Prevalence and Risk Factors of Lassa Seropositivity in Inhabitants of the Forest Region of Guinea: A Cross-Sectional Study

Background

Lassa fever is a viral hemorrhagic fever endemic in West Africa. The reservoir host of the virus is a multimammate rat, Mastomys natalensis. Prevalence estimates of Lassa virus antibodies in humans vary greatly between studies, and the main modes of transmission of the virus from rodents to humans remain unclear. We aimed to (i) estimate the prevalence of Lassa virus–specific IgG antibodies (LV IgG) in the human population of a rural area of Guinea, and (ii) identify risk factors for positive LV IgG.

Methods and Findings

A population-based cross-sectional study design was used. In April 2000, all individuals one year of age and older living in three prefectures located in the tropical secondary forest area of Guinea (Gueckedou, Lola and Yomou) were sampled using two-stage cluster sampling. For each individual identified by the sampling procedure and who agreed to participate, a standardized questionnaire was completed to collect data on personal exposure to potential risk factors for Lassa fever (mainly contact with rodents), and a blood sample was tested for LV IgG. A multiple logistic regression model was used to determine risk factors for positive LV IgG. A total of 1424 subjects were interviewed and 977 sera were tested. Prevalence of positive LV Ig was of 12.9% [10.8%–15.0%] and 10.0% [8.1%–11.9%] in rural and urban areas, respectively. Two risk factors of positive LV IgG were identified: to have, in the past twelve months, undergone an injection (odds ratio [OR] = 1.8 [1.1–3.1]), or lived with someone displaying a haemorrhage (OR = 1.7 [1.1–2.9]). No factors related to contacts with rats and/or mice remained statistically significant in the multivariate analysis.

Conclusions

Our study underlines the potential importance of person-to-person transmission of Lassa fever, via close contact in the same household or nosocomial exposure.     

Molecular Diagnostics for Lassa Fever at Irrua Specialist Teaching Hospital,Nigeria: Lessons Learnt from Two Years of Laboratory Operation

Background

Lassa fever is a viral hemorrhagic fever endemic in West Africa. However, none of the hospitals in the endemic areas of Nigeria has the capacity to perform Lassa virus diagnostics. Case identification and management solely relies on non-specific clinical criteria. The Irrua Specialist Teaching Hospital (ISTH) in the central senatorial district of Edo State struggled with this challenge for many years.

Methodology/Principal Findings

A laboratory for molecular diagnosis of Lassa fever, complying with basic standards of diagnostic PCR facilities, was established at ISTH in 2008. During 2009 through 2010, samples of 1,650 suspected cases were processed, of which 198 (12%) tested positive by Lassa virus RT-PCR. No remarkable demographic differences were observed between PCR-positive and negative patients. The case fatality rate for Lassa fever was 31%. Nearly two thirds of confirmed cases attended the emergency departments of ISTH. The time window for therapeutic intervention was extremely short, as 50% of the fatal cases died within 2 days of hospitalization—often before ribavirin treatment could be commenced. Fatal Lassa fever cases were older (p = 0.005), had lower body temperature (p<0.0001), and had higher creatinine (p<0.0001) and blood urea levels (p<0.0001) than survivors. Lassa fever incidence in the hospital followed a seasonal pattern with a peak between November and March. Lassa virus sequences obtained from the patients originating from Edo State formed—within lineage II—a separate clade that could be further subdivided into three clusters.

Conclusions/Significance

Lassa fever case management was improved at a tertiary health institution in Nigeria through establishment of a laboratory for routine diagnostics of Lassa virus. Data collected in two years of operation demonstrate that Lassa fever is a serious public health problem in Edo State and reveal new insights into the disease in hospitalized patients.     

Cost-Effectiveness of an Intervention to Reduce Emergency Re-Admissions to Hospital among Older Patients

Background

The objective is to estimate the cost-effectiveness of an intervention that reduces hospital re-admission among older people at high risk. A cost-effectiveness model to estimate the costs and health benefits of the intervention was implemented.

Methodology/Principal Findings

The model used data from a randomised controlled trial conducted in an Australian tertiary metropolitan hospital. Participants were acute medical admissions aged >65 years with at least one risk factor for re-admission: multiple comorbidities, impaired functionality, aged >75 years, recent multiple admissions, poor social support, history of depression. The intervention was a comprehensive nursing and physiotherapy assessment and an individually tailored program of exercise strategies and nurse home visits with telephone follow-up; commencing in hospital and continuing following discharge for 24 weeks. The change to cost outcomes, including the costs of implementing the intervention and all subsequent use of health care services, and, the change to health benefits, represented by quality adjusted life years, were estimated for the intervention as compared to existing practice. The mean change to total costs and quality adjusted life years for an average individual over 24 weeks participating in the intervention were: cost savings of $333 (95% Bayesian credible interval $ -1,932∶1,282) and 0.118 extra quality adjusted life years (95% Bayesian credible interval 0.1∶0.136). The mean net-monetary-benefit per individual for the intervention group compared to the usual care condition was $7,907 (95% Bayesian credible interval $5,959∶$9,995) for the 24 week period.

Conclusions/Significance

The estimation model that describes this intervention predicts cost savings and improved health outcomes. A decision to remain with existing practices causes unnecessary costs and reduced health. Decision makers should consider adopting this program for elderly hospitalised patients.     

Massive Fluid Requirements and an Unusual BUN/Creatinine Ratio for Pre-Renal Failure in Patients with Cholera

Background

Cholera is an important infectious cause of secretory diarrhea. The primary symptom of infection is the sudden onset of watery diarrhea with subsequent volume depletion causing renal insufficiency. The objective of this research is to study the level of dehydration at presentation and subsequent fluid management in patients with cholera.

Methods

This study was conducted on 191 patients of Cholera admitted at a tertiary care hospital in Karachi, Pakistan during the period of 5 years. Medical charts were evaluated retrospectively for initial hydration status, baseline lab investigations on admission and discharge and fluid therapy given to all the patients while their stay in the hospital and the data was analyzed on SPSS 15.0.

Results

Out of the 191 patients, 83(43%) were males and 108 (57%) were females with mean age of 42.3 years (SD±18.34). The average duration of symptoms was 3.75 days (SD±2.04). Of 191 patients, 175 (92.1%) presented with dehydration, 80 (42.3%) were given Ringer''s Lactate (R/L) + Normal Saline (N/S), 45 (24%) patients were given R/L + N/S + Oral Rehydration Therapy (ORS), 27 (14.3%) of the patients were kept on R/L only and remaining were given various combinations of R/L, N/S, ORS and Dextrose Saline (D/S). On admission mean Blood Urea Nitrogen (BUN) was 24.54 (SD±16.6), mean creatinine was 2.47 (SD±2.35) and mean BUN/Creatinine ratio was 11.63 (SD±5.7).

Conclusion

Aggressive fluid rehydration remains the cornerstone of management of cholera. Instead of presenting with a classical BUN/Creatinine ratio of >20∶1, patients with pre-renal failure in cholera may present with a BUN/Creatinine ratio of <15∶1.     

When Can Antibiotic Treatments for Trachoma Be Discontinued? Graduating Communities in Three African Countries

Background

Repeated mass azithromycin distributions are effective in controlling the ocular strains of chlamydia that cause trachoma. However, it is unclear when treatments can be discontinued. Investigators have proposed graduating communities when the prevalence of infection identified in children decreases below a threshold. While this can be tested empirically, results will not be available for years. Here we use a mathematical model to predict results with different graduation strategies in three African countries.

Methods

A stochastic model of trachoma transmission was constructed, using the parameters with the maximum likelihood of obtaining results observed from studies in Tanzania (with 16% infection in children pre-treatment), The Gambia (9%), and Ethiopia (64%). The expected prevalence of infection at 3 years was obtained, given different thresholds for graduation and varying the characteristics of the diagnostic test.

Results

The model projects that three annual treatments at 80% coverage would reduce the mean prevalence of infection to 0.03% in Tanzanian, 2.4% in Gambian, and 12.9% in the Ethiopian communities. If communities graduate when the prevalence of infection falls below 5%, then the mean prevalence at 3 years with the new strategy would be 0.3%, 3.9%, and 14.4%, respectively. Graduations reduced antibiotic usage by 63% in Tanzania, 56% in The Gambia, and 11% in Ethiopia.

Conclusion

Models suggest that graduating communities from a program when the infection is reduced to 5% is a reasonable strategy and could reduce the amount of antibiotic distributed in some areas by more than 2-fold.     

Task Shifting Routine Inpatient Pediatric HIV Testing Improves Program Outcomes in Urban Malawi: A Retrospective Observational Study

Background

This study evaluated two models of routine HIV testing of hospitalized children in a high HIV-prevalence resource-constrained African setting. Both models incorporated “task shifting,” or the allocation of tasks to the least-costly, capable health worker.

Methods and Findings

Two models were piloted for three months each within the pediatric department of a referral hospital in Lilongwe, Malawi between January 1 and June 30, 2008. Model 1 utilized lay counselors for HIV testing instead of nurses and clinicians. Model 2 further shifted program flow and advocacy responsibilities from counselors to volunteer parents of HIV-infected children, called “patient escorts.” A retrospective review of data from 6318 hospitalized children offered HIV testing between January-December 2008 was conducted. The pilot quarters of Model 1 and Model 2 were compared, with Model 2 selected to continue after the pilot period. There was a 2-fold increase in patients offered HIV testing with Model 2 compared with Model 1 (43.1% vs 19.9%, p<0.001). Furthermore, patients in Model 2 were younger (17.3 vs 26.7 months, p<0.001) and tested sooner after admission (1.77 vs 2.44 days, p<0.001). There were no differences in test acceptance or enrollment rates into HIV care, and the program trends continued 6 months after the pilot period. Overall, 10244 HIV antibody tests (4779 maternal; 5465 child) and 453 DNA-PCR tests were completed, with 97.8% accepting testing. 19.6% of all mothers (n = 1112) and 8.5% of all children (n = 525) were HIV-infected. Furthermore, 6.5% of children were HIV-exposed (n = 405). Cumulatively, 72.9% (n = 678) of eligible children were evaluated in the hospital by a HIV-trained clinician, and 68.3% (n = 387) successfully enrolled into outpatient HIV care.

Conclusions/Significance

The strategy presented here, task shifting from lay counselors alone to lay counselors and patient escorts, greatly improved program outcomes while only marginally increasing operational costs. The wider implementation of this strategy could accelerate pediatric HIV care access in high-prevalence settings.     

Successional Change in Phosphorus Stoichiometry Explains the Inverse Relationship between Herbivory and Lupin Density on Mount St. Helens

Background

The average nitrogen-to-phosphorus ratio (N∶P) of insect herbivores is less than that of leaves, suggesting that P may mediate plant-insect interactions more often than appreciated. We investigated whether succession-related heterogeneity in N and P stoichiometry influences herbivore performance on N-fixing lupin (Lupinus lepidus) colonizing primary successional volcanic surfaces, where the abundances of several specialist lepidopteran herbivores are inversely related to lupin density and are known to alter lupin colonization dynamics. We examined larval performance in response to leaf nutritional characteristics using gelechiid and pyralid leaf-tiers, and a noctuid leaf-cutter.

Methodology/Principal Findings

We conducted four studies. First, growth of larvae raised on wild-collected leaves responded positively to leaf %P and negatively to leaf carbon (%C), but there was no effect of %N or quinolizidine alkaloids (QAs). Noctuid survival was also positively related to %P. Second, we raised gelechiid larvae on greenhouse-grown lupins with factorial manipulation of competitors and soil N and P. In the presence of competition, larval mass was highest at intermediate leaf N∶P and high %P. Third, survival of gelechiid larvae placed on lupins in high-density patches was greater when plant competitors were removed than on controls. Fourth, surveys of field-collected leaves in 2000, 2002, and 2003 indicated that both %P and %N were generally greater in plants from low-density areas. QAs in plants from low-density areas were equal to or higher than QAs in high-density areas.

Conclusions/Significance

Our results demonstrate that declines in lupin P content under competitive conditions are associated with decreased larval growth and survival sufficient to cause the observed negative relationship between herbivore abundance and host density. The results support the theoretical finding that declines in stoichiometric resource quality (caused here by succession) have the potential to cause a decrease in consumer abundance despite very dense quantities of the resource.     

Clinical and Epidemiological Features of Typhoid Fever in Pemba,Zanzibar: Assessment of the Performance of the WHO Case Definitions

Background

The gold standard for diagnosis of typhoid fever is blood culture (BC). Because blood culture is often not available in impoverished settings it would be helpful to have alternative diagnostic approaches. We therefore investigated the usefulness of clinical signs, WHO case definition and Widal test for the diagnosis of typhoid fever.

Methodology/Principal Findings

Participants with a body temperature ≥37.5°C or a history of fever were enrolled over 17 to 22 months in three hospitals on Pemba Island, Tanzania. Clinical signs and symptoms of participants upon presentation as well as blood and serum for BC and Widal testing were collected. Clinical signs and symptoms of typhoid fever cases were compared to other cases of invasive bacterial diseases and BC negative participants. The relationship of typhoid fever cases with rainfall, temperature, and religious festivals was explored. The performance of the WHO case definitions for suspected and probable typhoid fever and a local cut off titre for the Widal test was assessed. 79 of 2209 participants had invasive bacterial disease. 46 isolates were identified as typhoid fever. Apart from a longer duration of fever prior to admission clinical signs and symptoms were not significantly different among patients with typhoid fever than from other febrile patients. We did not detect any significant seasonal patterns nor correlation with rainfall or festivals. The sensitivity and specificity of the WHO case definition for suspected and probable typhoid fever were 82.6% and 41.3% and 36.3 and 99.7% respectively. Sensitivity and specificity of the Widal test was 47.8% and 99.4 both forfor O-agglutinin and H- agglutinin at a cut-off titre of 1∶80.

Conclusions/Significance

Typhoid fever prevalence rates on Pemba are high and its clinical signs and symptoms are non-specific. The sensitivity of the Widal test is low and the WHO case definition performed better than the Widal test.     

IL-1β, IL-6, and RANTES as Biomarkers of Chikungunya Severity

Background

Little is known about the immunopathogenesis of Chikungunya virus. Circulating levels of immune mediators and growth factors were analyzed from patients infected during the first Singaporean Chikungunya fever outbreak in early 2008 to establish biomarkers associated with infection and/or disease severity.

Methods and Findings

Adult patients with laboratory-confirmed Chikungunya fever infection, who were referred to the Communicable Disease Centre/Tan Tock Seng Hospital during the period from January to February 2008, were included in this retrospective study. Plasma fractions were analyzed using a multiplex-microbead immunoassay. Among the patients, the most common clinical features were fever (100%), arthralgia (90%), rash (50%) and conjunctivitis (40%). Profiles of 30 cytokines, chemokines, and growth factors were able to discriminate the clinical forms of Chikungunya from healthy controls, with patients classified as non-severe and severe disease. Levels of 8 plasma cytokines and 4 growth factors were significantly elevated. Statistical analysis showed that an increase in IL-1β, IL-6 and a decrease in RANTES were associated with disease severity.

Conclusions

This is the first comprehensive report on the production of cytokines, chemokines, and growth factors during acute Chikungunya virus infection. Using these biomarkers, we were able to distinguish between mild disease and more severe forms of Chikungunya fever, thus enabling the identification of patients with poor prognosis and monitoring of the disease.     

Bone T-Scores and Functional Status: A Cross-Sectional Study on German Elderly

Background

We explore the association between bone T-scores, used in osteoporosis diagnosis, and functional status since we hypothesized that bone health can impact elderly functional status and indirectly independence.

Methods

In a cross-sectional study (2005–2006) on community dwelling elderly (> = 75 years) from Herne, Germany we measured bone T-scores with Dual-energy X-ray Absorptiometry, and functional status indexed by five geriatric tests: activities of daily living, instrumental activities of daily living, test of dementia, geriatric depression score and the timed-up-and-go test, and two pooled indexes: raw and standardized. Generalized linear regression was used to determine the relationship between T-scores and functional status.

Results

From 3243 addresses, only 632 (19%) completed a clinical visit, of which only 440 (male∶female, 243∶197) could be included in analysis. T-scores (−0.99, 95% confidence interval [CI], −1.1–0.9) predicted activities of daily living (95.3 CI, 94.5–96.2), instrumental activities of daily living (7.3 CI, 94.5–96.2), and timed-up-and-go test (10.7 CI, 10.0–11.3) (P< = 0.05). Pooled data showed that a unit improvement in T-score improved standardized pooled functional status (15 CI, 14.7–15.3) by 0.41 and the raw (99.4 CI, 97.8–101.0) by 2.27 units. These results were limited due to pooling of different scoring directions, selection bias, and a need to follow-up with evidence testing.

Conclusions

T-scores associated with lower functional status in community-dwelling elderly. Regular screening of osteoporosis as a preventive strategy might help maintain life quality with aging.     

Geographic Distribution and Genetic Characterization of Lassa Virus in Sub-Saharan Mali

Background

Lassa fever is an acute viral illness characterized by multi-organ failure and hemorrhagic manifestations. Lassa fever is most frequently diagnosed in Nigeria, Sierra Leone, Liberia, and Guinea, although sporadic cases have been recorded in other West African countries, including Mali. The etiological agent of Lassa fever is Lassa virus (LASV), an Arenavirus which is maintained in nature and frequently transmitted to humans by Mastomys natalensis. The purpose of this study was to better define the geographic distribution of LASV-infected rodents in sub-Saharan Mali.

Methodologies/Principal Findings

Small mammals were live-trapped at various locations across Mali for the purpose of identifying potential zoonotic pathogens. Serological and molecular assays were employed and determined LASV infected rodents were exclusively found in the southern Mali near the border of Côte d''Ivoire. Overall, 19.4% of Mastomys natalensis sampled in this region had evidence of LASV infection, with prevalence rates for individual villages ranging from 0 to 52%. Full-length genomic sequences were determined using high throughput sequencing methodologies for LASV isolates generated from tissue samples of rodents collected in four villages and confirmed the phylogenetic clustering of Malian LASV with strain AV.

Conclusions/Significance

The risk of human infections with LASV is greatest in villages in southern Mali. Lassa fever should be considered in the differential diagnosis for febrile individuals and appropriate diagnostic techniques need to be established to determine the incidence of infection and disease in these regions.     

Fulfilling the Promise of Personalized Medicine? Systematic Review and Field Synopsis of Pharmacogenetic Studies

Background

Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics).

Objectives

We conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research.

Data Sources

Original research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests.

Study Eligibility Criteria, Participants, and Intervention Criteria

We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans.

Study Appraisal and Synthesis Methods

Study characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study.

Results

From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25∶1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40–222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of ≥4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points.

Conclusions and Implications of Key Findings

The high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines.

Systematic Review Registration Number

Not Registered     

Early Experience in the Treatment of Intra-Cranial Aneurysms by Endovascular Flow Diversion: A Multicentre Prospective Study

Introduction

Flow diversion is a new approach to the endovascular treatment of intracranial aneurysms which uses a high density mesh stent to induce sac thrombosis. These devices have been designed for the treatment of complex shaped and large size aneurysms. So far published safety and efficacy data on this approach is sparse.

Material and Methods

Over 8 months, standardized clinical and angiographic data were collected on 70 patients treated with a flow diverter device (SILK flow diverter (SFD)) in 18 centres worldwide. Treatment and early follow up details were audited centrally. SFDs were deployed alone in 57 (81%) or with endosaccular coils in 10 (14%) aneurysms, which included: 44 (63%) saccular, 26 (37%) fusiform shapes and 18 (26%) small, 37 (53%) large, 15 (21%) giant sizes. Treatment outcome data up to 30 days were reported for all patients, with clinical (50 patients) and imaging (49 patients) follow up (median 119 days) data available.

Results

Difficulties in SFD deployment were reported in 15 (21%) and parent artery thrombosis in 8 (11%) procedures. Procedural complications caused stroke in 1 and serious extracranial bleeding in 3 patients; 2 of whom developed fatal pneumonias. Delayed worsening of symptoms occurred in 5 patients (3 transient, 1 permanent neurological deficit, and 1 death) and fatal aneurysm bleeding in 1 patient. Overall permanent morbidity rates were 2 (4%) and mortality 4 (8%). Statistical analysis revealed no significant association between complications and variables related to treated aneurysm morphology or rupture status.

Conclusion

This series is the largest reporting outcome of the new treatment approach and provides data for future study design. Procedural difficulties in SFD deployment were frequent and anti-thrombosis prophylaxis appears to reduce the resulting clinical sequelae, but at the cost of morbidity due to extracranial bleeding. Delayed morbidity appears to be a consequence of the new approach and warrants care in selecting patients for treatment and future larger studies.     

Early clinical manifestations associated with death from visceral leishmaniasis

Background

In Brazil, lethality from visceral leishmaniasis (VL) is high and few studies have addressed prognostic factors. This historical cohort study was designed to investigate the prognostic factors for death from VL in Belo Horizonte (Brazil).

Methodology

The analysis was based on data of the Reportable Disease Information System-SINAN (Brazilian Ministry of Health) relating to the clinical manifestations of the disease. During the study period (2002–2009), the SINAN changed platform from a Windows to a Net-version that differed with respect to some of the parameters collected. Multivariate logistic regression models were performed to identify variables associated with death from VL, and these were included in prognostic score.

Principal Findings

Model 1 (period 2002–2009; 111 deaths from VL and 777 cured patients) included the variables present in both SINAN versions, whereas Model 2 (period 2007–2009; 49 deaths from VL and 327 cured patients) included variables common to both SINAN versions plus the additional variables included in the Net version. In Model 1, the variables significantly associated with a greater risk of death from VL were weakness (OR 2.9; 95%CI 1.3–6.4), Leishmania-HIV co-infection (OR 2.4; 95%CI 1.2–4.8) and age ≥60 years (OR 2.5; 95%CI 1.5–4.3). In Model 2, the variables were bleeding (OR 3.5; 95%CI 1.2–10.3), other associated infections (OR 3.2; 95%CI 1.3–7.8), jaundice (OR 10.1; 95%CI 3.7–27.2) and age ≥60 years (OR 3.1; 95%CI 1.4–7.1). The prognosis score was developed using the variables associated with death from VL of the latest version of the SINAN (Model 2). The predictive performance of which was evaluated by sensitivity (71.4%), specificity (73.7%), positive and negative predictive values (28.9% and 94.5%) and area under the receiver operating characteristic curve (75.6%).

Conclusions

Knowledge regarding the factors associated with death from VL may improve clinical management of patients and contribute to lower mortality.     

Reductions in the Prevalence and Incidence of Geohelminth Infections following a City-wide Sanitation Program in a Brazilian Urban Centre

Objective

In the city of Salvador, a large urban centre in Northeast Brazil, a city-wide sanitation intervention started in 1997, aimed at improving the sewerage coverage of households from 26% to 80%. Our aim was to study the impact of the intervention on the prevalence and incidence of geohelminths in the school-aged population.

Methods

The study comprised two comparable cohorts: the first assembled in 1997, before the intervention, and the second assembled in 2003, after the intervention. Both were sampled from 24 sentinel areas chosen to represent the different environmental conditions throughout the city. Copro-parasitological examinations were carried out on every individual from both cohorts, at baseline and nine months later. Demographic, socio-economic, and environmental data were collected using semi-structured questionnaires and environmental surveys. A hierarchical modelling approach fitting a sequence of Poisson multivariate linear models was undertaken to test the effect of the intervention variables on the prevalence and incidence rate ratios.

Findings

729 and 890 children aged 7–14 years (mean = 10.4 y, SD = 0.05 y) were analysed over the first and the second cohorts, respectively. The adjusted reductions of the prevalence and incidence rates at the second in relation to the first cohort were 27% and 34%, 25% and 32%, 33% and 26%, and 82% and 42% for geohelminths overall, Ascaris lumbricoides, Trichuris trichiura, and hookworm, respectively. Hierarchical modelling showed that a major part of each of these reductions was explained by the intervention.

Conclusion

Our results show that a city-wide sanitation program may reduce significantly the prevalence and incidence of geohelminths.     

Demographic and Clinical Features of Dengue Fever in Pakistan from 2003–2007: A Retrospective Cross-Sectional Study

Background

Demographic features of dengue fever have changed tremendously in Pakistan over the past two decades. Small scale studies from all over the country have reported different aspects of individual outbreaks during this time. However, there is scarcity of data looking at the overall trend of dengue virus infection in the country. In this study, we examined annual trends, seasonality, and clinical features of dengue fever in the Pakistani population.

Methods

Demographic information and dengue IgM status of all patients tested for dengue IgM antibody at Aga Khan University Hospital from January 2003 to December 2007 were analyzed to look for trends of IgM-positive cases in Pakistan. In addition, clinical and biochemical parameters were abstracted retrospectively from medical records of all patients hospitalized with IgM-proven dengue fever between January 2006 and December 2007. These patients were categorized into dengue fever and dengue hemorrhagic fever according to the WHO severity grading scale.

Results

Out of a total of 15040 patients (63.2% male and 36.8% female), 3952 (26.3%) tested positive for dengue IgM antibody. 209 IgM proven dengue patients were hospitalized during the study period. During 2003, IgM positive cases were seen only during the months of July-December. In contrast, such cases were detected throughout the year from the 2004–2007. The median age of IgM positive patients decreased every year from 32.0 years in 2003 to 24.0 years in 2007 (p<0.001). Among hospitalized patients, nausea was the most common presenting feature found in 124/209 (59.3%) patients. Children presented with a higher median body temperature than adults (p = 0.010). In addition, neutropenia was seen more commonly in children while raised serum ALT levels were seen more commonly in adults (both p = 0.006). While a low total white cell count was more common in patients with dengue fever as compared to Dengue Hemorrhagic Fever (p = 0.020), neutropenia (p = 0.019), monocytosis (p = 0.001) and raised serum ALT level (p = 0.005) were observed more commonly in the latter group.

Conclusions

Dengue virus is now endemic in Pakistan, circulating throughout the year with a peak incidence in the post monsoon period. Median age of dengue patients has decreased and younger patients may be more susceptible. Total and differential leukocyte counts may help identify patients at risk of hemorrhage.     

Evaluation of RTS,S/AS02A and RTS,S/AS01B in Adults in a High Malaria Transmission Area

Background

This study advances the clinical development of the RTS,S/AS01B candidate malaria vaccine to malaria endemic populations. As a primary objective it compares the safety and reactogenicity of RTS,S/AS01B to the more extensively evaluated RTS,S/AS02A vaccine.

Methodology

A Phase IIb, single centre, double-blind, controlled trial of 6 months duration with a subsequent 6 month single-blind follow-up conducted in Kisumu West District, Kenya between August 2005 and August 2006. 255 healthy adults aged 18 to 35 years were randomized (1∶1∶1) to receive 3 doses of RTS,S/AS02A, RTS,S/AS01B or rabies vaccine (Rabipur®; Chiron Behring GmbH) at months 0, 1, 2. The primary objective was the occurrence of severe (grade 3) solicited or unsolicited general (i.e. systemic) adverse events (AEs) during 7 days follow up after each vaccination.

Principal Findings

Both candidate vaccines had a good safety profile and were well tolerated. One grade 3 systemic AE occurred within 7 days of vaccination (RTS,S/AS01B group). No unsolicited AEs or SAEs were related to vaccine. A marked increase in anti-CS antibody GMTs was observed post Dose 2 of both RTS,S/AS01B (31.6 EU/mL [95% CI: 23.9 to 41.6]) and RTS,S/AS02A (16.7 EU/mL [95% CI: 12.9 to 21.7]). A further increase was observed post Dose 3 in both the RTS,S/AS01B (41.4 EU/mL [95% CI: 31.7 to 54.2]) and RTS,S/AS02A (21.4 EU/mL [95% CI: 16.0 to 28.7]) groups. Anti-CS antibody GMTs were significantly greater with RTS,S/AS01B compared to RTS,S/AS02A at all time points post Dose 2 and Dose 3. Both candidate vaccines produced strong anti-HBs responses. Vaccine efficacy in the RTS,S/AS01B group was 29.5% (95% CI: −15.4 to 56.9, p = 0.164) and in the RTS,S/AS02A group 31.7% (95% CI: −11.6 to 58.2, p = 0.128).

Conclusions

Both candidate malaria vaccines were well tolerated over a 12 month surveillance period. A more favorable immunogenicity profile was observed with RTS,S/AS01B than with RTS,S/AS02A.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00197054","term_id":"NCT00197054"}}NCT00197054     

Changing Epidemiology of Serious Bacterial Infections in Febrile Infants without Localizing Signs

Objective

Historically, management of infants with fever without localizing signs (FWLS) has generated much controversy, with attempts to risk stratify based on several criteria. Advances in medical practice may have altered the epidemiology of serious bacterial infections (SBIs) in this population. We conducted this study to test the hypothesis that the rate of SBIs in this patient population has changed over time.

Patients and Methods

We performed a retrospective review of all infants meeting FWLS criteria at our institution from 1997–2006. We examined all clinical and outcome data and performed statistical analysis of SBI rates and ampicillin resistance rates.

Results

668 infants met criteria for FWLS. The overall rate of SBIs was 10.8%, with a significant increase from 2002–2006 (52/361, 14.4%) compared to 1997–2001 (20/307, 6.5%) (p = 0.001). This increase was driven by an increase in E. coli urinary tract infections (UTI), particularly in older infants (31–90 days).

Conclusions

We observed a significant increase in E. coli UTI among FWLS infants with high rates of ampicillin resistance. The reasons are likely to be multifactorial, but the results themselves emphasize the need to examine urine in all febrile infants <90days and consider local resistance patterns when choosing empiric antibiotics.     

Redox-Sensitive Induction of Src/PI3-kinase/Akt and MAPKs Pathways Activate eNOS in Response to EPA:DHA 6:1

Aims

Omega-3 fatty acid products containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have vasoprotective effects, in part, by stimulating the endothelial formation of nitric oxide (NO). This study determined the role of the EPA:DHA ratio and amount, and characterized the mechanism leading to endothelial NO synthase (eNOS) activation.

Methods and Results

EPA:DHA 6∶1 and 9∶1 caused significantly greater endothelium-dependent relaxations in porcine coronary artery rings than EPA:DHA 3∶1, 1∶1, 1∶3, 1∶6, 1∶9, EPA and DHA alone, and EPA:DHA 6∶1 with a reduced EPA + DHA amount, which were inhibited by an eNOS inhibitor. Relaxations to EPA:DHA 6∶1 were insensitive to cyclooxygenase inhibition, and reduced by inhibitors of either oxidative stress, Src kinase, PI3-kinase, p38 MAPK, MEK, or JNK. EPA:DHA 6∶1 induced phosphorylation of Src, Akt, p38 MAPK, ERK, JNK and eNOS; these effects were inhibited by MnTMPyP. EPA:DHA 6∶1 induced the endothelial formation of ROS in coronary artery sections as assessed by dihydroethidium, and of superoxide anions and hydrogen peroxide in cultured endothelial cells as assessed by electron spin resonance with the spin probe CMH, and the Amplex Red based assay, respectively.

Conclusion

Omega-3 fatty acids cause endothelium-dependent NO-mediated relaxations in coronary artery rings, which are dependent on the EPA:DHA ratio and amount, and involve an intracellular activation of the redox-sensitive PI3-kinase/Akt and MAPKs pathways to activate eNOS.