Influence of infection on malaria-specific antibody dynamics in a cohort exposed to intense malaria transmission in northern Uganda.

The role of submicroscopic infections in modulating malaria antibody responses is poorly understood and requires longitudinal studies. A cohort of 249 children ≤5 years of age, 126 children between 6 and 10 years and 134 adults ≥20 years was recruited in an area of intense malaria transmission in Apac, Uganda and treated with artemether/lumefantrine at enrolment. Parasite carriage was determined at enrolment and after 6 and 16 weeks using microscopy and PCR. Antibody prevalence and titres to circumsporozoite protein, apical membrane antigen-1 (AMA-1), merozoite surface protein-1 (MSP-119 ), merozoite surface protein-2 (MSP-2) and Anopheles gambiae salivary gland protein 6 (gSG6) were determined by ELISA. Plasmodium falciparum infections were detected in 38·1% (194/509) of the individuals by microscopy and in 57·1% (284/493) of the individuals by PCR at enrolment. Antibody prevalence and titre against AMA-1, MSP-119 , MSP-2 and gSG6 were related to concurrent (sub-)microscopic parasitaemia. Responses were stable in children who were continuously infected with malaria parasites but declined in children who were never parasitaemic during the study or were not re-infected after treatment. These findings indicate that continued malaria infections are required to maintain antibody titres in an area of intense malaria transmission

Invasive mediastinal nodal staging of resectable non-small cell lung cancer

Patients with resectable non-small cell lung cancer and increased risk of mediastinal nodal involvement require invasive staging to exclude patients with N2-3 metastases for surgical resection. The current guidelines recommend endosonography as initial staging procedure followed by confirmatory mediastinoscopy in case of absence of N2-3 metastases after endosonography. The role of confirmatory mediastinoscopy is however under debate due to its limited additional diagnostic value and its associated morbidity, hospital admission and delay in definite lung cancer treatment.The first part of the thesis focusses on the daily practice of invasive mediastinal nodal staging and adherence to the (inter)national guidelines. We performed a multicenter retrospective analysis, a nationwide Dutch Lung Cancer Audit analysis and a nationwide Netherlands Cancer Registry analysis which showed poor adherence to the guidelines regarding performance of endosonography followed by confirmatory mediastinoscopy. The use of endosonography significantly increased over the years, while the use of mediastinoscopy decreased, despite these changes unforeseen N2 metastases after resection remained stable.The second part focusses on the value of confirmatory mediastinoscopy after tumor negative endosonography. A patient preferences study showed that the length of the staging period was significantly the most important attribute. A meta-analysis showed comparable unforeseen N2 results after staging by endosonography with or without confirmatory mediastinoscopy. The randomised MEDIASTrial ultimately showed that on the basis of non-inferiority in unforeseen N2 (as surrogate marker of clinically relevant diagnostic accuracy) confirmatory mediastinoscopy after negative systematic endosonography can be omitted in patients with resectable NSCLC and an indication for mediastinal staging

Can field-based mosquito feeding assays be used for evaluating transmission-blocking interventions?

A recent meta-analysis of mosquito feeding assays to determine the Plasmodium falciparum transmission potential of naturally infected gametocyte carriers highlighted considerable variation in transmission efficiency between assay methodologies and between laboratories. This begs the question as to whether mosquito feeding assays should be used for the evaluation of transmission-reducing interventions in the field and whether these field-based mosquito assays are currently standardized sufficiently to enable accurate evaluations. Here, we address biological and methodological reasons for the observed variations, discuss whether these preclude the use of field-based mosquito feeding assays in field evaluations of transmission-blocking interventions, and propose how we can maximize the precision of estimates. Altogether, we underscore the significant advantages of field-based mosquito feeding assays in basic malaria research and field trials

Prospective cohort study of routine use of risk assessment scales for prediction of pressure ulcers

Objective To evaluate whether risk assessment scales can be used to identify patients who are likely to get pressure ulcers.Design Prospective cohort study.Setting Two large hospitals in the Netherlands.Participants 1229 patients admitted to the surgical, internal, neurological, or geriatric wards between January 1999 and June 2000.Main outcome measure Occurrence of a pressure ulcer of grade 2 or worse while in hospital.Results 135 patients developed pressure ulcers during four weeks after admission. The weekly incidence of patients with pressure ulcers was 6.2% (95% confidence interval 5.2% to 7.2%). The area under the receiver operating characteristic curve was 0.56 (0.51 to 0.61) for the Norton scale, 0.55 (0.49 to 0.60) for the Braden scale, and 0.61 (0.56 to 0.66) for the Waterlow scale; the areas for the subpopulation, excluding patients who received preventive measures without developing pressure ulcers and excluding surgical patients, were 0.71 (0.65 to 0.77), 0.71 (0.64 to 0.78), and 0.68 (0.61 to 0.74), respectively. In this subpopulation, using the recommended cut­off points, the positive predictive value was 7.0% for the Norton, 7.8% for the Braden, and 5.3% for the Waterlow scale.Conclusion Although risk assessment scales predict the occurrence of pressure ulcers to some extent, routine use of these scales leads to inefficient use of preventive measures. An accurate risk assessment scale based on prospectively gathered data should be developed

Learning and Adaptation in Polycentric Transport Governance:The Case of the Dutch Brabant Accessibility Agenda

The future of urban-regional transport crucially depends on the ability of transport governance systems to adapt. Polycentric theory claims that the presence of polycentric attributes and conditions enables governance systems to learn and adapt. However, an analysis of the Dutch Brabant Accessibility Agenda shows that their presence says little about the adaptive capacity of transport governance systems because learning and adaptation are influenced by dependencies. To optimize the adaptive capacity of transport governance systems, it is therefore vital to acknowledge both the diverse ways in how they learn and adapt, and the dependencies that shape these processes

Low-dose primaquine for falciparum malaria

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Ultralow-density Plasmodium falciparum Infections in African Settings.

Contains fulltext : 208941.pdf (publisher's version ) (Open Access

Two-Faced Immunity? The Evidence for Antibody Enhancement of Malaria Transmission.

Plasmodium gametocytes can induce an immune response in humans that interferes with the development of sexual-stage parasites in the mosquito gut. Many early studies of the sexual-stage immune response noted that mosquito infection could be enhanced as well as reduced by immune sera. For Plasmodium falciparum, these reports are scarce, and the phenomenon is generally regarded as a methodological artefact. Plasmodium transmission enhancement (TE) remains contentious, but the clinical development of transmission-blocking vaccines based on sexual-stage antigens requires that it is further studied. In this essay, we review the early literature on the sexual-stage immune response and transmission-modulating immunity. We discuss hypotheses for the mechanism of TE, suggest experiments to prove or disprove its existence, and discuss its possible implications

A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model.

BACKGROUND: Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. METHODS: In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes. Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. RESULTS: Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). CONCLUSIONS: The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. FUNDING: Funded by PATH Malaria Vaccine Initiative (MVI). CLINICAL TRIAL NUMBER: NCT02836002

Gametocytes: insights gained during a decade of molecular monitoring

In vertebrate hosts, malaria parasites produce specialized male and female sexual stages (gametocytes). Soon after being taken up by a mosquito, gametocytes rapidly produce gametes and, once mated, they infect their vector and can be transmitted to new hosts. Despite being the parasite stages that were first identified (over a century ago), gametocytes have remained elusive, and basic questions remain concerning their biology. However, the postgenomic era has substantiated information on the specialized molecular machinery of gametocytogenesis and expedited the development of molecular tools to detect and quantify gametocytes. The application of such highly sensitive and specific tools has opened up novel approaches and provided new insights into gametocyte biology. Here, we review the discoveries made during the past decade, highlight unanswered questions and suggest new directions