Influenza Monitoring Vaccine Effectiveness in Europe network (established to monitor seasonal and pandemic influenza vaccine effectiveness) conducted seven case-control and three cohort studies in seven European countries in 2009–2010 to estimate the effectiveness of the pandemic and seasonal vaccines. Data from the seven pilot case-control studies were pooled to provide overall adjusted estimates of vaccine effectiveness. Why Was This Study Done? After seasonal and pandemic vaccines are made available to populations, it is necessary to estimate the effectiveness of the vaccines at the population level during every influenza season. Therefore, this study was conducted in European countries to estimate the pandemic influenza vaccine effectiveness and seasonal influenza vaccine effectiveness against people presenting to their doctor with influenza-like illness who were confirmed (by laboratory tests) to be infected with pH1N1. What Did the Researchers Do and Find? The researchers conducted a multicenter case-control study on the basis of practitioner surveillance networks from seven countries—France, Hungary, Ireland, Italy, Romania, Portugal, and Spain. Patients consulting a participating practitioner for influenza-like illness had a nasal or throat swab taken within 8 days of symptom onset. Cases were swabbed patients who tested positive for pH1N1. Patients presenting with influenza-like illness whose swab tested negative for any influenza virus were controls. Individuals were considered vaccinated if they had received a dose of the vaccine more than 14 days before the date of onset of influenza-like illness and unvaccinated if they were not vaccinated at all, or if the vaccine was given less than 15 days before the onset of symptoms. The researchers analyzed pandemic influenza vaccination effectiveness in those vaccinated less than 8 days, those vaccinated between and including 8 and 14 days, and those vaccinated more than 14 days before onset of symptoms compared to those who had never been vaccinated. The researchers used modeling (taking account of all potential confounding factors) to estimate adjusted vaccine effectiveness and stratified the adjusted pandemic influenza vaccine effectiveness and the adjusted seasonal influenza vaccine effectiveness in three age groups (

The global burden of HIV-associated cryptococcal meningitis is estimated at nearly one million cases per year, causing up to a third of all AIDS-related deaths. Molecular epidemiology constitutes the main methodology for understanding the factors underpinning the emergence of this understudied, yet increasingly important, group of pathogenic fungi. Cryptococcus species are notable in the degree that virulence differs amongst lineages, and highly-virulent emerging lineages are changing patterns of human disease both temporally and spatially. Cryptococcus neoformans variety grubii (Cng, serotype A) constitutes the most ubiquitous cause of cryptococcal meningitis worldwide, however patterns of molecular diversity are understudied across some regions experiencing significant burdens of disease. We compared 183 clinical and environmental isolates of Cng from one such region, Thailand, Southeast Asia, against a global MLST database of 77 Cng isolates. Population genetic analyses showed that Thailand isolates from 11 provinces were highly homogenous, consisting of the same genetic background (globally known as VNI) and exhibiting only ten nearly identical sequence types (STs), with three (STs 44, 45 and 46) dominating our sample. This population contains significantly less diversity when compared against the global population of Cng, specifically Africa. Genetic diversity in Cng was significantly subdivided at the continental level with nearly half (47%) of the global STs unique to a genetically diverse and recombining population in Botswana. These patterns of diversity, when combined with evidence from haplotypic networks and coalescent analyses of global populations, are highly suggestive of an expansion of the Cng VNI clade out of Africa, leading to a limited number of genotypes founding the Asian populations. Divergence time testing estimates the time to the most common ancestor between the African and Asian populations to be 6,920 years ago (95% HPD 122.96 - 27,177.76). Further high-density sampling of global Cng STs is now necessary to resolve the temporal sequence underlying the global emergence of this human pathogen., Author Summary Cryptococcus neoformans is a species complex of often highly pathogenic fungi that cause significant disease in humans. Cryptococcus is notable in the degree that virulence differs amongst genotypes, and highly-virulent emerging lineages are changing patterns of disease in time and space. Cryptococcus neoformans variety grubii (Cng) causes meningitis among HIV/AIDS patients, up to 1 million cases/year resulting in over 600,000 mortalities. Despite these rates of mortality being comparable to those caused by malaria (one million mortalities per annum), cryptococcal meningitis receives only a fraction of the attention, funding and control granted to more widely recognised diseases. This study uses multilocus sequence typing to compare the genetic diversity of Cng in a largely unstudied country with an emerging HIV epidemic, Thailand, against the diversity seen elsewhere. We found that Cng in Thailand exhibits significantly less genetic diversity in comparison to other areas of the world, especially Africa. Analyses dating the pathogen's origin in Thailand support the introduction of a limited number of genotypes into Southeast Asia from an ancestral African population within the last 7,000 years. These findings show the power associated with the collection of global sequence databases in order to better understand the evolution of major fungal pathogens.

Background: Infection with multiple types of human papillomavirus (HPV) is one of the main risk factors associated with the development of cervical lesions. In this study, cervical samples collected from 1, 810 women with diverse sociocultural backgrounds, who attended to their cervical screening program in different geographical regions of Colombia, were examined for the presence of cervical lesions and HPV by Papanicolau testing and DNA PCR detection, respectively. Principal Findings: The negative binomial distribution model used in this study showed differences between the observed and expected values within some risk factor categories analyzed. Particularly in the case of single infection and coinfection with more than 4 HPV types, observed frequencies were smaller than expected, while the number of women infected with 2 to 4 viral types were higher than expected. Data analysis according to a negative binomial regression showed an increase in the risk of acquiring more HPV types in women who were of indigenous ethnicity (+37.8%), while this risk decreased in women who had given birth more than 4 times (-31.1%), or were of mestizo (-24.6%) or black (-40.9%) ethnicity. Conclusions: According to a theoretical probability distribution, the observed number of women having either a single infection or more than 4 viral types was smaller than expected, while for those infected with 2-4 HPV types it was larger than expected. Taking into account that this study showed a higher HPV coinfection rate in the indigenous ethnicity, the role of underlying factors should be assessed in detail in future studies. This project was funded by Asociacion Investigacion Solidaria SADAR, Caja Navarra (Navarra, Spain) and the Spanish Agency for International Development Cooperation (AECID) (Project 08-CAP2-0609).

Several candidate gene studies have provided evidence for a role of host genetics in susceptibility to tuberculosis (TB). However, the results of these studies have been very inconsistent, even within a study population. Here, we review the design of these studies from a genetic epidemiological perspective, illustrating important differences in phenotype definition in both cases and controls, consideration of latent M. tuberculosis infection versus active TB disease, population genetic factors such as population substructure and linkage disequilibrium, polymorphism selection, and potential global differences in M. tuberculosis strain. These considerable differences between studies should be accounted for when examining the current literature. Recommendations are made for future studies to further clarify the host genetics of TB.

Background: Preoperative screening for nasal S. aureus carriage, followed by eradication treatment of identified carriers with nasal mupirocine ointment and chlorhexidine soap was highly effective in preventing deep-seated S. aureus infections. It is unknown how cost-effectiveness of this intervention is affected by suboptimal S. aureus screening. We determined cost-effectiveness of different preoperative S. aureus screening regimes. Methods: We compared different screening scenarios (ranging from treating all patients without screening to treating only identified S. aureus carriers) to the base case scenario without any screening and treatment. Screening and treatment costs as well as costs and mortality due to deep-seated S. aureus infection were derived from hospital databases and prospectively collected data, respectively. Results: As compared to the base case scenario, all scenarios are associated with improved health care outcomes at reduced costs. Treating all patients without screening is most cost-beneficial, saving (sic)7339 per life year gained, as compared to (sic)3330 when only identified carriers are treated. In sensitivity analysis, outcomes are susceptible to the sensitivity of the screening test and the efficacy of treatment. Reductions in these parameters would reduce the cost-effectiveness of scenarios in which treatment is based on screening. When only identified S. aureus carriers are treated costs of screening should be less than (sic)6.23 to become the dominant strategy. Conclusions: Preoperative screening and eradication of S. aureus carriage to prevent deep-seated S. aureus infections saves both life years and medical costs at the same time, although treating all patients without screening is the dominant strategy, resulting in most health gains and largest savings.

Objective To assess the operational effectiveness of long-lasting insecticide treated materials (ITMs), when used at household level, for the control of Aedes aegypti in moderately infested urban and suburban areas. Methods In an intervention study, ITMs consisting of curtains and water jar-covers (made from PermaNet) were distributed under routine field conditions in 10 clusters (5 urban and 5 suburban), with over 4000 houses, in Trujillo, Venezuela. Impact of the interventions were determined by comparing pre-and post-intervention measures of the Breteau index (BI, number of positive containers/100 houses) and pupae per person index (PPI), and by comparison with indices from untreated areas of the same municipalities. The effect of ITM coverage was modeled. Results At distribution, the proportion of households with ≥1 ITM curtain was 79.7% in urban and 75.2% in suburban clusters, but decreased to 32.3% and 39.0%, respectively, after 18 months. The corresponding figures for the proportion of jars using ITM covers were 34.0% and 50.8% at distribution and 17.0% and 21.0% after 18 months, respectively. Prior to intervention, the BI was 8.5 in urban clusters and 42.4 in suburban clusters, and the PPI was 0.2 and 0.9, respectively. In both urban and suburban clusters, the BI showed a sustained 55% decrease, while no discernable pattern was observed at the municipal level. After controlling for confounding factors, the percentage ITM curtain coverage, but not ITM jar-cover coverage, was significantly associated with both entomological indices (Incidence Rate Ratio = 0.98; 95%CI 0.97–0.99). The IRR implied that ITM curtain coverage of at least 50% was necessary to reduce A. aegypti infestation levels by 50%. Conclusion Deployment of insecticide treated window curtains in households can result in significant reductions in A. aegypti levels when dengue vector infestations are moderate, but the magnitude of the effect depends on the coverage attained, which itself can decline rapidly over time., Author Summary An estimated 40% of the world's population lives at risk of contracting dengue, and it inflicts a significant health, economic and social burden on the populations of endemic areas. In the absence of a vaccine, vector control is the only available strategy to prevent transmission. Some control methods against Aedes aegypti (the main dengue vector) have been successful in reducing vector infestation levels, but rarely sustained the reductions for a prolonged period. We report here on the first effectiveness trial of insecticide treated curtains and jar covers against A. aegypti implemented under ‘real-life’ conditions. The coverage of tools was high at distribution, but declined quickly over the 18 months of follow up. The vector infestation levels showed a sustained 55% decrease in the intervention clusters, while no discernable pattern was observed at the municipal level. At least 50% curtain coverage was needed to reduce A. aegypti infestation levels by 50%. We concluded that deployment of insecticide treated window curtains in households can result in significant reductions in dengue vector levels, which are related to dengue transmission risk. The magnitude of the effect depends on the curtain coverage attained, which itself can decline rapidly over time.

Background Dengue is a disease of great complexity, due to interactions between humans, mosquitoes and various virus serotypes as well as efficient vector survival strategies. Thus, understanding the factors influencing the persistence of the disease has been a challenge for scientists and policy makers. The aim of this study is to investigate the influence of various factors related to humans and vectors in the maintenance of viral transmission during extended periods. Methodology/Principal Findings We developed a stochastic cellular automata model to simulate the spread of dengue fever in a dense community. Each cell can correspond to a built area, and human and mosquito populations are individually monitored during the simulations. Human mobility and renewal, as well as vector infestation, are taken into consideration. To investigate the factors influencing the maintenance of viral circulation, two sets of simulations were performed: (1st) varying human renewal rates and human population sizes and (2nd) varying the house index (fraction of infested buildings) and vector per human ratio. We found that viral transmission is inhibited with the combination of small human populations with low renewal rates. It is also shown that maintenance of viral circulation for extended periods is possible at low values of house index. Based on the results of the model and on a study conducted in the city of Recife, Brazil, which associates vector infestation with Aedes aegytpi egg counts, we question the current methodology used in calculating the house index, based on larval survey. Conclusions/Significance This study contributed to a better understanding of the dynamics of dengue subsistence. Using basic concepts of metapopulations, we concluded that low infestation rates in a few neighborhoods ensure the persistence of dengue in large cities and suggested that better strategies should be implemented to obtain measures of house index values, in order to improve the dengue monitoring and control system., Author Summary Dengue is the most rapidly spreading mosquito-borne viral disease in the world and approximately 2.5 billion people live in dengue endemic countries. In Brazil it is mainly transmitted by Aedes aegypti mosquitoes. The wide clinical spectrum ranges from asymptomatic infections or mild illness, to the more severe forms of infection such as dengue hemorrhagic fever or dengue shock syndrome. The spread and dramatic increase in the occurrence of dengue cases in tropical and subtropical countries has been blamed on uncontrolled urbanization, population growth and international traveling. Vaccines are under development and the only current disease control strategy is trying to keep the vector quantity at the lowest possible levels. Mathematical models have been developed to help understand the disease's epidemiology. These models aim not only to predict epidemics but also to expand the capacity of phenomena explanation. We developed a spatially explicit model to simulate the dengue transmission in a densely populated area. The model involves the dynamic interactions between humans and mosquitoes and takes into account human mobility as an important factor of disease spread. We investigated the importance of human population size, human renewal rate, household infestation and ratio of vectors per person in the maintenance of sustained viral circulation.

Background Dengue virus (DENV) was reintroduced into Brazil in 1986 and by 1995 it had spread throughout the country. In 2007 the number of dengue hemorrhagic fever (DHF) cases more than doubled and a shift in the age distribution was reported. While previously the majority of DHF cases occurred among adults, in 2007 53% of cases occurred in children under 15 years old. The reasons for this shift have not been determined. Methods and Findings Age stratified cross-sectional seroepidemiologic survey conducted in Recife, Brazil in 2006. Serostatus was determined by ELISA based detection of Dengue IgG. We estimated time-constant and time-varying forces of infection of DENV between 1986 and 2006. We used discrete-time simulation to estimate the accumulation of monotypic and multitypic immunity over time in a population previously completely susceptible to DENV. We projected the age distribution of population immunity to dengue assuming similar hazards of infection in future years. The overall prevalence of DENV IgG was 0.80 (n = 1427). The time-constant force of infection for the period was estimated to be 0.052 (95% CI 0.041, 0.063), corresponding to 5.2% of susceptible individuals becoming infected each year by each serotype. Simulations show that as time since re-emergence of dengue goes by, multitypic immunity accumulates in adults while an increasing proportion of susceptible individuals and those with monotypic immunity are among young age groups. The median age of those monotypically immune can be expected to shift from 24 years, 10 years after introduction, to 13 years, 50 years after introduction. Of those monotypically immune, the proportion under 15 years old shifts from 27% to 58%. These results are consistent with the dengue notification records from the same region since 1995. Interpretation Assuming that persons who have been monotypically exposed are at highest risk for severe dengue, the shift towards younger patient ages observed in Brazil can be partially explained by the accumulation of multitypic immunity against DENV-1, 2, and 3 in older age groups, 22 years after the re-introduction of these viruses. Serotype specific seroepidemiologic studies are necessary to accurately estimate the serotype specific forces of infection., Author Summary The spread of dengue virus is a major public health problem. Though the burden of dengue has historically been concentrated in Southeast Asian countries, Brazil has become the country that reports the largest number of cases in the world. While prior to 2007 the disease affected mostly adults, during the 2007 epidemic the number of dengue hemorrhagic fever cases more than doubled, and over 53% of cases were in children under 15 years of age. In this paper, we propose that the conditions for the shift were being set gradually since the re-introduction of dengue in 1986 and that they represent the transition from re-emergence to hyperendemicity. Using data from an age stratified seroprevalence study conducted in Recife, we estimated the force of infection (a measure of transmission intensity) between 1986–2006 and used these estimates to simulate the accumulation of immunity since the re-emergence. As the length of time that dengue has circulated increases, adults have a lower probability of remaining susceptible to primary or secondary infection and thus, cases become on average younger. If in fact the shift represents the transition from re-emergence to hyperendemicity, similar shifts are likely to be observed in the rest of Brazil, the American continent and other regions where transmission emerges.

When avian influenza viruses (AIVs) are transmitted from their reservoir hosts (wild waterfowl and shorebirds) to domestic bird species, they undergo genetic changes that have been linked to higher virulence and broader host range. Common genetic AIV modifications in viral proteins of poultry isolates are deletions in the stalk region of the neuraminidase (NA) and additions of glycosylation sites on the hemagglutinin (HA). Even though these NA deletion mutations occur in several AIV subtypes, they have not been analyzed comprehensively. In this study, 4,920 NA nucleotide sequences, 5,596 HA nucleotide and 4,702 HA amino acid sequences were analyzed to elucidate the widespread emergence of NA stalk deletions in gallinaceous hosts, the genetic polymorphism of the deletion patterns and association between the stalk deletions in NA and amino acid variants in HA. Forty-seven different NA stalk deletion patterns were identified in six NA subtypes, N1–N3 and N5–N7. An analysis that controlled for phylogenetic dependence due to shared ancestry showed that NA stalk deletions are statistically correlated with gallinaceous hosts and certain amino acid features on the HA protein. Those HA features included five glycosylation sites, one insertion and one deletion. The correlations between NA stalk deletions and HA features are HA-NA-subtype-specific. Our results demonstrate that stalk deletions in the NA proteins of AIV are relatively common. Understanding the NA stalk deletion and related HA features may be important for vaccine and drug development and could be useful in establishing effective early detection and warning systems for the poultry industry.

The effectiveness of seasonal influenza vaccination programs depends on individual-level compliance. Perceptions about risks associated with infection and vaccination can strongly influence vaccination decisions and thus the ultimate course of an epidemic. Here we investigate the interplay between contact patterns, influenza-related behavior, and disease dynamics by incorporating game theory into network models. When individuals make decisions based on past epidemics, we find that individuals with many contacts vaccinate, whereas individuals with few contacts do not. However, the threshold number of contacts above which to vaccinate is highly dependent on the overall network structure of the population and has the potential to oscillate more wildly than has been observed empirically. When we increase the number of prior seasons that individuals recall when making vaccination decisions, behavior and thus disease dynamics become less variable. For some networks, we also find that higher flu transmission rates may, counterintuitively, lead to lower (vaccine-mediated) disease prevalence. Our work demonstrates that rich and complex dynamics can result from the interaction between infectious diseases, human contact patterns, and behavior., Author Summary When influenza spreads through a human population, its dynamics are shaped by both the complex patterns of contact that arise through our daily activities and individual decisions about the prevention and treatment of flu infections. However, until recently, mathematical models of flu transmission have ignored complex interaction and behavioral patterns in order to facilitate mathematical analyses. Here, we combine two recent approaches to modeling flu–network theory and game theory–to address the interplay between contact patterns and host vaccination decisions during seasonal flu outbreaks. Intuitively, the more contacts one has, the more likely he or she is to vaccinate. However, under the assumption that people make rational decisions based on complete information about the prior seasonal epidemic, vaccination decisions are predicted to vacillate dramatically. A severe epidemic in one year inspires high vaccination rates in the following year; this causes a milder epidemic which then leads to lower vaccination rates in the following year; and the cycle begins anew. We find further that the more homogeneous the contact patterns, the more pronounced the vacillations will be, and that decision-making based on multiple past seasons (rather than just one) leads to much more consistent behavior.

Background Infrared thermal image scanners (ITIS) appear an attractive option for the mass screening of travellers for influenza, but there are no published data on their performance in airports. Methods ITIS was used to measure cutaneous temperature in 1275 airline travellers who had agreed to tympanic temperature measurement and respiratory sampling. The prediction by ITIS of tympanic temperature (37.8°C and 37.5°C) and of influenza infection was assessed using Receiver Operating Characteristic (ROC) curves and estimated sensitivity, specificity and positive predictive value (PPV). Findings Using front of face ITIS for prediction of tympanic temperature ≥37.8°C, the area under the ROC curve was 0.86 (95%CI 0.75–0.97) and setting sensitivity at 86% gave specificity of 71%. The PPV in this population of travellers, of whom 0.5% were febrile using this definition, was 1.5%. We identified influenza virus infection in 30 travellers (3 Type A and 27 Type B). For ITIS prediction of influenza infection the area under the ROC curve was 0.66 (0.56–0.75), a sensitivity of 87% gave specificity of 39%, and PPV of 2.8%. None of the 30 influenza-positive travellers had tympanic temperature ≥37.8°C at screening (95%CI 0% to 12%); three had no influenza symptoms. Conclusion ITIS performed moderately well in detecting fever but in this study, during a seasonal epidemic of predominantly influenza type B, the proportion of influenza-infected travellers who were febrile was low and ITIS were not much better than chance at identifying travellers likely to be influenza-infected. Although febrile illness is more common in influenza A infections than influenza B infections, many influenza A infections are afebrile. Our findings therefore suggest that ITIS is unlikely to be effective for entry screening of travellers to detect influenza infection with the intention of preventing entry of the virus into a country.

Background The persistent spread of Rhodesian human African trypanosomiasis (HAT) in Uganda in recent years has increased concerns of a potential overlap with the Gambian form of the disease. Recent research has aimed to increase the evidence base for targeting control measures by focusing on the environmental and climatic factors that control the spatial distribution of the disease. Objectives One recent study used simple logistic regression methods to explore the relationship between prevalence of Rhodesian HAT and several social, environmental and climatic variables in two of the most recently affected districts of Uganda, and suggested the disease had spread into the study area due to the movement of infected, untreated livestock. Here we extend this study to account for spatial autocorrelation, incorporate uncertainty in input data and model parameters and undertake predictive mapping for risk of high HAT prevalence in future. Materials and Methods Using a spatial analysis in which a generalised linear geostatistical model is used in a Bayesian framework to account explicitly for spatial autocorrelation and incorporate uncertainty in input data and model parameters we are able to demonstrate a more rigorous analytical approach, potentially resulting in more accurate parameter and significance estimates and increased predictive accuracy, thereby allowing an assessment of the validity of the livestock movement hypothesis given more robust parameter estimation and appropriate assessment of covariate effects. Results Analysis strongly supports the theory that Rhodesian HAT was imported to the study area via the movement of untreated, infected livestock from endemic areas. The confounding effect of health care accessibility on the spatial distribution of Rhodesian HAT and the linkages between the disease's distribution and minimum land surface temperature have also been confirmed via the application of these methods. Conclusions Predictive mapping indicates an increased risk of high HAT prevalence in the future in areas surrounding livestock markets, demonstrating the importance of livestock trading for continuing disease spread. Adherence to government policy to treat livestock at the point of sale is essential to prevent the spread of sleeping sickness in Uganda., Author Summary The tsetse transmitted parasites, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, cause the fatal disease human African trypanosomiasis (HAT); the clinical progression, as well as the preferred diagnostic and treatment methods differ between the two types. Currently, the two do not overlap, although recent spread of Rhodesian HAT in Uganda has raised concerns over a potential future overlap. A recent study using geo-referenced HAT case records suggested that the most recent spread of Rhodesian HAT may have been due to movements of infected, untreated livestock (the main reservoir of the parasite). Here, the initial analysis has been extended by explicitly accounting for spatial locations and their proximity to one another, providing improved accuracy. The results provide strengthened evidence of the significance of livestock movements for the continued spread of Rhodesian HAT within Uganda, despite the introduction of cattle treatment regulations which were implemented in an effort to curb the disease's spread. The application of predictive mapping indicates an increased risk of HAT in areas surrounding livestock markets, demonstrating the importance of livestock trading for continuing disease spread. This robust evidence can be used for the targeting of disease control efforts within Uganda to prevent further spread of Rhodesian HAT.

BackgroundPneumocystis jirovecii remains an important cause of fatal pneumonia (Pneumocystis pneumonia or PcP) in HIV+ patients and other immunocompromised hosts. Despite many previous attempts, a clinically useful serologic test for P. jirovecii infection has never been developed.Methods/principal findingsWe analyzed serum antibody responses to the P. jirovecii major surface glycoprotein recombinant fragment C1 (MsgC1) in 110 HIV+ patients with active PcP (cases) and 63 HIV+ patients with pneumonia due to other causes (controls) by an enzyme-linked immunosorbent assay (ELISA). The cases had significantly higher IgG and IgM antibody levels to MsgC1 than the controls at hospital admission (week 0) and intervals up to at least 1 month thereafter. The sensitivity, specificity and positive predictive value (PPV) of IgG antibody levels increased from 57.2%, 61.7% and 71.5% at week 0 to 63.4%, 100%, and 100%, respectively, at weeks 3-4. The sensitivity, specificity and PPV of IgM antibody levels rose from 59.7%, 61.3%, and 79.3% at week 0 to 74.6%, 73.7%, and 89.8%, respectively, at weeks 3-4. Multivariate analysis revealed that a diagnosis of PcP was the only independent predictor of high IgG and IgM antibody levels to MsgC1. A high LDH level, a nonspecific marker of lung damage, was an independent predictor of low IgG antibody levels to MsgC1.Conclusions/significanceThe results suggest that the ELISA shows promise as an aid to the diagnosis of PCP in situations where diagnostic procedures cannot be performed. Further studies in other patient populations are needed to better define the usefulness of this serologic test.

Although overall pollinator populations have declined over the last couple of decades, the honey bee (Apis mellifera) malady, colony collapse disorder (CCD), has caused major concern in the agricultural community. Among honey bee pathogens, RNA viruses are emerging as a serious threat and are suspected as major contributors to CCD. Recent detection of these viral species in bumble bees suggests a possible wider environmental spread of these viruses with potential broader impact. It is therefore vital to study the ecology and epidemiology of these viruses in the hymenopteran pollinator community as a whole. We studied the viral distribution in honey bees, in their pollen loads, and in other non-Apis hymenopteran pollinators collected from flowering plants in Pennsylvania, New York, and Illinois in the United States. Viruses in the samples were detected using reverse transcriptase-PCR and confirmed by sequencing. For the first time, we report the molecular detection of picorna-like RNA viruses (deformed wing virus, sacbrood virus and black queen cell virus) in pollen pellets collected directly from forager bees. Pollen pellets from several uninfected forager bees were detected with virus, indicating that pollen itself may harbor viruses. The viruses in the pollen and honey stored in the hive were demonstrated to be infective, with the queen becoming infected and laying infected eggs after these virus-contaminated foods were given to virus-free colonies. These viruses were detected in eleven other non-Apis hymenopteran species, ranging from many solitary bees to bumble bees and wasps. This finding further expands the viral host range and implies a possible deeper impact on the health of our ecosystem. Phylogenetic analyses support that these viruses are disseminating freely among the pollinators via the flower pollen itself. Notably, in cases where honey bee apiaries affected by CCD harbored honey bees with Israeli Acute Paralysis virus (IAPV), nearby non-Apis hymenopteran pollinators also had IAPV, while those near apiaries without IAPV did not. In containment greenhouse experiments, IAPV moved from infected honey bees to bumble bees and from infected bumble bees to honey bees within a week, demonstrating that the viruses could be transmitted from one species to another. This study adds to our present understanding of virus epidemiology and may help explain bee disease patterns and pollinator population decline in general.

Knowledge of social contact patterns still represents the most critical step for understanding the spread of directly transmitted infections. Data on social contact patterns are, however, expensive to obtain. A major issue is then whether the simulation of synthetic societies might be helpful to reliably reconstruct such data. In this paper, we compute a variety of synthetic age-specific contact matrices through simulation of a simple individual-based model (IBM). The model is informed by Italian Time Use data and routine socio-demographic data (e.g., school and workplace attendance, household structure, etc.). The model is named “Little Italy” because each artificial agent is a clone of a real person. In other words, each agent's daily diary is the one observed in a corresponding real individual sampled in the Italian Time Use Survey. We also generated contact matrices from the socio-demographic model underlying the Italian IBM for pandemic prediction. These synthetic matrices are then validated against recently collected Italian serological data for Varicella (VZV) and ParvoVirus (B19). Their performance in fitting sero-profiles are compared with other matrices available for Italy, such as the Polymod matrix. Synthetic matrices show the same qualitative features of the ones estimated from sample surveys: for example, strong assortativeness and the presence of super- and sub-diagonal stripes related to contacts between parents and children. Once validated against serological data, Little Italy matrices fit worse than the Polymod one for VZV, but better than concurrent matrices for B19. This is the first occasion where synthetic contact matrices are systematically compared with real ones, and validated against epidemiological data. The results suggest that simple, carefully designed, synthetic matrices can provide a fruitful complementary approach to questionnaire-based matrices. The paper also supports the idea that, depending on the transmissibility level of the infection, either the number of different contacts, or repeated exposure, may be the key factor for transmission., Author Summary Data on social contact patterns are fundamental to design adequate control policies for directly transmissible infectious diseases, ranging from a flu pandemic to tuberculosis, to recurrent epidemics of childhood diseases. Most countries in the world do not dispose of such data. We propose an approach to generate synthetic contact data by simulating an artificial society that integrates routinely available socio-demographic data, such as data on household composition or on school participation, with Time Use data, which are increasingly available. We then validate the ensuing simulated contact data against real epidemiological data for varicella and parvo-virus. The results suggest that the approach is potentially a very fruitful one, and provide some insights on the biology of transmission of close-contact infectious diseases.

A significant feature of influenza pandemics is multiple waves of morbidity and mortality over a few months or years. The size of these successive waves depends on intervention strategies including antivirals and vaccination, as well as the effects of immunity gained from previous infection. However, the global vaccine manufacturing capacity is limited. Also, antiviral stockpiles are costly and thus, are limited to very few countries. The combined effect of antivirals and vaccination in successive waves of a pandemic has not been quantified. The effect of acquired immunity from vaccination and previous infection has also not been characterized. In times of a pandemic threat countries must consider the effects of a limited vaccine, limited antiviral use and the effects of prior immunity so as to adopt a pandemic strategy that will best aid the population. We developed a mathematical model describing the first and second waves of an influenza pandemic including drug therapy, vaccination and acquired immunity. The first wave model includes the use of antiviral drugs under different treatment profiles. In the second wave model the effects of antivirals, vaccination and immunity gained from the first wave are considered. The models are used to characterize the severity of infection in a population under different drug therapy and vaccination strategies, as well as school closure, so that public health policies regarding future influenza pandemics are better informed.

Tissue-encysting coccidia, including Toxoplasma gondii and Sarcocystis neurona, are heterogamous parasites with sexual and asexual life stages in definitive and intermediate hosts, respectively. During its sexual life stage, T. gondii reproduces either by genetic out-crossing or via clonal amplification of a single strain through self-mating. Out-crossing has been experimentally verified as a potent mechanism capable of producing offspring possessing a range of adaptive and virulence potentials. In contrast, selfing and other life history traits, such as asexual expansion of tissue-cysts by oral transmission among intermediate hosts, have been proposed to explain the genetic basis for the clonal population structure of T. gondii. In this study, we investigated the contributing roles self-mating and sexual recombination play in nature to maintain clonal population structures and produce or expand parasite clones capable of causing disease epidemics for two tissue encysting parasites. We applied high-resolution genotyping against strains isolated from a T. gondii waterborne outbreak that caused symptomatic disease in 155 immune-competent people in Brazil and a S. neurona outbreak that resulted in a mass mortality event in Southern sea otters. In both cases, a single, genetically distinct clone was found infecting outbreak-exposed individuals. Furthermore, the T. gondii outbreak clone was one of several apparently recombinant progeny recovered from the local environment. Since oocysts or sporocysts were the infectious form implicated in each outbreak, the expansion of the epidemic clone can be explained by self-mating. The results also show that out-crossing preceded selfing to produce the virulent T. gondii clone. For the tissue encysting coccidia, self-mating exists as a key adaptation potentiating the epidemic expansion and transmission of newly emerged parasite clones that can profoundly shape parasite population genetic structures or cause devastating disease outbreaks., Author Summary The parasites Toxoplasma gondii and Sarcocystis neurona have lifecycles that include a sexual stage in a definitive host and an asexual stage in intermediate hosts. For T. gondii, laboratory studies have demonstrated that the sexual stage can serve the dual purpose of producing new, virulent genotypes through recombination and promoting expansion of single clones via self-mating. Self-mating and other life history traits of T. gondii, including transmission of asexual stages among intermediate hosts, are assumed to account for the clonal population genetic structure of this organism. However, the relative contributions of sexual recombination and self-mating verses other life history traits in causing disease outbreaks or in shaping Toxoplasma's population genetic structure have not been verified in nature, nor have these traits been extensively examined in related parasites. To address this knowledge gap, we conducted population genetic analyses on T. gondii and S. neurona strains isolated from naturally occurring outbreaks affecting humans and sea otters, respectively. Our results identify self-mating as a key trait potentiating disease outbreaks through the rapid amplification of a single clone into millions of infectious units. Selfing is likely a key adaptation for enhancing transmission of recently emerged, recombinant clones and reshaping population genetic structures among the tissue-cyst coccidia.

A systematic review by Iacopo Baussano and colleagues synthesizes published research to show that improved tuberculosis (TB) control in prisons could significantly reduce the burden of TB both inside and outside prisons., Background Transmission of tuberculosis (TB) in prisons has been reported worldwide to be much higher than that reported for the corresponding general population. Methods and Findings A systematic review has been performed to assess the risk of incident latent tuberculosis infection (LTBI) and TB disease in prisons, as compared to the incidence in the corresponding local general population, and to estimate the fraction of TB in the general population attributable (PAF%) to transmission within prisons. Primary peer-reviewed studies have been searched to assess the incidence of LTBI and/or TB within prisons published until June 2010; both inmates and prison staff were considered. Studies, which were independently screened by two reviewers, were eligible for inclusion if they reported the incidence of LTBI and TB disease in prisons. Available data were collected from 23 studies out of 582 potentially relevant unique citations. Five studies from the US and one from Brazil were available to assess the incidence of LTBI in prisons, while 19 studies were available to assess the incidence of TB. The median estimated annual incidence rate ratio (IRR) for LTBI and TB were 26.4 (interquartile range [IQR]: 13.0–61.8) and 23.0 (IQR: 11.7–36.1), respectively. The median estimated fraction (PAF%) of tuberculosis in the general population attributable to the exposure in prisons for TB was 8.5% (IQR: 1.9%–17.9%) and 6.3% (IQR: 2.7%–17.2%) in high- and middle/low-income countries, respectively. Conclusions The very high IRR and the substantial population attributable fraction show that much better TB control in prisons could potentially protect prisoners and staff from within-prison spread of TB and would significantly reduce the national burden of TB. Future studies should measure the impact of the conditions in prisons on TB transmission and assess the population attributable risk of prison-to-community spread. Please see later in the article for the Editors' Summary, Editors' Summary Background Every year, nearly 10 million people develop tuberculosis (TB)—a contagious bacterial infection usually of the lungs—and nearly two million people die from the disease. TB is caused by Mycobacterium tuberculosis, which spreads in airborne droplets when people with the disease cough or sneeze. Most people infected with M. tuberculosis never become ill—their immune system contains the infection. However, the bacteria remain dormant (latent) within the body, and a latent TB infection (LTBI) can cause active disease many years after the initial infection if host immunity declines. The symptoms of TB include a persistent cough, weight loss, and night sweats. Infection with M. tuberculosis can be diagnosed using the tuberculin skin test; tests for TB itself include chest X-rays and sputum cultures (in which bacteriologists try to grow M. tuberculosis from sputum samples, mucus brought up from the lungs by coughing). TB can usually be cured by taking several powerful antibiotics daily for several months. Why Was This Study Done? Last century, global control efforts began to reduce the incidence (number of new cases in a population in a given time) and prevalence (the number of affected people in a population) of LTBI and TB in many countries. Now, the emergence of antibiotic-resistant bacterial strains is thwarting these efforts. Consequently, it is important to identify settings where TB transmission is particularly high. One such setting is thought to be prisons. In these facilities, overcrowding, late case detection, inadequate treatment, and poor implementation of infection control measures (including incomplete segregation of people with active TB) might increase the TB transmission rate. However, it is not known how many people in prison become infected with M. tuberculosis or develop TB each year compared to the general population nor what percentage of LTBI and TB in the general population is attributable to exposure to M. tuberculosis in prison (the population attributable fraction or PAF%). Here, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) to investigate the incidence of TB in prisons. What Did the Researchers Do and Find? The researchers identified 23 studies that reported the incidence of LTBI and/or TB in prisons among both staff and prisoners. They estimated the incidence of TB in relevant general populations using World Health Organization data; estimates of the incidence of LTBI in the general population came from the studies themselves. The researchers then calculated the ratio between the incidence rates for LTBI and TB in prison and in the general population (incidence rate ratios or IRRs) for each study. For both LTBI and TB, the IRR varied widely between studies. The average IRR for LTBI was 26.4. That is, the average incidence of LTBI in prisons was 26.4 times higher than in the general population; the average IRR for TB was 23.0. The researchers also estimated the fraction of TB in the general population attributable to within-prison exposure to M. tuberculosis for each study. Again, there was considerable heterogeneity between the studies but, on average, the PAF% for TB in high-income countries was 8.5% (that is, one in 11 cases of TB in the general population was attributable to within-prison spread of TB); in middle-to-low–income countries, the average PAF% was 6.3%. What Do These Findings Mean? These findings suggest that the risk of LTBI and TB is at least an order of magnitude higher in prisons than in the general population and that the within-prison spread of LTBI and TB is likely to substantially affect the incidence of LTBI and TB in the general population. The accuracy and generalizability of these findings are limited by the small number of studies identified, by the relative paucity of studies from countries other than the USA, by study heterogeneity, and by assumptions made in the calculation of PAF%. Even so, these findings suggest that improvements in TB control in prisons would not only help to protect prisoners and staff from within-prison spread of TB but would also reduce national TB burdens. Further studies are now needed to identify the specific conditions in prisons that influence TB transmission so that rational policies can be developed to improve TB control in correctional facilities. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000381. This study is discussed in the December 2010 PLoS Medicine Editorial The World Health Organization provides information on all aspects of TB, including information on TB in prisons and on the Stop TB Partnership (some information is in several languages) The US Centers for Disease Control and Prevention has information about TB and on TB in prisons The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of TB

Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4–15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the “mysterious disease” because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge., Author Summary Buruli ulcer (BU) is a serious necrotizing cutaneous infection caused by Mycobacterium ulcerans. It is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis (TB). Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. BU is a disease found in rural areas located near wetlands (ponds, swamps, marshes, impoundments, backwaters) and slow-moving rivers, especially in areas prone to human-made disturbance and flooding. Despite considerable research on this disease in recent years, the mode of transmission remains unclear, although several hypotheses have been proposed. In this article we review the current state of knowledge on the ecology and transmission of M. ulcerans in Africa and Australia, discuss traditional and non-traditional methods for investigating transmission, and suggest an intellectual framework for establishing criteria for transmission.

BCG vaccine drives a strong T helper 1 cellular immunity which is essential for the protection against mycobacteria, however recent studies suggest that BCG vaccination can have non-specific beneficial effects unrelated to tuberculosis. In the present cohort study the development of cytokine profiles following BCG vaccination was investigated. Immune responses to PPD were assessed before vaccination and at ages of 5 months, 1 year, and 2 years, followed by BCG scar measurement at 4 years of age. BCG was shown to induce both Th1 and Th2 type responses against PPD at about 5 months of age after vaccination, and while Th1 response was sustained, Th2 responses declined over time. However, BCG scar size was strongly correlated with Th2 responses to PPD at 5 months of age. Importantly, we observed no clear effects of BCG vaccination on innate immune responses in terms of early IL-10 or TNF-alpha production whereas some alterations in general adaptive immune responses to PHA were observed.

Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A (S. Typhi and S. Paratyphi A) remains a major public health problem in many settings. The disease is limited to locations with poor sanitation which facilitates the transmission of the infecting organisms. Efficacious and inexpensive vaccines are available for S. Typhi, yet are not commonly deployed to control the disease. Lack of vaccination is due partly to uncertainty of the disease burden arising from a paucity of epidemiological information in key locations. We have collected and analyzed data from 3,898 cases of blood culture-confirmed enteric fever from Patan Hospital in Lalitpur Sub-Metropolitan City (LSMC), between June 2005 and May 2009. Demographic data was available for a subset of these patients (n = 527) that were resident in LSMC and who were enrolled in trials. We show a considerable burden of enteric fever caused by S. Typhi (2,672; 68.5%) and S. Paratyphi A (1,226; 31.5%) at this Hospital over a four year period, which correlate with seasonal fluctuations in rainfall. We found that local population density was not related to incidence and we identified a focus of infections in the east of LSMC. With data from patients resident in LSMC we found that the median age of those with S. Typhi (16 years) was significantly less than S. Paratyphi A (20 years) and that males aged 15 to 25 were disproportionately infected. Our findings provide a snapshot into the epidemiological patterns of enteric fever in Kathmandu. The uneven distribution of enteric fever patients within the population suggests local variation in risk factors, such as contaminated drinking water. These findings are important for initiating a vaccination scheme and improvements in sanitation. We suggest any such intervention should be implemented throughout the LSMC area.

Early data from the 2009 H1N1 pandemic (H1N1pdm) suggest that previous studies over-estimated the within-country rate of spatial spread of pandemic influenza. As large spatially resolved data sets are constructed, the need for efficient simulation code with which to investigate the spatial patterns of the pandemic becomes clear. Here, we present a significant improvement to the efficiency of an individual based stochastic disease simulation framework commonly used in multiple previous studies. We quantify the efficiency of the revised algorithm and present an alternative parameterization of the model in terms of the basic reproductive number. We apply the model to the population of Taiwan and demonstrate how the location of the initial seed can influence spatial incidence profiles and the overall spread of the epidemic. Differences in incidence are driven by the relative connectivity of alternate seed locations. The ability to perform efficient simulation allows us to run a batch of simulations and take account of their average in real time. The averaged data are stable and can be used to differentiate spreading patterns that are not readily seen by only conducting a few runs. © 2010 Tsai et al., published_or_final_version

Background Facemasks and respirators have been stockpiled during pandemic preparedness. However, data on their effectiveness for limiting transmission are scarce. We evaluated the effectiveness of facemask use by index cases for limiting influenza transmission by large droplets produced during coughing in households. Methodology and principal findings A cluster randomized intervention trial was conducted in France during the 2008-2009 influenza season. Households were recruited during a medical visit of a household member with a positive rapid influenza A test and symptoms lasting less than 48 hours. Households were randomized either to the mask or control group for 7 days. In the intervention arm, the index case had to wear a surgical mask from the medical visit and for a period of 5 days. The trial was initially intended to include 372 households but was prematurely interrupted after the inclusion of 105 households (306 contacts) following the advice of an independent steering committee. We used generalized estimating equations to test the association between the intervention and the proportion of household contacts who developed an influenza-like illness during the 7 days following the inclusion. Influenza-like illness was reported in 24/148 (16.2%) of the contacts in the intervention arm and in 25/158 (15.8%) of the contacts in the control arm and the difference between arms was 0.40% (95%CI: -10% to 11%, P = 1.00). We observed a good adherence to the intervention. In various sensitivity analyses, we did not identify any trend in the results suggesting effectiveness of facemasks. Conclusion This study should be interpreted with caution since the lack of statistical power prevents us to draw formal conclusion regarding effectiveness of facemasks in the context of a seasonal epidemic. Trial registration clinicaltrials.gov NCT00774774.

Background Mass drug administration (MDA) is part of the current trachoma control strategy, but it can be costly and results in many uninfected individuals receiving treatment. Here we explore whether alternative, targeted approaches are effective antibiotic-sparing strategies. Methodology/Principal Findings We analysed data on the prevalence of ocular infection with Chlamydia trachomatis and of active trachoma disease among 4,436 individuals from two communities in The Gambia (West Africa) and two communities in Tanzania (East Africa). An age- and household-structured mathematical model of transmission was fitted to these data using maximum likelihood. The presence of active inflammatory disease as a marker of infection in a household was, in general, significantly more sensitive (between 79% [95%CI: 60%–92%] and 86% [71%–95%] across the four communities) than as a marker of infection in an individual (24% [16%–33%]–66% [56%–76%]). Model simulations, under the best fit models for each community, showed that targeting treatment to households has the potential to be as effective as and significantly more cost-effective than mass treatment when antibiotics are not donated. The cost (2007US$) per incident infection averted ranged from 1.5 to 3.1 for MDA, from 1.0 to 1.7 for household-targeted treatment assuming equivalent coverage, and from 0.4 to 1.7 if household visits increased treatment coverage to 100% in selected households. Assuming antibiotics were donated, MDA was predicted to be more cost-effective unless opportunity costs incurred by individuals collecting antibiotics were included or household visits improved treatment uptake. Limiting MDA to children was not as effective in reducing infection as the other aforementioned distribution strategies. Conclusions/Significance Our model suggests that targeting antibiotics to households with active trachoma has the potential to be a cost-effective trachoma control measure, but further work is required to assess if costs can be reduced and to what extent the approach can increase the treatment coverage of infected individuals compared to MDA in different settings., Author Summary Repeated ocular infection with the bacterium Chlamydia trachomatis leads to the development of trachoma, a major cause of infectious blindness worldwide. Mass distribution of antibiotics, a component of the current trachoma control strategy, has had success in reducing infection in some areas, but results in a large number of uninfected people receiving antibiotics. We have previously shown that transmission of the bacteria between people in the same household is very efficient. Here, we investigated the effectiveness and cost-effectiveness of targeting antibiotics to households with active trachoma (inflammatory disease) compared to mass distribution, using data from four trachoma-endemic populations and a mathematical model of transmission. We found a high correspondence between households with active trachoma and infected households. In all populations the household targeted approach was predicted to be as effective as mass distribution, but it reduced the number of uninfected individuals receiving antibiotics, making the targeted strategy more cost-effective when antibiotics are not donated. Assuming antibiotics are donated, we predicted the targeted strategy to be more cost effective if it increases the proportion of infected individuals receiving treatment. Further work to address the feasibility and the cost variability in implementing the targeted approach in different settings is now required.

Background: Detailed analysis of the dynamic interactions among biological, environmental, social, and economic factors that favour the spread of certain diseases is extremely useful for designing effective control strategies. Diseases like tuberculosis that kills somebody every 15 seconds in the world, require methods that take into account the disease dynamics to design truly efficient control and surveillance strategies. The usual and well established statistical approaches provide insights into the cause-effect relationships that favour disease transmission but they only estimate risk areas, spatial or temporal trends. Here we introduce a novel approach that allows figuring out the dynamical behaviour of the disease spreading. This information can subsequently be used to validate mathematical models of the dissemination process from which the underlying mechanisms that are responsible for this spreading could be inferred. Methodology/Principal Findings: The method presented here is based on the analysis of the spread of tuberculosis in a Brazilian endemic city during five consecutive years. The detailed analysis of the spatio-temporal correlation of the yearly geo-referenced data, using different characteristic times of the disease evolution, allowed us to trace the temporal path of the aetiological agent, to locate the sources of infection, and to characterize the dynamics of disease spreading. Consequently, the method also allowed for the identification of socio-economic factors that influence the process. Conclusions/Significance: The information obtained can contribute to more effective budget allocation, drug distribution and recruitment of human skilled resources, as well as guiding the design of vaccination programs. We propose that this novel strategy can also be applied to the evaluation of other diseases as well as other social processes. © 2010 Zorzenon dos Santos et al. Fil: Zorzenon dos Santos, Rita M.. Universidade Federal de Pernambuco; Brasil Fil: Amador, Ana. Universidade Federal de Pernambuco; Brasil. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina Fil: de Souza, Wayner V.. Fundación Oswaldo Cruz; Brasil Fil: de Albuquerque, Maria Fatima P. M.. Universidade Federal de Pernambuco; Brasil. Fundación Oswaldo Cruz; Brasil Fil: Ponce Dawson, Silvina Martha. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina Fil: Ruffino-Netto, Antonio. Universidade de Sao Paulo; Brasil Fil: Zárate-Bladés, Carlos R.. Universidade de Sao Paulo; Brasil Fil: Silva, Celio L.. Universidade de Sao Paulo; Brasil

Background To evaluate the type and frequency of antiretroviral drug stock-outs, and their impact on death and interruption in care among HIV-infected patients in Abidjan, Côte d'Ivoire. Methods and Findings We conducted a cohort study of patients who initiated combination antiretroviral therapy (cART) in three adult HIV clinics between February 1, 2006 and June 1, 2007. Follow-up ended on February 1, 2008. The primary outcome was cART regimen modification, defined as at least one drug substitution, or discontinuation for at least one month due to drug stock-outs at the clinic pharmacy. The secondary outcome for patients who were on cART for at least six months was interruption in care, or death. A Cox regression model with time-dependent variables was used to assess the impact of antiretroviral drug stock-outs on interruption in care or death. Overall, 1,554 adults initiated cART and were followed for a mean of 13.2 months. During this time, 72 patients discontinued treatment and 98 modified their regimen because of drug stock-outs. Stock-outs involved nevirapine and fixed-dose combination zidovudine/lamivudine in 27% and 51% of cases. Of 1,554 patients, 839 (54%) initiated cART with fixed-dose stavudine/lamivudine/nevirapine and did not face stock-outs during the study period. Among the 975 patients who were on cART for at least six months, stock-out-related cART discontinuations increased the risk of interruption in care or death (adjusted hazard ratio [HR], 2.83; 95%CI, 1.25–6.44) but cART modifications did not (adjusted HR, 1.21; 95%CI, 0.46–3.16). Conclusions cART stock-outs affected at least 11% of population on treatment. Treatment discontinuations due to stock-outs were frequent and doubled the risk of interruption in care or death. These stock-outs did not involve the most common first-line regimen. As access to cART continues to increase in sub-Saharan Africa, first-line regimens should be standardized to decrease the probability of drug stock-outs.