720 research outputs found
Data for: Oral versus Intravenous Antibiotics for Bone and Joint Infection – Randomised controlled trial
No full textThe management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. The OVIVA study investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication.
We collected data on 1054 adults treated for bone of joint infection at 26 UK centres.
Participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy.
The primary end point was definitive treatment failure within 1 year after randomisation. Additional data on clinical variables (including information on line complications, episodes of C-Diff), antibiotic use, clinical reviews, severe adverse events, inpatient admissions and patient reported outcomes (EQ-5D-3L and Oxford Hip Score/ Oxford Knee Score for participants with infections in their hips/ knees). </p
Replication Data for: Twenty-Seven Years of Clinical Surveillance of Severe Malaria in Kilifi County, Kenya
No full textThis dataset contains clinical data from 18,000 children with severe malaria admitted to Kilifi County Hospital, Kenya, during a 27-year period of reducing transmission. Data collection was done through continuous surveillance of hospital admissions is ongoing in KCH since May 1989 as a partnership between the Research Programme and Kilifi County Department of Health. The dataset also includes demographic characteristics and malaria control activities such as distributions of insecticide-treated bed nets. A more detailed description of the data collection methodology is included in the related publication. </p
Replication Data for: Twenty-Seven Years of Clinical Surveillance of Severe Malaria in Kilifi County, Kenya
No full textThis dataset contains clinical data from 18,000 children with severe malaria admitted to Kilifi County Hospital, Kenya, during a 27-year period of reducing transmission. Data collection was done through continuous surveillance of hospital admissions is ongoing in KCH since May 1989 as a partnership between the Research Programme and Kilifi County Department of Health. The dataset also includes demographic characteristics and malaria control activities such as distributions of insecticide-treated bed nets. A more detailed description of the data collection methodology is included in the related publication. </p
Associations between antibodies to a panel of Plasmodium falciparum specific antigens and response to sub-optimal antimalarial therapy in Kampala, Uganda.
No full textAntibodies are important in the control of blood stage Plasmodium falciparum infection. It is unclear which antibody responses are responsible for, or even associated with protection, partly due to confounding by heterogeneous exposure. Assessment of response to partially effective antimalarial therapy, which requires the host to assist in clearing parasites, offers an opportunity to measure protection independent of exposure.A cohort of children aged 1-10 years in Kampala, Uganda were treated with amodiaquine+sulfadoxine-pyrimethamine for uncomplicated malaria. Serum samples from the time of malaria diagnosis and 14 days later were analyzed for total IgG to 8 P. falciparum antigens using a quantitative indirect ELISA. Associations between antibody levels and risk of treatment failure were estimated using Cox proportional hazard regression.Higher levels of antibodies to apical membrane antigen 1 (AMA-1), but to none of the other 7 antigens were significantly associated with protection against treatment failure (HR 0.57 per 10-fold increase in antibody level, CI 0.41-0.79, p = 0.001). Protection increased consistently across the entire range of antibody levels.Measurement of antibody levels to AMA-1 at the time of malaria may offer a quantitative biomarker of blood stage immunity to P. falciparum, a tool which is currently lacking
Interactions between age and ITN use determine the risk of febrile malaria in children
No full textBackground: Control measures which reduce individual exposure to malaria are expected to reduce disease, but also to eventually reduce immunity. Reassuringly, long term data following community wide ITN distribution show sustained benefits at a population level. However, the more common practice in Sub-Saharan Africa is to target ITN distribution on young children. There are few data on the long term outcomes of this practice.Methodology/Principal Findings: Episodes of febrile malaria were identified by active surveillance in 383 children over 18 months of follow up. In order to compare the short and long term outcomes of ITN use, we examined interactions between ITN use and age (12-42 months of age versus 42-80 months) in determining the risk of febrile malaria. ITN use and older age protected against the first or only episode of malaria (Hazard Ratio [HR] =0.33, 95%CI 0.17-0.65 and HR =0.30, 95%CI0.17-0.51, respectively). The interaction term between ITN use and older age was HR =2.91, 95%CI 1.02-8.3, p=0.045, indicating that ITNs did not protect older children. When multiple episodes were included in analysis, ITN use and older age were again protective against malaria episodes (Incident Rate Ratio [IRR] =0.43 95%CI 0.27-0.7) and IRR = 0.23, 95%CI 0.13-0.42, respectively) and the interaction term indicated that ITNs did not protect older children (IRR =2.71, 95%CI 1.3-5.7, p=0.008). Conclusions/Significance: These data on age interactions with ITN use suggest that larger scale studies on the long term individual outcomes should be undertaken if the policy of targeted ITN use for vulnerable groups is to continue. © 2009 Bejon et al
Health facility data to describe the epidemiology of malaria in sub-Saharan Africa
No full textThe current understanding of malaria burden in Africa relies on modelled estimates based on incomplete and outdated data. The WHO defines malaria disease surveillance as a central pillar of its Global Technical Strategy. The thesis examines the precision of existing models to predict malaria burden changes and interrogation of malaria metrics from health facility and community surveys on the Kenyan coast.
Geostatistical, epidemiological models provide approximations of malaria disease burden but are rarely tested against empirical data. A systematic review included 93 health facility sites across Africa with a minimum of 5 complete years of temporal data. There was a broad congruence in the matched changes at 70 sites, but significant discordance at 23 sites which showed stagnated or upward trends.
Data on the pathway from infection to death, necessary to parametrise models of morbidity and mortality risk are rare. Prospective 12-month surveillance at six health facilities, the county hospital and repeat surveys among 36 matched communities was used to describe the epidemiology of malaria in all age groups. Despite conditions of declining transmission intensity, immunity to disease and the fatal consequences of infection continue to be acquired in early childhood, faster than anti-parasitic immunity and without evidence of emerging burdens of severe malaria or mortality among young-older non-pregnant adults.
The value of routinely collected data from health facilities to define malaria risk was explored at 36 health facility-community pairs. There was a direct non-linear polynomial relationship between passively detected fever test-positivity and traditional community-based parasite prevalence. Information obtained through routine testing of febrile patients for malaria was able to identify spatial and temporal heterogeneities of malaria risk.
Routine data offers important insights into local malaria transmission patterns, disease burdens and changing patterns of disease. An increased effort is required to replace malaria burden models with empirical data
Targeted Amplicon deep sequencing of ama1 and mdr1 to track within-host P. falciparum diversity in Kilifi, KENYA
No full textThese data were generated from targeted amplicon sequencing of Plasmodium falciparum ama1 and mdr1 genes in samples collected from Kilifi, at the coast of Kenya.
Two objectives were explored:
[1] To determine temporal changes in the genetic diversity of malaria parasites in asymptomatic and febrile infections.
[2] To track within-host parasite diversity, throughout treatment in a clinical drug trial
Accessing complex genomic variation in Plasmodium falciparum natural infections
No full textGenetic polymorphism in Plasmodium falciparum is a considerable obstacle to malaria intervention. Parasites have repeatedly evolved to overcome every front-line antimalarial deployed throughout history, and artemisinin resistant populations are expanding in Southeast Asia. Promising vaccine candidates routinely fail when challenged by the genetic diversity of natural parasite populations, and a recent trial using a blood-stage antigen showed immunity was allele specific. Modern sequencing technologies have revolutionized our understanding of parasite genomics and population genetics by providing access to single nucleotide variation, but characterizing more complex polymorphism remains a key challenge. Solving this problem is important because the selective pressures from drugs and host immunity often create complex polymorphism in the most clinically relevant genes that is missed using standard genotyping methods. In three sections, this thesis is a narrative about 1) encountering complex variation, 2) overcoming it with novel tools, and then 3) innovatively applying those tools to old and new questions. I first show examples of complex variation in a vaccine candidate (EBA-175) and a drug resistance gene (pfcrt) while reporting SNP based analyses of Kenyan and Tanzanian field isolates. While introducing this complex variation I also describe biological insights discovered in these populations. In Kenya I show evidence that chloroquine resistance selects for parasites that are primaquine sensitive, use a GWAS approach to discover new drug resistance loci, and catalogue variation in known resistance genes. In Tanzania I describe the population structure and allele frequencies of parasites from two geographic regions. In the second section of the thesis I develop methods for accessing complex variation and demonstrate their utility by producing de novo assemblies of eba-175, pfcrt, ama1, and msp3.4 from thousands of sequenced samples. Finally, in the third section I apply these tools in depth to eba-175. I comprehensively characterize the SNP and structural variation in eba-175 using an alignment of 1419 de novo assemblies. I use this resource to illustrate the profiles of positive selection across the gene, and corroborate these signals of balancing selection by showing the geographic distribution of the F/C indels and a lesser known 6bp indel positioned between the DBL domains. I then use the alignments to design Sequenom genotyping assays that facilitate a genome wide association study, testing for human associations with the eba-175 indels in the infecting parasite. I close by reporting a potential association on human chromosome 14 with the 6bp indel in eba-175
Malaria parasites hide in plain sight in the dry season
No full textPlasmodium falciparum parasites survive the dry season by accepting increased clearance rates through the host spleen, which leads to a persistent lower-level infection
Long term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country
No full textMalaria remains an important cause of morbidity and mortality among children in sub-Saharan Africa despite recent reductions in malaria incidence in some parts of Africa. Current control tools face threats such as the emergence of drug resistant parasites and insecticide resistant mosquitoes. A malaria vaccine is needed to complement and/or replace existing tools in order to achieve better malaria control and eventually eliminate the disease. RTS,S/AS01E is the most clinically advanced pre-erythrocytic malaria vaccine candidate and is currently being tested in a phase III trial. The short-term efficacy of RTS,S/AS01E is known but the duration of protection is unknown. Furthermore, although RTS,S is protective, it is unclear which immunological assays predict efficacy: hence there are no known correlates of vaccine-induced protection against clinical malaria. In a randomized controlled trial, I assessed the efficacy of RTS,S/AS01E in children (5-17 months old) residing in Kilifi, Kenya, over 4 years of follow-up and determined the correlates of protection against clinical malaria. In order to examine the effect of variations in malaria exposure on vaccine efficacy, I developed an individual marker of malaria exposure calculated as distance-weighted prevalence of malaria infection within 1 km radius of every child. Over 4 years of follow-up, RTS,S/AS01E had an efficacy of 29.9% (95%CI: 10.3% to 45.3%, p=0.005) and 16.8% (95%CI: -8.6% to 36.3% p=0.18) against first and all malaria episodes, respectively (by intention to treat analysis). Vaccine efficacy waned over time and with increasing malaria exposure. RTS,S/AS01E efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Vaccine efficacy was 45.1% (95%CI 11.3% to 66.0%) among children with lower than average malaria exposure index, but 15.9% (95%CI -11.0 to 36.4%) among children with higher than average malaria exposure index. Despite waning in efficacy, RTS,S/AS01E averted 65 cases of malaria per 100 vaccinated children, with more cases averted among the children in the higher malaria-exposure cohort (78 cases per 100 vaccinated children) than those the low exposure cohort (62 cases per 100 vaccinated children). RTS,S/AS01E induced high titres of anti-CS protein antibodies and CD4+ T cell but not CD8+ T cell responses. Anti-CS antibody titres and the frequency of TNF-α producing CD4+ T cell responses were independently associated with protection from clinical malaria, and the combination of both anti-CS titers and TNF-α producing CD4+ T cell response satisfied the Prentice criteria for surrogate markers of protection. There was no association between avidity of RTS,S-induced anti-CS protein antibodies and protection from clinical malaria. Conclusions: RTS,S/AS01E efficacy against all episodes is 16.8% over the 4 years of follow-up. The vaccine efficacy wanes over time and with increasing malaria exposure. RTS,S/AS01E-induced TNF-α producing CD4 T cell and anti-CS protein antibody responses were independently associated with protection from clinical malaria. Anti-CS avidity did not predict protection from clinical malaria. Long-term follow-ups of malaria vaccine trials are essential in the evaluation of the longevity of vaccine efficacy
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