The phenology and population dynamics of Culicoides spp. in different ecosystems in the Netherlands

The Netherlands has enjoyed a relatively free state of vector-borne diseases of economic importance for more than one century. Emerging infectious diseases may change this situation, threatening the health of humans, domestic livestock and wildlife. In order to be prepared for the potential outbreak of vector-borne diseases, a study was undertaken to investigate the distribution and seasonal dynamics of candidate vectors of infectious diseases with emphasis on bluetongue vectors (Culicoides spp.). The study focused primarily on the relationship between characteristic ecosystems suitable for bluetongue vectors and climate, as well as on the phenology and population dynamics of these vectors. Twelve locations were selected, distributed over four distinct habitats: a wetland area, three riverine systems, four peat land areas and four livestock farms. Culicoides populations were sampled continuously using CO2-baited counterflow traps from July 2005 until August 2006, with an interruption from November 2005 to March 2006. All vectors were identified to species level. Meteorological and environmental data were collected at each location. Culicoides species were found in all four different habitat types studied. Wetland areas and peat bogs were rich in Culicoides spp. The taxonomic groups Culicoides obsoletus (Meigen) and Culicoides pulicaris (Linnaeus) were strongly associated with farms. Eighty-eight percent of all Culicoides consisted of the taxon C. obsoletus/Culicoides scoticus. On the livestock farms, 3% of Culicoides existed of the alleged bluetongue vector Culicoides dewulfi Goetghebuer. Culicoides impunctatus Goetghebuer was strongly associated with wetland and peat bog. Many Culicoides species were found until late in the phenological season and their activity was strongly associated with climate throughout the year. High annual variations in population dynamics were observed within the same study areas, which were probably caused by annual variations in environmental conditions. The study demonstrates that candidate vectors of bluetongue virus are present in natural and livestock-farm habitats in the Netherlands, distributed widely across the country. Under favourable climatic conditions, following virus introduction, bluetongue can spread among livestock (cattle, sheep and goats), depending on the nature of the viral serotype. The question now arises whether the virus can survive the winter conditions in north-western Europe and whether measures can be taken that effectively halt further spread of the disease

The entomopathogenic fungus Metarhizium anisopliae for mosquito control. Impact on the adult stage of the African malaria vector Anopheles gambiae and filariasis vector Culex quinquefasciatus

Insect-pathogenie fungi for mosquito control (Chapters 1-3)Malaria and lymphatic tilariasis impose serious human health burdens in the tropics. Up to 500 million cases of malaria are reported annually, resulting in an estimated 1.5-2.7million deaths, of which 90% occur in sub-Saharan Africa. Malaria is caused by protozoa of the genus Plasmodium and is transmitted through bites of mosquitoes belonging to the genus Anopheles. Lymphatic filariasis is caused by helminths, the most widespread species being Wuchereria bancrofti, and is transmitted through bites of mainly Culex quinquefasciatus and certain Anopheles species. Worldwide, approximately 146 million people are infected with the disease.Mosquito vector control is an important way to tight these diseases. In Africa, vector control is almost exclusively based on chemical insecticides, used predominantly to impregnate bed nets and for indoor residual spraying. Growing concerns about their negative impact on human health, on the environment, and about insecticide resistance are the reasons for increasing interests in vector control methods that are not based on chemicais, such as biological contro!.veral biological control agents are known to be effective against mosquitoes such as predatory tish (e.g. Gambusia ajfinis and Poecilia reticulata), nematodes (e.g. Romanomermis culicivorax), microsporidia (e.g. Nosema algerae), bacteria (e.g. Bacil/us thuringiensis israelensis and B. sphaericus), and insect- pathogenie fungi (e.g. Lagenidium, Coelomomyces and Culicinomyces).All of these, however, target the larval stages of mosquitoes. To date, there is no biological control agent for use against the adult stage of mosquitoes. However, reduction in survival of adult mosquitoes is considered to have a much higher impact on transmission than a reduction in the number of mosquito larvae. The objective of this PhD thesis was therefore to search for a biological control agent for adult mosquitoes, and to develop a method to use such an agent in integrated vector management (IVM) in Africa. The primary targets for this research were the major malaria vector Anopheles gambiae s.l., and, to alesser degree, the lymphatic tilariasis vector Culex quinquefasciatus. In Chapter 2 the most important insect-pathogenic fungi for (mostly) larval mosquito control are reviewed. Of these, the Hyphomycetes possess a characteristic that gives them a major advantage over other biocontrol agents to be used for killing adult mosquitoes: Unlike with bacteria, nematodes or microsporidia, the infectious propagules of these fungi do not need to be ingested. Instead, contact with the cuticle is enough for the infective propagules (conidia) to infect the mosquito. A conidium penetrates the insect cuticle by secreting cuticle­degrading enzymes. Once inside, the fungus grows rapidly and secretes toxins, which kill the mosquito. Depending on temperature, fungal dosage, and susceptibility of the mosquito to the fungus, the process from inoculation to host death may take between approximately three and ten (or even more) days. After host death, and under favourable conditions of high humidity, the fungus will grow out of the cadaver and produce conidia asexually (sporulation).The strategy envisaged to infect and kill wild mosquitoes in sub-Saharan Africa is based both on the characteristic of Hyphomycetous fungi to infect insects through contact by penetrating the cuticle, and on the behavioural characteristic of An. gambiae mosquitoes to blood feed predominantly inside houses during the night, and remain indoors for at least several hours afterwards to rest and digest the blood mea!. If conidia are applied indoors on so-called 'mosquito resting targets' (see Chapter 9), mosquitoes are expected to acquire an infection ofthe fungus by resting on those targets.In Chapter 3, five different Hyphomycetous insect pathogenie fungi were tested on adult An. gambiae, including Beauveria bassiana, a Fusarium sp. and three isolates of Metarhizium anisopliae. Four of these fungi were isolated from insects in western Kenya, an area of endemie malaria. Isolate ICIPE30 of M. anisopliae proved to be highly virulent for the tested mosquito species, and it was decided to continue further studies with this isolate.The effect of the insect-pathogenie fungus Metarhizium anisopliae on African mosquito vectors (Chapters 4-7)As described in Chapter 4, M. anisopliae was tested both on An. gambiae as weil as on Cx. quinquefasciatus, and a standard contamination technique to infect adult mosquitoes was developed. Using this technique, the effect ofthe fungus on An. gambiae was quantified in more detail by a dose-response bioassay. This experiment showed that at a dose of 1.6 x 1010 conidia m-z, >83% were infected (i.e. mosquito cadavers with sporulating fungus), with a mean LT50 value of 5.6::1: 0.4 days. Later experiments (Chapters 6 and 8) showed that the fungus could be even more effective at that same dose, with infection levels up to 96.4%, and all mosquitoes dead by day 6, whereas uninfected female An. gambiae lived much longer with L T 50 values > 18 days.Apart from the principal effect of the fungus, causing mosquito death by direct contact with conidia, infection with M. anisopliae also caused at least two secondary effects (Chapter 5). One ofthose secondary effects is a reduction in feeding propensity. In one ofthe experiments of Chapter 5, individual female An. gambiae s.s. were offered a total of 8 blood meals. It was found that mosquitoes, inoculated with a moderately high dose of fungal conidia (1.6 x 109 conidia mOz), exhibited reduced appetite upon increasing effects of fungal growth. Of the fungus-infected females, the proportion of mosquitoes taking a second blood meal was reduced with 51 %. This was further reduced to 35.3% for the 4th blood meal. The other observed secondary effect was that infected females took smaller blood meals, resulting in fewer eggs per gonotrophic cycle.In order to achieve the highest possible impact on mosquito populations, it is desirabIe that other contamination pathways besides the primary mode of contamination are utilized to spread the fungus through the population, such as horizontal transmission. The results of experiments described in Chapter 6 showed that, under laboratory conditions, conidia can be transferred from an inoculated female to a 'clean' male during the process of mating, with mean male infection rates between 10.7::1: 302% and 33.3 ::I: 3.8%.Since the mosquito inoculation method described above is based on mosquitoes that rest on conidia-impregnated sheets, it is desirabIe that mosquitoes are not repelled by conidia. To test this, behavioural effects of female An. gambiae in close vicinity of the fungus were investigated (Chapter 7). The results showed that dry conidia have a significant repellent effect (p<0.05). However, when conidia were applied in a suspension of 8% adjuvant vegetable-oil formulation and impregnated on paper, this effect ceased (p=0.205). The results suggest that if the fungus is to be applied as a biological control agent against Afrotropical mosquitoes, conidia should be impregnated on e.g. cotton sheets in an oil-based formulation to avoid repellency effects.Practical approach to mosquito vector control in Africa using M. anisopliae (Chapters 8-10).From a practical and economic point of view, the interval between applications ofthe control agent should ideally be as long as possible, without the agent losing too much efficacy. In the case of commonly used chemical residual insecticides such as permethrin this is about 6 months. Laboratory experiments (Chapter 8) showed that M. anisopliae conidia impregnated on paper and on netting material remained virulent to An. gambiae up to one month after impregnation. Experiments on conidial shelf life under different conditions showed that conidia kept in 8% vegetable oil remained viabie up to at least I month. Conidia stored in 0.05% Tween 80 exhibited only slightly reduced viability after 3 months at 27° and after 6 months at 4°C. Dry conidia stored with silica gel retained viability for at least 6 months. The results suggest that, if applied in the field, re-impregnation should be carrPractical approach to mosquito vector control in Africa using M. anisopliae (Chapters 8-10).From a practical and economic point of view, the interval between applications ofthe control agent should ideally be as long as possible, without the agent losing too much efficacy. In the case of commonly used chemical residual insecticides such as permethrin this is about 6 months. Laboratory experiments (Chapter 8) showed that M. anisopliae conidia impregnated on paper and on netting material remained virulent to An. gambiae up to one month after impregnation. Experiments on conidial shelf life under different conditions showed that condidia kept in 8% vegetable oil remained viable up to at least 1 month. Condidia stored in 0.05% Tween 80 exhibited only slightly reduced viability for a least 6 months. The results suggest that, if applied in the field, re-impregnation should be carried out monthly, but dry conidia can be stored for at least 6 months under conditions of very low relative humidity. Chapter 9 of this thesis describes a field study of domestic application of M. anisopliae in houses in south east Tanzania, a region holoendemic for malaria and lymphatic filariasis. The fungus was applied on black cotton sheets, attached to ceilings as indoor mosquito resting targets. Indoor resting catches of mosquitoes were carried out daily and collected mosquitoes were kept alive in small containers as long as possible to determine survival. Almost 90% of all collected mosquitoes were An. gambiae s.l. (of which 94.7% were An. gambiae s.s. and 5.3% An. arabiensis). In total, 181 wild An. gambiae s.l. and 6 wild Cx. quinquefasciatus were infected with the fungus. Infected mosquitoes died significantly sooner than uninfected mosquitoes, with an average daily survival rate of 0.722 for infected female An. gambiae, against 0.869 for uninfected females. Calculated from the total number of An. gambiae s.l. and Cx. quinquefasciatus that were caught from the fungus­impregnated resting targets, respectively 33.6 and 10.0% had acquired fungal infection. Of the total number of 580 female An. gambiae collected from the houses containing fungus­impregnated sheets, 132 were infected, which is an effective coverage of22.8%. Ifthis same coverage level is assumed at village level, and, together with the reduced daily survival rate, is introduced into a malaria transmission model, the total number of infectious bites per person per year (Entomological Inoculation Rate; EIR) drops from 262 to 14 (Chapter 10). Although the field experiment was on a relatively small scale and of short duration, the predictions of the malaria transmission model strongly indicate that application of M. anisopliae, aimed at the adult stage of African mosquito vectors can have a high impact on transmission intensity. It is argued that large-scale application of this method, implemented as part of an integrated vector management (IVM) strategy including larval control using biological control agents, the use of repellent plants and of unimpregnated bednets, malaria can effectively be controlled without the use of chemical insecticides. This thesis may form a first step towards such a strategy. Further research is necessary, especially in 1) searching for a fungal isolate that has even higher virulence against the targeted mosquito species, 2) testing of non-target effects and safety of the most effective fungal strain for registration, 3) searching for the most optimal formulation and application method to increase infection percentages

Het toenemend belang van infectieziekten die worden overgebracht door vectoren

Dit artikel gaat over de voor Nederland belangrijkste arthropodenvectoren (geleedpotigen, in dit artikel voornamelijk muggen en teken) en de door hen overgebrachte infectieziekten. Daarnaast wordt de rol van landschappelijke aanpassingen, klimaatverandering, intensiever internationaal reizigers- en handelsverkeer en veranderend gedrag met betrekking tot recreatie beschreven. Tenslotte wordt de verdere kennisbehoefte aangegeve

The (cost-)effectiveness of early intervention (MBT-early) versus standard protocolized treatment (CBT) for emerging borderline personality disorder in adolescents (the EARLY study):a study protocol for a randomized controlled trial

Background: Although clinical guidelines prioritize the treatment of depression and anxiety in young persons, there is accumulating evidence that the presence of symptoms of borderline personality disorder (BPD) is associated with the limited effectiveness of these standard treatments. These findings stress the need for interventions addressing early-stage BPD in young people with presenting symptoms of anxiety and depressive disorders. The aim of this study is to investigate the (cost-)effectiveness of an early intervention programme for BPD (MBT-early) compared to first-choice psychological treatment for depression and anxiety according to Dutch treatment guidelines (CBT), in adolescents with either depression, anxiety, or both, in combination with early-stage BPD. Methods: This study is a multi-centre randomized controlled trial. A total of 132 adolescents, presenting with either depression, anxiety, or both and significant BPD features will be randomized to either MBT-early or CBT. The severity of BPD, symptoms of depression and anxiety, personality, social and academic functioning, and quality of life will be assessed at baseline, end of treatment, and at 12-, 18-, and 24-month follow-up, along with medical costs and costs of productivity losses for cost-effectiveness analyses.Discussion: This study will provide an empirical evaluation of the potential surplus value of early intervention in young people for whom treatment oriented at common mental disorders like anxiety and depression may be insufficient given their underlying personality problems. Trial registration: Netherlands Trial registration: Netherlands trial register, NL9569. Registered on June 15, 2021<br/

Prenatal exome sequencing: a useful tool for the fetal neurologist

Prenatal exome sequencing (pES) is a promising tool for diagnosing genetic disorders when structural anomalies are detected on prenatal ultrasound. The aim of this study was to investigate the diagnostic yield and clinical impact of pES as an additional modality for fetal neurologists who counsel parents in case of congenital anomalies of the central nervous system (CNS). We assessed 20 pregnancies of 19 couples who were consecutively referred to the fetal neurologist for CNS anomalies. pES had a diagnostic yield of 53% (10/19) with most diagnosed pregnancies having agenesis or hypoplasia of the corpus callosum (7/10). Overall clinical impact was 63% (12/19), of which the pES result aided parental decision making in 55% of cases (6/11), guided perinatal management in 75% of cases (3/4), and was helpful in approving a late termination of pregnancy request in 75% of cases (3/4). Our data suggest that pES had a high diagnostic yield when CNS anomalies are present, although this study is limited by its small sample size. Moreover, pES had substantial clinical impact, which warrants implementation of pES in the routine care of the fetal neurologist in close collaboration with gynecologists and clinical geneticists.Neuro Imaging Researc

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters

Measurement of the inclusive isolated prompt photon cross-section in pp collisions at sqrt(s)= 7 TeV using 35 pb-1 of ATLAS data

A measurement of the differential cross-section for the inclusive production of isolated prompt photons in pp collisions at a center-of-mass energy sqrt(s) = 7 TeV is presented. The measurement covers the pseudorapidity ranges |eta|<1.37 and 1.52<=|eta|<2.37 in the transverse energy range 45<=E_T<400GeV. The results are based on an integrated luminosity of 35 pb-1, collected with the ATLAS detector at the LHC. The yields of the signal photons are measured using a data-driven technique, based on the observed distribution of the hadronic energy in a narrow cone around the photon candidate and the photon selection criteria. The results are compared with next-to-leading order perturbative QCD calculations and found to be in good agreement over four orders of magnitude in cross-section.Comment: 7 pages plus author list (18 pages total), 2 figures, 4 tables, final version published in Physics Letters

Measurement of D*+/- meson production in jets from pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

This paper reports a measurement of D*+/- meson production in jets from proton-proton collisions at a center-of-mass energy of sqrt(s) = 7 TeV at the CERN Large Hadron Collider. The measurement is based on a data sample recorded with the ATLAS detector with an integrated luminosity of 0.30 pb^-1 for jets with transverse momentum between 25 and 70 GeV in the pseudorapidity range |eta| < 2.5. D*+/- mesons found in jets are fully reconstructed in the decay chain: D*+ -> D0pi+, D0 -> K-pi+, and its charge conjugate. The production rate is found to be N(D*+/-)/N(jet) = 0.025 +/- 0.001(stat.) +/- 0.004(syst.) for D*+/- mesons that carry a fraction z of the jet momentum in the range 0.3 < z < 1. Monte Carlo predictions fail to describe the data at small values of z, and this is most marked at low jet transverse momentum.Comment: 10 pages plus author list (22 pages total), 5 figures, 1 table, matches published version in Physical Review