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  • 1.
    Abdulla, Salim
    et al.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Bassat, Quique
    Univ Barcelona, Ctr Invest Saude Manhica Manhica Mozamb & ISGloba, Barcelona Ctr Int Hlth Res CRESIB, Hosp Clin, Barcelona, Spain..
    Bethell, Delia
    AFRIMS, Dept Immunol & Med, Bangkok, Thailand..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Borrmann, Steffen
    Kenya Govt Med Res Ctr, Wellcome Trust Res Programme, Kilifi, Kenya.;Univ Magdeburg, Sch Med, D-39106 Magdeburg, Germany..
    D'Alessandro, Umberto
    Inst Trop Med, Unit Malariol, B-2000 Antwerp, Belgium.;MRC Unit, Fajara, Gambia..
    Dahal, Prabin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Day, Nicholas P.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Diakite, Mahamadou
    Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali..
    Djimde, Abdoulaye A.
    Dondorp, Arjen M.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Duong, Socheat
    Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Edstein, Michael D.
    Fairhurst, Rick M.
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA..
    Faiz, M. Abul
    Malaria Res Grp MRG & Dev Care Fdn, Dhaka, Bangladesh..
    Falade, Catherine
    Univ Ibadan, Coll Med, Ibadan, Nigeria..
    Flegg, Jennifer A.
    Monash Univ, Sch Math Sci, Clayton, Vic 3800, Australia..
    Fogg, Carole
    Univ Portsmouth, Portsmouth, Hants, England..
    Gonzalez, Raquel
    Ctr Invest Saude Manhica Manhica Mozamb, Barcelona, Spain.;CRESIB, Barcelona, Spain..
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England..
    Guerin, Philippe J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Guthmann, Jean-Paul
    Epicentre, Paris, France..
    Hamed, Kamal
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hien, Tran Tinh
    Htut, Ye
    Dept Med Res, Lower Myanmar, Yangon, Myanmar..
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Lim, Pharath
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA.;US & Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Mårtensson, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Microbiol Cell & Tumour Biol, Dept Publ Hlth Sci, Malaria Res, Stockholm, Sweden..
    Mayxay, Mayfong
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos.;Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos..
    Mokuolu, Olugbenga A.
    Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria..
    Moreira, Clarissa
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Newton, Paul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos..
    Noedl, Harald
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria..
    Nosten, Francois
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, US Army Med Res Unit, Kisumu, Kenya..
    Onyamboko, Marie A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO..
    Owusu-Agyei, Seth
    Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Phyo, Aung Pyae
    Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Premji, Zul
    Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania..
    Price, Ric N.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.;Charles Darwin Univ, Darwin, NT 0909, Australia..
    Pukrittayakamee, Sasithon
    Mahidol Univ, Fac Trop Med, Bangkok 10700, Thailand..
    Ramharter, Michael
    Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med 1, Vienna, Austria.;Univ Tubingen, Inst Tropenmed, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Sagara, Issaka
    Univ Bamako, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali..
    Se, Youry
    AFRIMS, Phnom Penh, Cambodia..
    Suon, Seila
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Stepniewska, Kasia
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Ward, Stephen A.
    Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    White, Nicholas J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Winstanley, Peter A.
    Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England..
    Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, artikel-id 359Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

  • 2. Albrecht, Letusa
    et al.
    Moll, Kirsten
    Blomqvist, Karin
    Normark, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Chen, Qijun
    Wahlgren, Mats
    var gene transcription and PfEMP1 expression in the rosetting and cytoadhesive Plasmodium falciparum clone FCR3S1.22011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, artikel-id 17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The pathogenicity of Plasmodium falciparum is in part due to the ability of the parasitized red blood cell (pRBC) to adhere to intra- vascular host cell receptors and serum-proteins. Binding of the pRBC is mediated by Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a large multi-variant molecule encoded by a family of approximate to 60 var genes. Methods: The study of var gene transcription in the parasite clone FCR3S1.2 was performed by semi-quantitative PCR and quantitative PCR (qPCR). The expression of the major PfEMP1 in FCR3S1.2 pRBC was analysed with polyclonal sera in rosette disruption assays and immunofluorecence. Results: Transcripts from var1 (FCR3S1.2(var1); IT4var21) and other var genes were detected by semi-quantitative PCR but results from qPCR showed that one var gene transcript dominated over the others (FCR3S1.2var2; IT4var60). Antibodies raised in rats to the recombinant NTS-DBL1a of var2 produced in E. coli completely and dosedependently disrupted rosettes (approximate to 95% at a dilution of 1/5). The sera reacted with the Maurer's clefts in trophozoite stages (IFA) and to the infected erythrocyte surface (FACS) indicating that FCR3S1.2var2 encodes the dominant PfEMP1 expressed in this parasite. Conclusion: The major transcript in the rosetting model parasite FCR3S1.2 is FCR3S1.2var2 (IT4var60). The results suggest that this gene encodes the PfEMP1-species responsible for the rosetting phenotype of this parasite. The activity of previously raised antibodies to the NTS-DBL1a of FCR3S1.2var1 is likely due to cross-reactivity with NTS-DBL1 alpha of the var2 encoded PfEMP1.

  • 3. Anchang-Kimbi, Judith K.
    et al.
    Achidi, Eric A.
    Apinjoh, Tobias O.
    Mugri, Regina N.
    Chi, Hanesh Fru
    Tata, Rolland B.
    Nkegoum, Blaise
    Mendimi, Joseph-Marie N.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Troye Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Antenatal care visit attendance, intermittent preventive treatment during pregnancy (IPTp) and malaria parasitaemia at delivery2014Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, s. 162-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The determinants and barriers for delivery and uptake of IPTp vary with different regions in sub-Saharan Africa. This study evaluated the determinants of ANC clinic attendance and IPTp-SP uptake among parturient women from Mount Cameroon Area and hypothesized that time of first ANC clinic attendance could influence uptake of IPTp-SP/dosage and consequently malaria parasite infection status at delivery. Methods: Two cross sectional surveys were carried out at the Government Medical Centre in the Mutengene Health Area, Mt Cameroon Area from March to October 2007 and June 2008 to April 2009. Consented parturient women were consecutively enrolled in both surveys. In 2007, socio-demographic data, ANC clinic attendance, gestational age, fever history and reported use/dosage of IPTp-SP were documented using a structured questionnaire. In the second survey only IPT-SP usage/dosage was recorded. Malaria parasitaemia at delivery was determined by blood smear microscopy and placental histology. Results and discussion: In 2007, among the 287 women interviewed, 2.2%, 59.7%, and 38.1% enrolled in the first, second and third trimester respectively. About 90% of women received at least one dose SP but only 53% received the two doses in 2007 and by 2009 IPTp-two doses coverage increased to 64%. Early clinic attendance was associated (P = 0.016) with fever history while being unmarried (OR = 2.2; 95% CI: 1.3-3.8) was significantly associated with fewer clinic visits (<4visits). Women who received one SP dose (OR = 3.7; 95% CI: 2.0-6.8) were more likely not to have attended >= 4visits. A higher proportion (P < 0.001) of women with first visit during the third trimester received only one dose, meanwhile, those who had an early first ANC attendance were more likely (OR = 0.4; 95% CI = 0.2 - 0.7) to receive two or more doses. Microscopic parasitaemia at delivery was frequent (P = 0.007) among women who enrolled in the third trimester and had received only one SP dose than in those with two doses. Conclusion: In the study area, late first ANC clinic enrolment and fewer clinic visits may prevent the uptake of two SP doses and education on early and regular ANC clinic visits can increase IPTp coverage.

  • 4. Anchang-Kimbi, Judith K
    et al.
    Achidi, Eric A
    Nkegoum, Blaise
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Diagnostic comparison of malaria infection in peripheral blood, placental blood and placental biopsies in Cameroonian parturient women.2009Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, s. 126-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: In sub-Saharan Africa, Plasmodium falciparum malaria in pregnancy presents an enormous diagnostic challenge. The epidemiological and clinical relevance of the different types of malaria diagnosis as well as risk factors associated with malaria infection at delivery were investigated. METHOD: In a cross-sectional survey, 306 women reporting for delivery in the Mutenegene maternity clinic, Fako division, South West province, Cameroon were screened for P. falciparum in peripheral blood, placental blood and placental tissue sections by microscopy. Information relating to the use of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine, history of fever attack, infant birth weights and maternal anaemia were recorded. RESULTS: Among these women, P. falciparum infection was detected in 5.6%, 25.5% and 60.5% of the cases in peripheral blood, placental blood and placental histological sections respectively. Placental histology was more sensitive (97.4%) than placental blood film (41.5%) and peripheral blood (8.0%) microscopy. In multivariate analysis, age (< or = 20 years old) (OR = 4.61, 95% CI = 1.47 - 14.70), history of fever attack (OR = 2.98, 95% CI = 1.58 - 5.73) were significant risk factors associated with microscopically detected parasitaemia. The use of > or = 2 SP doses (OR = 0.18, 95% CI = 0.06 - 0.52) was associated with a significant reduction in the prevalence of microscopic parasitaemia at delivery. Age (>20 years) (OR = 0.34, 95% CI = 0.15 - 0.75) was the only significant risk factor associated with parasitaemia diagnosed by histology only in univariate analysis. Microscopic parasitaemia (OR = 2.74, 95% CI = 1.33-5.62) was a significant risk factor for maternal anaemia at delivery, but neither infection detected by histology only, nor past infection were associated with increased risk of anaemia. CONCLUSION: Placenta histological examination was the most sensitive indicator of malaria infection at delivery. Microscopically detected parasitaemia was associated with increased risk of maternal anaemia at delivery, but not low-grade parasitaemia detected by placental histology only.

  • 5. Awor, Phyllis
    et al.
    Wamani, Henry
    Tylleskar, Thorkild
    Peterson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Drug seller adherence to clinical protocols with integrated management of malaria, pneumonia and diarrhoea at drug shops in Uganda2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, artikel-id 277Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Drug shops are usually the first source of care for febrile children in Uganda although the quality of care they provide is known to be poor. Within a larger quasi-experimental study introducing the WHO/UNICEF recommended integrated community case management (iCCM) of malaria, pneumonia and diarrhoea intervention for community health workers in registered drug shops, the level of adherence to clinical protocols by drug sellers was determined. Methods: All drug shops (N = 44) in the intervention area were included and all child visits (N = 7,667) from October 2011-June 2012 to the participating drug shops were analysed. Drug shops maintained a standard iCCM register where they recorded the children seen, their symptoms, diagnostic test performed, treatments given and actions taken. The proportion of children correctly assessed and treated was determined from the registers. Results: Malaria management: 6,140 of 7,667 (80.1%) total visits to drug shops were of children with fever. 5986 (97.5%) children with fever received a malaria rapid diagnostic test (RDT) and the RDT positivity rate was 78% (95% CI 77-79). 4,961/5,307 (93.4%) children with a positive RDT received artemisinin combination therapy. Pneumonia management: after respiratory rate assessment of children with cough and fast/difficult breathing, 3,437 (44.8%) were categorized as "pneumonia", 3,126 (91.0%) of whom received the recommended drug-amoxicillin. Diarrhoea management: 2,335 (30.5%) child visits were for diarrhoea with 2,068 (88.6%) correctly treated with oral rehydration salts and zinc sulphate. Dual/Triple classification: 2,387 (31.1%) children had both malaria and pneumonia and 664 (8.7%) were classified as having three illnesses. Over 90% of the children with dual or triple classification were treated appropriately. Meanwhile, 381 children were categorized as severely sick (with a danger sign) with 309 (81.1%) of them referred for appropriate management. Conclusion: With the introduction of the iCCM intervention at drug shops in Eastern Uganda, it was possible to achieve high adherence to the treatment protocols, which is likely compatible with increased quality of care.

  • 6.
    Boström, Stephanie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Giusti, Pablo
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Arama, Charles
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut. University of Bamako, Mali.
    Persson, Jan-Olov
    Stockholms universitet, Naturvetenskapliga fakulteten, Matematiska institutionen.
    Dara, Victor
    Traore, Boubacar
    Dolo, Amagana
    Doumbo, Ogobara
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Changes in the levels of cytokines, chemokines and malaria specific antibodies in response to Plasmodium falciparum infection in children living in sympatry in Mali2012Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, s. 109-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The Fulani are known to be less susceptible to Plasmodium falciparum malaria as reflected by lower parasitaemia and fewer clinical symptoms than other sympatric ethnic groups. So far most studies in these groups have been performed on adults, which is why little is known about these responses in children. This study was designed to provide more information on this gap. Methods: Circulating inflammatory factors and antibody levels in children from the Fulani and Dogon ethnic groups were measured. The inflammatory cytokines; interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12p70, tumor necrosis factor (TNF) and the chemokines; regulated on activation normal T cell expressed and secreted (RANTES), monokine-induced by IFN-gamma (MIG), monocyte chemotactic protein (MCP)-1 and IFN-gamma-inducible protein (IP)-10 were measured by cytometric bead arrays. The levels of interferon (IFN)-alpha, IFN-gamma and malaria-specific antibodies; immunoglobulin (Ig) G, IgM and IgG subclasses (IgG1-IgG4) were measured by ELISA. Results: The results revealed that the Fulani children had higher levels of all tested cytokines compared to the Dogon, in particular IFN-gamma, a cytokine known to be involved in parasite clearance. Out of all the tested chemokines, only MCP-1 was increased in the Fulani compared to the Dogon. When dividing the children into infected and uninfected individuals, infected Dogon had significantly lower levels of RANTES compared to their uninfected peers, and significantly higher levels of MIG and IP-10 as well as MCP-1, although the latter did not reach statistical significance. In contrast, such patterns were not seen in the infected Fulani children and their chemokine levels remained unchanged upon infection compared to uninfected counterparts. Furthermore, the Fulani also had higher titres of malaria-specific IgG and IgM as well as IgG1-3 subclasses compared to the Dogon. Conclusions: Taken together, this study demonstrates, in accordance with previous work, that Fulani children mount a stronger inflammatory and antibody response against P. falciparum parasites compared to the Dogon and that these differences are evident already at an early age. The inflammatory responses in the Fulani were not influenced by an active infection which could explain why less clinical symptoms are seen in this group.

  • 7. Carlsson, Anja M
    et al.
    Ngasala, Billy E
    Dahlström, Sabina
    Membi, Christopher
    Veiga, Isabel M
    Rombo, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Abdulla, Salim
    Premji, Zul
    Gil, J Pedro
    Björkman, Anders
    Mårtensson, Andreas
    Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment in Tanzanian children with acute uncomplicated malaria2011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, s. 380-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    This study aimed to explore Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment with artemisinin-based combination therapy in children with clinical malaria in a high transmission area in Africa.

    METHODS:

    A total of 50 children aged 1-10 years with acute uncomplicated P. falciparum malaria in Bagamoyo District, Tanzania, were enrolled. Participants were hospitalized and received supervised standard treatment with artemether-lumefantrine according to body weight in six doses over 3 days. Blood samples were collected 11 times, i.e. at time of diagnosis (-2 h) and 0, 2, 4, 8, 16, 24, 36, 48, 60 and 72 h after initiation of treatment. Parasite population dynamics were assessed using nested polymerase chain reaction (PCR)-genotyping of merozoite surface protein (msp) 1 and 2.

    RESULTS:

    PCR-analyses from nine sequential blood samples collected after initiation of treatment identified 20 and 21 additional genotypes in 15/50 (30%) and 14/50 (28%) children with msp1 and msp2, respectively, non-detectable in the pre-treatment samples (-2 and 0 h combined). Some 15/20 (75%) and 14/21 (67%) of these genotypes were identified within 24 h, whereas 17/20 (85%) and 19/21 (90%) within 48 h for msp1 and msp2, respectively. The genotype profile was diverse, and varied considerably over time both within and between patients, molecular markers and their respective families.

    CONCLUSION:

    PCR analyses from multiple blood samples collected during the early treatment phase revealed a complex picture of parasite sub-populations. This underlines the importance of interpreting PCR-outcomes with caution and suggests that the present use of PCR-adjustment from paired blood samples in anti-malarial drug trials may overestimate assessment of drug efficacy in high transmission areas in Africa.The study is registered at http://www.clinicaltrials.gov with identifier NCT00336375.

  • 8. Cherif, Mariama
    et al.
    Amoako-Sakyi, Daniel
    Dolo, Amagana
    Pearson, Jan-Olov
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Gyan, Ben
    Obiri-Yeboah, Dorcas
    Nebie, Issa
    Sirima, Sodiomon B.
    Doumbo, Ogobara
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bakary, Maiga
    Distribution of Fc gamma R gene polymorphisms among two sympatric populations in Mali: differing allele frequencies, associations with malariometric indices and implications for genetic susceptibility to malaria2016Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, artikel-id 29Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Genetic polymorphisms in the complex gene cluster encoding human Fc-gamma receptors (Fc gamma Rs) may influence malaria susceptibility and pathogenesis. Studying genetic susceptibility to malaria is ideal among sympatric populations because the distribution of polymorphic genes among such populations can help in the identification malaria candidate genes. This study determined the distribution of three FcyRs single nucleotide polymorphisms (SNPs) (Fc gamma RIIB-rs1050519, Fc gamma RIIC-rs3933769 and Fc gamma RIIIA-rs396991) among sympatric Fulani and Dogon children with uncomplicated malaria. The association of these SNPs with clinical, malariometric and immunological indices was also tested. Methods: This study involved 242 Fulani and Dogon volunteers from Mali age under 15 years. All SNPs were genotyped with predesigned TaqMan (R) SNP Genotyping Assays. Genotypic and allelic distribution of SNPs was compared across ethnic groups using the Fisher exact test. Variations in clinical, malariometric and immunologic indices between groups were tested with Kruskal-Wallis H, Mann-Whitney U test and Fisher exact test where appropriate. Results: The study confirmed known malariometric and immunologic differences between sympatric Fulani and non-Fulani tribes. Parasite density was lower in the Fulani than the Dogon (p < 0.0001). The mutant allele of Fc gamma RIIC (rs3933769) was found more frequently in the Fulani than the Dogon (p < 0.0001) while that of Fc gamma RIIIA (rs396991) occurred less frequently in the Fulani than Dogon (p = 0.0043). The difference in the mutant allele frequency of Fc gamma RIIB (rs1050519) between the two ethnic groups was however not statistically significant (p = 0.064). The mutant allele of rs396991 was associated with high malaria-specific IgG1 and IgG3 in the entire study population and Dogon tribe, p = 0.023 and 0.015, respectively. Parasite burden was lower in carriers of the Fc gamma RIIC (rs3933769) mutant allele than non-carriers in the entire study population (p < 0.0001). Carriers of this allele harboured less than half the parasites found in non-carriers. Conclusion: Differences in the allelic frequencies of rs3933769 and rs396991 among Fulani and Dogon indirectly suggest that these SNPs may influence malaria susceptibility and pathogenesis in the study population. The high frequency of the Fc gamma RIIC (rs3933769) mutant allele in the Fulani and its subsequent association with low parasite burden in the entire study population is noteworthy.

  • 9. Cook, Jackie
    et al.
    Aydin-Schmidt, Berit
    Gonzalez, Iveth J.
    Bell, David
    Edlund, Elin
    Nassor, Majda H.
    Msellem, Mwinyi
    Ali, Abdullah
    Abass, Ali K.
    Mårtensson, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Bjorkman, Anders
    Loop-mediated isothermal amplification (LAMP) for point-of-care detection of asymptomatic low-density malaria parasite carriers in Zanzibar2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, s. 43-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Asymptomatic, low parasite density malaria infections are difficult to detect with currently available point-of-care diagnostics. This study piloted a loop-mediated isothermal amplification (LAMP) kit for field-friendly, high-throughput detection of asymptomatic malaria infections during mass screening and treatment (MSAT) in Zanzibar, a malaria pre-elimination setting. Methods: Screening took place in three known hotspot areas prior to the short rains in November. Finger-prick blood was taken for screening by rapid diagnostic test (RDT) and LAMP and collected on filter paper for subsequent polymerase chain reaction (PCR) analyses. LAMP results were compared to RDT and to PCR using McNemar's test. Results: Approximately 1,000 people were screened. RDT detected ten infections (1.0% (95% CI 0.3-1.6)) whilst both LAMP and PCR detected 18 (1.8% (95% CI 0.9-2.6)) infections. However, PCR identified three infections that LAMP did not detect and vice versa. LAMP testing was easy to scale-up in field conditions requiring minimal training and equipment, with results ready one to three hours after screening. Conclusions: Despite lower than expected prevalence, LAMP detected a higher number of infections than the currently used diagnostic, RDT. LAMP is a field-friendly, sensitive diagnostic test that could be useful for MSAT malaria campaigns which require quick results to enable prompt treatment.

  • 10.
    Cotter, Chris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition. Univ Calif San Francisco, Global Hlth Grp, Malaria Eliminat Initiat, 550 16th St,3rd Floor, San Francisco, CA 94158 USA.
    Sudathip, Prayuth
    Minist Publ Hlth, Dept Dis Control, Bur Vector Borne Dis, Nonthaburi, Thailand.
    Herdiana, Herdiana
    UN Childrens Fund UNICEF, Aceh Field Off, Banda Aceh, Indonesia;Paritrana Asia Fdn, Jakarta, Indonesia.
    Cao, Yuanyuan
    Jiangsu Inst Parasit Dis, Jiangsu Prov Key Lab Parasite & Vector Control Te, Key Lab, Natl Hlth & Family Planning Commiss Parasit Dis C, Wuxi, Jiangsu, Peoples R China.
    Liu, Yaobao
    Jiangsu Inst Parasit Dis, Jiangsu Prov Key Lab Parasite & Vector Control Te, Key Lab, Natl Hlth & Family Planning Commiss Parasit Dis C, Wuxi, Jiangsu, Peoples R China.
    Luo, Alex
    Univ Calif San Francisco, Global Hlth Sci, San Francisco, CA 94158 USA.
    Ranasinghe, Neil
    Thomson Reuters Ltd, London, England.
    Bennett, Adam
    Univ Calif San Francisco, Global Hlth Grp, Malaria Eliminat Initiat, 550 16th St,3rd Floor, San Francisco, CA 94158 USA;Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA.
    Cao, Jun
    Jiangsu Inst Parasit Dis, Jiangsu Prov Key Lab Parasite & Vector Control Te, Key Lab, Natl Hlth & Family Planning Commiss Parasit Dis C, Wuxi, Jiangsu, Peoples R China.
    Gosling, Roly D.
    Univ Calif San Francisco, Global Hlth Grp, Malaria Eliminat Initiat, 550 16th St,3rd Floor, San Francisco, CA 94158 USA;Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA.
    Piloting a programme tool to evaluate malaria case investigation and reactive case detection activities: results from 3 settings in the Asia Pacific2017Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, artikel-id 347Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Case investigation and reactive case detection (RACD) activities are widely-used in low transmission settings to determine the suspected origin of infection and identify and treat malaria infections nearby to the index patient household. Case investigation and RACD activities are time and resource intensive, include methodologies that vary across eliminating settings, and have no standardized metrics or tools available to monitor and evaluate them. Methods: In response to this gap, a simple programme tool was developed for monitoring and evaluating (M&E) RACD activities and piloted by national malaria programmes. During the development phase, four modules of the RACD M&E tool were created to assess and evaluate key case investigation and RACD activities and costs. A pilot phase was then carried out by programme implementers between 2013 and 2015, during which malaria surveillance teams in three different settings (China, Indonesia, Thailand) piloted the tool over a period of 3 months each. This study describes summary results of the pilots and feasibility and impact of the tool on programmes. Results: All three study areas implemented the RACD M&E tool modules, and pilot users reported the tool and evaluation process were helpful to identify gaps in RACD programme activities. In the 45 health facilities evaluated, 71.8% (97/135; min 35.3-max 100.0%) of the proper notification and reporting forms and 20.0% (27/135; min 0.0-max 100.0%) of standard operating procedures (SOPs) were available to support malaria elimination activities. The tool highlighted gaps in reporting key data indicators on the completeness for malaria case reporting (98.8%; min 93.3-max 100.0%), case investigations (65.6%; min 61.8-max 78.4%) and RACD activities (70.0%; min 64.7-max 100.0%). Evaluation of the SOPs showed that knowledge and practices of malaria personnel varied within and between study areas. Average monthly costs for conducting case investigation and RACD activities showed variation between study areas (min USD $844.80-max USD $2038.00) for the malaria personnel, commodities, services and other costs required to carry out the activities. Conclusion: The RACD M&E tool was implemented in the three pilot areas, identifying key gaps that led to impacts on programme decision making. Study findings support the need for routine M&E of malaria case reporting, case investigation and RACD activities. Scale-up of the RACD M&E tool in malaria-eliminating settings will contribute to improved programme performance to the high level that is required to reach elimination.

  • 11.
    Dahal, Prabin
    et al.
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, WorldWide Antimalarial Resistance Network WWARN, Oxford, England.
    Simpson, Julie Anne
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostatist, Melbourne, Vic, Australia.
    Abdulla, Salim
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.
    Achan, Jane
    MRC Unit, Banjul, Gambia.
    Adam, Ishag
    Univ Khartoum, Fac Med, Khartoum, Sudan.
    Agarwal, Aarti
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.
    Allan, Richard
    Mentor Initiat, Fajara, Gambia.
    Anvikar, Anupkumar R.
    Natl Inst Malaria Res, Sector 8, Dwarka, New Delhi 110077, India.
    Arinaitwe, Emmanuel
    Infect Dis Res Collaborat, Kampala, Uganda.
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Myanmar Oxford Clin Res Unit, Yangon, Myanmar.
    Awab, Ghulam Rahim
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand;Minist Publ Hlth, Islam Republ Afghanistan, Kabul, Afghanistan.
    Bassat, Quique
    Ctr Investigacao Saude Manhica CISM, Maputo, Mozambique;Univ Barcelona, Hosp Clin, ISGlobal, Barcelona, Spain;ICREA, Pg Lluis Companys 23, Barcelona 08010, Spain.
    Bjorkman, Anders
    Karolinska Inst, Depatment Microbiol Tumour & Cell Biol, Stockholm, Sweden.
    Bompart, Francois
    Sanofi Access Med, Gentilly, France.
    Borrmann, Steffen
    Kenya Med Res Inst Kilifi, Kilifi, Kenya;Wellcome Trust Res Programme, Kilifi, Kenya;Heidelberg Univ, Sch Med, Dept Infect Dis, Heidelberg, Germany.
    Bousema, Teun
    Radboud Inst Hlth Sci, Radboudumc Nijmegen, Nijmegen, Netherlands;Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands.
    Broek, Ingrid
    Centrum Infectieziektebestrijding, Epidemioloog Epidemiol Surveillance RIVM, Bilthoven, Netherlands.
    Bukirwa, Hasifa
    African Field Epidemiol Network, Kampala, Uganda.
    Carrara, Verena I.
    Shoklo Malaria Res Unit, Mae Sot, Bangkok, Thailand;Mahidol Oxford Univ Res Unit, Bangkok, Thailand.
    Corsi, Marco
    Private Consultancy Drug Dev Trop Dis, Sigma Tau SpA Ind Farmaceutiche Riunite, Pomezia, Rome, Italy.
    Cot, Michel
    Univ Paris 05, Sorbonne Paris Cite, MERIT, IRD, F-75006 Paris, France.
    D'Alessandro, Umberto
    MRC Unit, Fajara, Gambia;London Sch Hyg & Trop Med, London, England.
    Davis, Timothy M. E.
    Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia.
    de Wit, Marit
    Med Sans Frontieres Operat Ctr Amsterdam, Geneva, Switzerland.
    Deloron, Philippe
    Univ Paris 05, Sorbonne Paris Cite, MERIT, IRD, F-75006 Paris, France.
    Desai, Meghna
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.
    Dimbu, Pedro Rafael
    Natl Malaria Control Program, Luanda, Angola.
    Djalle, Djibrine
    Inst Pasteur, BP 923, Bangui, Cent Afr Republ.
    Djimde, Abdoulaye
    Univ Sci Techn & Technol Bamako, Fac Pharm, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Bamako, Mali.
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Doumbo, Ogobara K.
    Univ Sci Techn & Technol Bamako, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Fac Med & Odonto Stomatol, Bamako, Mali.
    Drakeley, Chris J.
    London Sch Hyg & Trop Med, Dept Infect & Immun, London, England.
    Duparc, Stephan
    Med Malaria Venture, Geneva, Switzerland.
    Edstein, Michael D.
    Australian Army Malaria Inst, Brisbane, Qld, Australia.
    Espie, Emmanuelle
    R&D Ctr, GSK Vaccines, Clin & Epidemiol Dept, Epicentre, Ave Fleming 20,1300 Wavre,8 Rue St Sabin, F-75011 Paris, France.
    Faiz, Abul
    Malaria Res Grp, Chittagong, Bangladesh;Dev Care Fdn, Dhaka, Bangladesh.
    Falade, Catherine
    Univ Ibadan, Coll Med, Dept Pharmacol & Therapeut, Ibadan, Nigeria.
    Fanello, Caterina
    Univ Oxford, Nuffield Dept Med, Ctr Global Hlth, Oxford, England.
    Faucher, Jean-Francois
    Besancon Univ Med Ctr, Dept Infect Dis, Mother & Child Hlth Trop Res Unit, Inst Rech Dev IRD, Besancon, France.
    Faye, Babacar
    Univ Cheikh Anta Diop, Fac Med, Dept Med Parasitol, Dakar, Senegal.
    Fortes, Filomeno de Jesus
    Natl Malaria Control Program, Luanda, Angola.
    Gadalla, Nahla B.
    Sudanese Amer Med Assoc, Fairfax, VA USA.
    Gaye, Oumar
    Univ Cheikh Anta Diop, Dept Med Parasitol, Fac Med, Dakar, Senegal.
    Gil, J. Pedro
    Karolinska Inst, Div Pharmacogenet, Dept Physiol & Pharmacol, Drug Resistance Unit, Stockholm, Sweden;Univ Lisbon, Ctr Biodivers Funct & Integrat Gen, Fac Ciencias, Lisbon, Portugal.
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England.
    Grivoyannis, Anastasia
    Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA.
    Hamed, Kamal
    Basilea Pharmaceut Int Ltd, Basel, Switzerland;Novartis Pharmaceut, E Hanover, NJ USA.
    Hien, Tran Tinh
    Oxford Univ Clin Res Unit OUCRU, Ctr Trop Med, Wellcome Trust Major Overseas Program MOP, Oxford, England.
    Hughes, David
    Novartis Int AG, Basel, Switzerland.
    Humphreys, Georgina
    Wellcome Trust Res Labs, London, England;World Wide Antimalarial Resistance Network WWARN, London, England.
    Hwang, Jimee
    US Centers Dis Control & Prevent, Div Parasit Dis & Malaria, US Presidents Malaria Initiat Malaria Branch, Atlanta, GA USA;Univ Calif San Francisco, San Francisco, CA 94143 USA;Global Hlth Grp, San Francisco, CA 94143 USA.
    Ibrahim, Maman Laminou
    Ctr Rech Med & Saniataire CERMES, Niamey, Niger.
    Janssens, Bart
    Medecins Sans Frontieres, Phnom Penh, Belgium.
    Jullien, Vincent
    Univ Paris 05, Assistance Publique Hop Paris, Serv Pharmacol Clin, Paris, France;Grp Hosp Cochin Saint Vincent Paul, Inserm U663, WWARN, Paris, France.
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya.
    Kamugisha, Erasmus
    Weill Bugando Univ Coll Hlth Sci, Mwanza, Tanzania.
    Karema, Corine
    Minist Hlth, Natl Malaria Control Program TRAC Plus, Kigali, Rwanda.
    Karunajeewa, Harin A.
    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia.
    Kiechel, Jean R.
    Drugs Neglected Dis initiat, Geneva, Switzerland.
    Kironde, Fred
    Islam Univ Uganda, Habib Med Sch, Kampala, Uganda.
    Kofoed, Poul-Erik
    Bandim Hlth Project, Indepth Network, Apartado 861, Bissau, Guinea Bissau;Lillebaelt Hosp, Hlth Serv Res Unit, Vejle, Denmark;IRS Univ Southern Denmark, Vejle, Denmark;Kolding Cty Hosp, Dept Paediat, Kolding, Denmark.
    Kremsner, Peter G.
    Univ Tubingen, Inst Trop Med, Tubingen, Germany;Ctr Recherches Medic Lambarene, Lambarene, Gabon.
    Lameyre, Valerie
    Sanofi Access Med, Gentilly, France.
    Lee, Sue J.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand;Churchill Hosp, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Marsh, Kevin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Wellcome Trust Res Programme, Kilifi, Kenya;Kenya Govt Med Res Ctr, Kilifi, Kenya.
    Mårtensson, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition.
    Mayxay, Mayfong
    Mahosot Hosp, Lao Oxford Mahosot Hospital, Wellcome Trust Res Unit, Microbiol Lab, Viangchan, Laos.
    Menan, Herve
    Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire;Univ Hlth Sci, Minist Hlth, Fac Postgraduate Studies, Viangchan, Laos.
    Mens, Petra
    Acad Med Ctr, Med Microbiol Parasitol, Amsterdam, Netherlands.
    Mutabingwa, Theonest K.
    Hubert Kairuki Mem Univ, Dar Es Salaam, Tanzania;London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London, England.
    Ndiaye, Jean-Louis
    Univ Cheikh Anta Diop, Fac Med, Parasitol & Mycol Lab, Dakar, Senegal.
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Malaria Res, Stockholm, Sweden.
    Noedl, Harald
    Med Univ Vienna, Vienna, Austria.
    Nosten, Francois
    Univ Oxford, Nuffield Dept Med Res Bldg, Ctr Trop Med & Global Hlth, Old Rd Campus, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Mae Sot, Thailand.
    Offianan, Andre Toure
    Inst Pasteur Cote Ivoire, Malariol Dept, Abidjan, Cote Ivoire.
    Oguike, Mary
    London Sch Hyg & Trop Med, Dept Immunol & Infect, London, England.
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, Kisumu, Kenya;US Army Med Res Unit, Kisumu, Kenya.
    Olliaro, Piero
    UNICEF, UNDP, World Bank, WHO TDR, Geneva, Switzerland.
    Ouedraogo, Jean Bosco
    Inst Rech Sci Sante, Direct Regionale Ouest, Bobo Dioulasso, Burkina Faso;Ctr Muraz Bobo Dioulasso, Non Transmissible Dis Dept, Bobo Dioulasso, Burkina Faso.
    Piola, Patrice
    Inst Pasteur Cambodge, Phnom Penh, Cambodia.
    Plowe, Christopher V.
    Duke Univ, Duke Global Hlth Inst, Durham, NC USA.
    Plucinski, Mateusz M.
    US Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, US Presidents Malaria Initiat, Atlanta, GA USA;Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA USA.
    Pratt, Oliver James
    Minist Hlth & Social Welf, Natl Malaria Control Program, Monrovia, Liberia.
    Premji, Zulfikarali
    Muhimbili Univ Coll Hlth Sci, Dar Es Salaam, Tanzania.
    Ramharter, Michael
    Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Bernhard Nocht Inst Trop Med, Dept Trop Med, Hamburg, Germany.
    Rogier, Christophe
    Div Expertise & Def Hlth strategy, Cent Directorate, French Mil Hlth Serv, Paris, France;IRBA, Bretigny Sur Orge, France;URMITE, UMR 6236, Marseille, France.
    Rombo, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Sawa, Patrick
    Human Hlth Div, Int Ctr Insect Physiol & Ecol, Mbita, Kenya.
    Schramm, Birgit
    Epicentre, Paris, France.
    Sibley, Carol
    WWARN, Oxford, England;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
    Sinou, Veronique
    Aix Marseille Univ, INSERM, SSA, IRBA,MCT, Marseille, France.
    Sirima, Sodiomon
    GRAS, 06 BP 10248, Ouagadougou 06, Burkina Faso.
    Smithuis, Frank
    Myanmar Oxford Clin Res Unit, Oxford, England.
    Staedke, Sarah G.
    Infect Dis Res Collaborat, Kampala, Uganda;London Sch Hyg & Trop Med, Dept Clin Res, London, England.
    Sutanto, Inge
    Univ Indonesia, Dept Parasitol, Fac Med, 6 Salemba Raya, Jakarta 10430, Indonesia.
    Talisuna, Ambrose Otau
    WHO, Reg Off Afr, Brazzaville, Rep Congo;Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England.
    Tarning, Joel
    WorldWide Antimalarial Resistance Network, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Taylor, Walter R. J.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand.
    Temu, Emmanuel
    MENTOR Initiat, Crawley, England.
    Thriemer, Kamala L.
    Charles Darwin Univ, Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.
    Thuy, Nhien Nguyen
    Oxford Univ Clin Res Unit OUCRU, Wellcome Trust Major Overseas Program MOP, Ctr Trop Med, Oxford, England.
    Udhayakumar, Venkatachalam
    Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Malaria Branch & Presidents Malaria Initiat, Atlanta, GA USA.
    Ursing, Johan
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC C1, Solna, Sweden;Danderyd Hosp, Dept Infect Dis, Danderyd, Sweden.
    van Herp, Michel
    Operat Ctr Brussels, Med Sans Frontieres, Brussels, Belgium;Univ Amsterdam, Acad Med Ctr, Div Infect Dis, Ctr Trop Med & Travel Med, Amsterdam, Netherlands.
    van Vugt, Michele
    Whitty, Christopher
    London Sch Hyg & Trop Med, Dept Infect & Trop Dis, Malaria Partnership, London, England.
    William, Yavo
    Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire.
    Winnips, Cornelis
    NovartisInternat AG, Basel, Switzerland.
    Zongo, Issaka
    Inst Rech Sci Sante, Direct Regionale lOuest, Bobo Dioulasso, Burkina Faso.
    Guerin, Philippe
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Price, Ric N.
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Menzies Sch Hlth Res Charles Darwin Univ, Darwin, NT, Australia;Churchill Hosp, Ctr Clin Vaccinol & Trop Med, Oxford, England.
    Stepniewska, Kasia
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, WorldWide Antimalarial Resistance Network WWARN, Oxford, England.
    Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis2019Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 18, artikel-id 225Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.

    Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.

    Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.

    Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.

  • 12. Dugassa, Sisay
    et al.
    Lindh, Jenny M.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Torr, Steve J.
    Oyieke, Florence
    Lindsay, Steven W.
    Fillinger, Ulrike
    Electric nets and sticky materials for analysing oviposition behaviour of gravid malaria vectors2012Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, s. 374-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Little is known about how malaria mosquitoes locate oviposition sites in nature. Such knowledge is important to help devise monitoring and control measures that could be used to target gravid females. This study set out to develop a suite of tools that can be used to study the attraction of gravid Anopheles gambiae s.s. towards visual or olfactory cues associated with aquatic habitats. Methods: Firstly, the study developed and assessed methods for using electrocuting nets to analyse the orientation of gravid females towards an aquatic habitat. Electric nets (1m high x 0.5m wide) were powered by a 12V battery via a spark box. High and low energy settings were compared for mosquito electrocution and a collection device developed to retain electrocuted mosquitoes when falling to the ground. Secondly, a range of sticky materials and a detergent were tested to quantify if and where gravid females land to lay their eggs, by treating the edge of the ponds and the water surface. A randomized complete block design was used for all experiments with 200 mosquitoes released each day. Experiments were conducted in screened semi-field systems using insectary-reared An. gambiae s.s. Data were analysed by generalized estimating equations. Results: An electric net operated at the highest spark box energy of a 400 volt direct current made the net spark, creating a crackling sound, a burst of light and a burning smell. This setting caught 64% less mosquitoes than a net powered by reduced voltage output that could neither be heard nor seen (odds ratio (OR) 0.46; 95% confidence interval (CI) 0.40-0.53, p < 0.001). Three sticky boards (transparent film, glue coated black fly-screen and yellow film) were evaluated as catching devices under electric nets and the transparent and shiny black surfaces were found highly attractive (OR 41.6, 95% CI 19.8 -87.3, p < 0.001 and OR 28.8, 95% CI 14.5 - 56.8, p < 0.001, respectively) for gravid mosquitoes to land on compared to a yellow sticky film board and therefore unsuitable as collection device under the e-nets. With a square of four e-nets around a pond combined with yellow sticky boards on average 33% (95% CI 28-38%) of mosquitoes released were collected. Sticky materials and detergent in the water worked well in collecting mosquitoes when landing on the edge of the pond or on the water surface. Over 80% of collected females were found on the water surface (mean 103, 95% CI 93-115) as compared to the edge of the artificial pond (mean 24, 95% CI 20-28). Conclusion: A square of four e-nets with yellow sticky boards as a collection device can be used for quantifying the numbers of mosquitoes approaching a small oviposition site. Shiny sticky surfaces attract gravid females possibly because they are visually mistaken as aquatic habitats. These materials might be developed further as gravid traps. Anopheles gambiae s.s. primarily land on the water surface for oviposition. This behaviour can be exploited for the development of new trapping and control strategies.

  • 13.
    Eneh, Lynda K.
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Okal, Michael N.
    Borg-Karlson, Anna-Karin
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Fillinger, Ulrike
    Lindh, Jenny M.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Gravid Anopheles gambiae sensu stricto avoid ovipositing in Bermuda grass hay infusion and it's volatiles in two choice egg-count bioassays2016Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, artikel-id 276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: A number of mosquito species in the Culex and Aedes genera prefer to lay eggs in Bermuda grass (Cynodon dactylon) hay infusions compared to water alone. These mosquitoes are attracted to volatile compounds from the hay infusions making the infusions effective baits in gravid traps used for monitoring vectors of arboviral and filarial pathogens. Since Bermuda grass is abundant and widespread, it is plausible to explore infusions made from it as a potential low cost bait for outdoor monitoring of the elusive malaria vector Anopheles gambiae s.s. Methods: This study investigated preferential egg laying of individual An. gambiae s.s. in hay infusion or in tap water treated with volatiles detected in hay infusion headspace compared to tap water alone, using two-choice egg-count bioassays. Infusions were prepared by mixing 90 g of dried Bermuda grass (hay) with 24 L of unchlorinated tap water in a bucket, and leaving it for 3 days at ambient temperature and humidity. The volatiles in the headspace of the hay infusion were sampled with Tenax TA traps for 20 h and analysed using gas chromatography coupled to mass spectrometry. Results: In total, 18 volatiles were detected in the infusion headspace. Nine of the detected compounds and nonanal were selected for bioassays. Eight of the selected compounds have previously been suggested to attract/stimulate egg laying in An. gambiae s.s. Gravid females were significantly (p < 0.05) less likely to lay eggs in hay infusion dilutions of 25, 50 and 100 % and in tap water containing any of six compounds (3-methylbutanol, phenol, 4-methylphenol, nonanal, indole, and 3-methylindole) compared to tap water alone. The oviposition response to 10 % hay infusion or any one of the remaining four volatiles (4-hepten-1-ol, phenylmethanol, 2-phenylethanol, or 4-ethylphenol) did not differ from that in tap water. Conclusions: Anopheles gambiae s.s. prefers to lay eggs in tap water rather than Bermuda grass hay infusion. This avoidance of the hay infusion appears to be mediated by volatile organic compounds from the infusion. It is, therefore, unlikely that Bermuda grass hay infusion as formulated and used in gravid traps for Culex and Aedes mosquitoes will be suitable baits for monitoring gravid An. gambiae s.s.

  • 14.
    Eneh, Lynda K.
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Saijo, Hiromi
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Borg-Karlson, Anna-Karin
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Lindh, Jenny M.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Rajarao, Gunaratna Kuttuva
    KTH, Skolan för bioteknologi (BIO), Industriell bioteknologi.
    Cedrol, a malaria mosquito oviposition attractant is produced by fungi isolated from rhizomes of the grass Cyperus rotundus2016Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, artikel-id 478Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Cedrol, a sesquiterpene alcohol, is the first identified oviposition attractant for African malaria vectors. Finding the natural source of this compound might help to elucidate why Anopheles gambiae and Anopheles arabiensis prefer to lay eggs in habitats containing it. Previous studies suggest that cedrol may be a fungal metabolite and the essential oil of grass rhizomes have been described to contain a high amount of different sesquiterpenes. Results: Rhizomes of the grass Cyperus rotundus were collected in a natural malaria mosquito breeding site. Two fungi were isolated from an aqueous infusion with these rhizomes. They were identified as Fusarium falciforme and a species in the Fusarium fujikuroi species complex. Volatile compounds were collected from the headspace above fungal cultures on Tenax traps which were analysed by gas chromatography-mass spectrometry (GCMS). Cedrol and a cedrol isomer were detected in the headspace above the F. fujikuroi culture, while only cedrol was detected above the F. falciforme culture. Conclusion: Cedrol an oviposition attractant for African malaria vectors is produced by two fungi species isolated from grass rhizomes collected from a natural mosquito breeding site.

  • 15. Fievet, Nadine
    et al.
    Varani, Stefania
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Ibitokou, Samad
    Briand, Valerie
    Louis, Stephanie
    Perrin, Rene Xavier
    Massougbogji, Achille
    Hosmalin, Anne
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Deloron, Philippe
    Plasmodium falciparum exposure in utero, maternal age and parity influence the innate activation of foetal antigen presenting cells2009Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, s. 251-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Malaria in pregnancy is associated with immunological abnormalities in the newborns, such as hampered T-helper 1 responses and increased T-regulatory responses, while the effect of maternal Plasmodium falciparum infection on foetal innate immunity is still controversial. Materials and methods: The immunophenotype and cytokine release by dendritic cells (DC) and monocytes were evaluated in cord blood from 59 Beninese women with or without malaria infection by using flow cytometry. Results: Accumulation of malaria pigment in placenta was associated with a partial maturation of cord blood myeloid and plasmacytoid DC, as reflected by an up-regulated expression of the major histocompatibility complex class II molecules, but not CD86 molecules. Cells of newborns of mothers with malaria pigment in their placenta also exhibited significantly increased cytokine responses upon TLR9 stimulation. In addition, maternal age and parity influenced the absolute numbers and activation status of cord blood antigen-presenting cells. Lastly, maternal age, but not parity, influenced TLR3, 4 and 9 responses in cord blood cells. Discussion: Our findings support the view that placental parasitization, as indicated by the presence of malaria pigment in placental leukocytes, is significantly associated with partial maturation of different DC subsets and also to slightly increased responses to TLR9 ligand in cord blood. Additionally, other factors, such as maternal age and parity should be taken into consideration when analysing foetal/neonatal innate immune responses. Conclusion: These data advocate a possible mechanism by which PAM may modulate foetal/neonatal innate immunity.

  • 16. Gbedande, Komi
    et al.
    Cottrell, Gilles
    Vianou, Bertin
    Ibitokou, Samad
    Fernando, Aurax
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Salanti, Ali
    Moutairou, Kabirou
    Massougbodji, Achille
    Ndam, Nicaise Tuikue
    Deloron, Philippe
    Luty, Adrian J. F.
    Fievet, Nadine
    Infections with Plasmodium falciparum during pregnancy affect VAR2CSA DBL-5 domain-specific T cell cytokine responses2016Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, artikel-id 485Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Current knowledge of human immunological responses to pregnancy-associated malaria-specific Plasmodium falciparum protein VAR2CSA concerns almost exclusively B cell-driven antibody-mediated activity. Knowledge of VAR2CSA-specific T cell-mediated activity is minimal by comparison, with only a single published report of a study investigating VAR2CSA-derived peptide-specific T cell responses. The study described here represents an attempt to redress this balance. Methods: Within the framework of a cohort study of 1037 pregnant Beninese, sub-groups were selected on the basis of the documented presence/absence of infection with P. falciparum and conducted detailed immunological assessments both at inclusion into the study and at delivery. Peripheral blood mononuclear cells were isolated, stimulated in vitro, and VAR2CSA DBL-5 domain-specific, IFN-gamma-secreting T-cell frequencies and cytokine responses were quantified using flow cytometric techniques. Multivariate analyses were used to determine primarily whether the T cell-mediated DBL5-specific activity measured was associated with infection by P. falciparum adjusted for gravidity, anaemia and other cofactors. Results: Infections with P. falciparum detected at inclusion were associated with enhanced non-specific TNF responses, whilst diminished non-specific and DBL-5-specific IL-10 responses were associated with infections detected at delivery. Infections during pregnancy led to enhanced non-specific and DBL-5-specific IFN-gamma responses detectable at delivery but to concomitantly lower DBL-5-specific CD8+ IFN-gamma responses. Prospective assessments indicated that non-specific pro-inflammatory responses detectable at inclusion in the study were associated with the occurrence of infections subsequently during pregnancy. Conclusions: The findings represent a first step in elucidating the quantity and quality of cellular immunological responses to VAR2CSA, which will help in the development of the primary vaccine candidate for prevention of pregnancy-associated malaria.

  • 17. Golassa, Lemu
    et al.
    Enweji, Nizar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Erko, Berhanu
    Aseffa, Abraham
    Swedberg, Göte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Detection of a substantial number of sub-microscopic Plasmodium falciparum infections by polymerase chain reaction: a potential threat to malaria control and diagnosis in Ethiopia2013Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, s. 352-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Prompt and effective malaria diagnosis not only alleviates individual suffering, but also decreases malaria transmission at the community level. The commonly used diagnostic methods, microscopy and rapid diagnostic tests, are usually insensitive at very low-density parasitaemia. Molecular techniques, on the other hand, allow the detection of low-level, sub-microscopic parasitaemia. This study aimed to explore the presence of sub-microscopic Plasmodium falciparum infections using polymerase chain reaction (PCR). The PCR-based parasite prevalence was compared against microscopy and rapid diagnostic test (RDT). Methods: This study used 1,453 blood samples collected from clinical patients and sub-clinical subjects to determine the prevalence of sub-microscopic P. falciparum carriages. Subsets of RDT and microscopy negative blood samples were tested by PCR while all RDT and microscopically confirmed P. falciparum-infected samples were subjected to PCR. Finger-prick blood samples spotted on filter paper were used for parasite genomic DNA extraction. Results: The prevalence of sub-microscopic P. falciparum carriage was 19.2% (77/400) (95% CI = 15.4-23.1). Microscopy-based prevalence of P. falciparum infection was 3.7% (54/1,453) while the prevalence was 6.9% (100/1,453) using RDT alone. Using microscopy and PCR, the estimated parasite prevalence was 20.6% if PCR were performed in 1,453 blood samples. The prevalence was estimated to be 22.7% if RDT and PCR were used. Of 54 microscopically confirmed P. falciparum-infected subjects, PCR detected 90.7% (49/54). Out of 100 RDT-confirmed P. falciparum infections; PCR detected 80.0% (80/100). The sensitivity of PCR relative to microscopy and RDT was, therefore, 90.7% and 80%, respectively. The sensitivity of microscopy and RDT relative to PCR was 16.5 (49/299) and 24.2% (80/330), respectively. The overall PCR-based prevalence of P. falciparum infection was 5.6- and 3.3 fold higher than that determined by microscopy and RDT, respectively. None of the sub-microscopic subjects had severe anaemia, though 29.4% had mild anaemia (10-11.9 g/dl). Conclusions: Asymptomatic, low-density malaria infection was common in the study area and PCR may be a better tool for measuring Plasmodium prevalence than microscopy and RDT. The inadequate sensitivity of the diagnostic methods to detect substantial number of sub-microscopic parasitaemia would undoubtedly affect malaria control efforts, making reduction of transmission more difficult. RDT and microscopy-based prevalence studies and subsequent reports of reduction in malaria incidence underestimate the true pictures of P. falciparum infections in the community. PCR, on the other hand, seems to have reasonable sensitivity to detect a higher number of infected subjects with low and sub-microscopic parasite densities than RDTs or microscopy.

  • 18. Golassa, Lemu
    et al.
    Enweji, Nizar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Erko, Berhanu
    Aseffa, Abraham
    Swedberg, Göte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    High prevalence of pfcrt-CVIET haplotype in isolates from asymptomatic and symptomatic patients in south-central Oromia, Ethiopia2014Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, s. 120-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: As a result of extensive chloroquine resistance (CQR) in Plasmodium falciparum in late 1990s, Ethiopia replaced CQ with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2004. Plasmodium falciparum resistance to CQ is determined by the mutation at K76T of the P. falciparum chloroquine resistance transporter (pfcrt) gene. Understanding diversity in the P. falciparum genome is crucial since it has the potential to influence important phenotypes of the parasite such as drug resistance. Limited data is available regarding the type of pfcrt mutant allelic type, the effect of CQ withdrawal and diversity of the parasite population in south-central Oromia, Ethiopia. Methods: Finger-pricked blood spotted on Whatman 3MM filter papers were collected from falciparum malaria patients. Parasite DNA was extracted from individual blood spots on the filter papers. The presence of K76T mutations was determined using nested PCR for all isolates. Complete sequencing of mutations in pfcrt 72-76 was done for a set of randomly selected resistant isolates. Four microsatellite (MS) markers were analysed to determine the heterozygosity. Results: Although CQ was withdrawn for more than a decade, 100% of the parasites still carried the pfcrt K76T mutation. All isolates were mutant at the K76T polymorphism. Based on combinations of MS markers, seven different Ethiopian CQR variants (E1-E7) were identified. Heterozygosity (He) for MS flanking the pfcrt chloroquine resistance allele ranged from 0.00 (mscrt -29, -29.268 kb) to 0.21 (mscrt -2, -2.814 kb). H-e ranged from 0.00 (msint 3, 0 kb) to 0.19 (msint 2, 0 kb) for MS within the pfcrt gene. Both intronic and MS flanking the pfcrt gene showed low levels of diversity. Conclusion: pfcrt CQR allele seems to be fixed in the study area. Of the different haplotypes associated with CQR, only the CVIET genotype was identified. No reversal to the wild-type has occurred in Ethiopia unlike in many Africa countries where CQR parasites declined after cessation of CQ use. Decreased diversity in CQR isolates surrounding pfcrt suggests CQ selection and homogenization among CQR parasite population. While mutation in msint 3 and mscrt -29 of the mutant pfcrt allele is being fixed, it seems that mutations in msint 2 and mscrt -2 are still evolving and may indicate the start of re-diversification of the population from a fixed 76 T population.

  • 19. Golassa, Lemu
    et al.
    Erko, Berhanu
    Baliraine, Frederick N.
    Aseffa, Abraham
    Swedberg, Göte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Polymorphisms in chloroquine resistance-associated genes in Plasmodium vivax in Ethiopia2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, artikel-id 164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Evidence for decreasing chloroquine (CQ) efficacy against Plasmodium vivax has been reported from many endemic countries in the world. In Ethiopia, P. vivax accounts for 40% of all malaria cases and CQ is the first-line drug for vivax malaria. Mutations in multidrug resistance 1 (pvmdr-1) and K10 insertion in the pvcrt-o genes have been identified as possible molecular markers of CQ-resistance (CQR) in P. vivax. Despite reports of CQ treatment failures, no data are currently available on the prevalence of molecular markers of P. vivax resistance in Ethiopia. The objective of this study was to determine the prevalence of mutations in the pvmdr-1 and K10 insertion in the pvcrt-o genes. Methods: A total of 36 P. vivax clinical isolates were collected from West Arsi district in Ethiopia. Sequencing was used to analyse polymorphisms of the pvcrt-o and pvmdr-1 genes. Results: Sequencing results of the pvmdr-1 fragment showed the presence of two non-synonymous mutations at positions 976 and 1076. The Y -> F change at codon 976 (TAC -> TTC) was observed in 21 (75%) of 28 the isolates while the F -> L change (at codon 1076), which was due to a single mutation (TTT -> CTT), was observed in 100% of the isolates. Of 33 samples successfully amplified for the pvcrt-o, the majority of the isolates (93.9%) were wild type, without K10 insertion. Conclusions: High prevalence of mutations in candidate genes conferring CQR in P. vivax was identified. The fact that CQ is still the first-line treatment for vivax malaria, the significance of mutations in the pvcrt-o and pvmdr-1 genes and the clinical response of the patients' to CQ treatment and whether thus an association exists between point mutations of the candidate genes and CQR requires further research in Ethiopia.

  • 20. Golassa, Lemu
    et al.
    Kamugisha, Erasmus
    Ishengoma, Deus S.
    Baraka, Vito
    Shayo, Alex
    Baliraine, Frederick N.
    Enweji, Nizar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Erko, Berhanu
    Aseffa, Abraham
    Choy, Angel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Swedberg, Göte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Identification of large variation in pfcrt, pfmdr-1 and pfubp-1 markers in Plasmodium falciparum isolates from Ethiopia and Tanzania2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, artikel-id 264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Plasmodium falciparum resistance to anti-malarials is a major drawback in effective malaria control and elimination globally. Artemisinin-combination therapy (ACT) is currently the key first-line treatment for uncomplicated falciparum malaria. Plasmodium falciparum genetic signatures at pfmdr-1, pfcrt, and pfubp-1 loci are known to modulate in vivo and in vitro parasite response to ACT. The objective of this study was to assess the distribution of these resistance gene markers in isolates collected from different malaria transmission intensity in Ethiopia and Tanzania. Methods: Plasmodium falciparum clinical isolates were collected from different regions of Ethiopia and Tanzania. Genetic polymorphisms in the genes pfcrt, pfmdr-1 and pfubp-1 were analysed by PCR and sequencing. Frequencies of the different alleles in the three genes were compared within and between regions, and between the two countries. Results: The majority of the isolates from Ethiopia were mutant for the pfcrt 76 and wild-type for pfmdr-1 86. In contrast, the majority of the Tanzanian samples were wild-type for both pfcrt and pfmdr-1 loci. Analysis of a variable linker region in pfmdr-1 showed substantial variation in isolates from Tanzania as compared to Ethiopian isolates that had minimal variation. Direct sequencing of the pfubp-1 region showed that 92.8% (26/28) of the Ethiopian isolates had identical genome sequence with the wild type reference P. falciparum strain 3D7. Of 42 isolates from Tanzania, only 13 (30.9%) had identical genome sequences with 3D7. In the Tanzanian samples, 10 variant haplotypes were identified. Conclusion: The majority of Ethiopian isolates carried the main marker for chloroquine (CQ) resistance, while the majority of the samples from Tanzania carried markers for CQ susceptibility. Polymorphic genes showed substantially more variation in Tanzanian isolates. The low variability in the polymorphic region of pfmdr-1 in Ethiopia may be a consequence of low transmission intensity as compared to high transmission intensity and large variations in Tanzania.

  • 21. Gordicho, Vasco
    et al.
    Vicente, Jose L.
    Sousa, Carla A.
    Caputo, Beniamino
    Pombi, Marco
    Dinis, Joao
    Seixas, Goncalo
    Pålsson, Katinka
    KTH.
    Weetman, David
    Rodrigues, Amabelia
    della Torre, Alessandra
    Pinto, Joao
    First report of an exophilic Anopheles arabiensis population in Bissau City, Guinea-Bissau: recent introduction or sampling bias?2014Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, s. 423-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The malaria vector Anopheles arabiensis exhibits greater behavioural and ecological plasticity than the other major vectors of the Anopheles gambiae complex, which presents challenges for major control methods. This study reports for the first time the presence of An. arabiensis in Antula, a suburb of Bissau city, the capital of Guinea Bissau, where high levels of hybridization between Anopheles coluzzii and An. gambiae have been reported. Given that previous surveys in the area, based on indoor collections, did not sample An. arabiensis, the possibility of a recently introduced exophilic population was investigated. Methods: Larval and adult mosquito collections were carried out in Antula at the end of the rainy season of 2010. Anopheles gambiae species composition, determined by rDNA-IGS and SINE200X6.1 markers, was compared with four previously collected samples dating back to 1993. Analysis of ten microsatellites was used to estimate levels of genetic diversity, relatedness and to investigate demographic stability. Results: Anopheles arabiensis comprised 54.0% of larvae and 25.6% of adults collected in 2010, but was absent in all previous collections, a highly unlikely observation by chance if the population was stable. This species had the lowest levels of genetic diversity, highest relatedness and, along with An. gambiae, exhibited evidence of a recent population expansion. Conclusions: Results point to the presence of a previously undetected outdoor population of An. arabiensis in Antula, which appears to have expanded recently, highlighting the importance of complementing indoor-based mosquito collections with sampling methods targeting outdoor adults and immature stages for a more complete assessment of mosquito biodiversity. A change in temporal dynamics in the species complex composition was also detected. Coupled with previous evidence of asymmetric introgression from An. coluzzii to An. gambiae, this suggests that the study area may be subject to ecological changes with a potential impact on both the genetics of these species and on malaria transmission.

  • 22. Herrera-Varela, Manuela
    et al.
    Lindh, Jenny
    KTH, Skolan för kemivetenskap (CHE), Kemi, Organisk kemi.
    Lindsay, Steven W.
    Fillinger, Ulrike
    Habitat discrimination by gravid Anopheles gambiae sensu lato - a push-pull system2014Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, nr 1, s. 133-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The non-random distribution of anopheline larvae in natural habitats suggests that gravid females discriminate between habitats of different quality. Whilst physical and chemical cues used by Culex and Aedes vector mosquitoes for selecting an oviposition site have been extensively studied, those for Anopheles remain poorly explored. Here the habitat selection by Anopheles gambiae sensu lato (s.l.), the principal African malaria vector, was investigated when presented with a choice of two infusions made from rabbit food pellets, or soil. Methods: Natural colonization and larval survival was evaluated in artificial ponds filled randomly with either infusion. Dual-choice, egg-count bioassays evaluated the responses of caged gravid females to (1) two- to six-day old infusions versus lake water; (2) autoclaved versus non-autoclaved soil infusions; and assessed (3) the olfactory memory of gravid females conditioned in pellet infusion as larvae. Results: Wild Anopheles exclusively colonized ponds with soil infusion and avoided those with pellet infusion. When the individual infusions were tested in comparison with lake water, caged An. gambiae sensu stricto (s.s.) showed a dose response: females increasingly avoided the pellet infusion with increasing infusion age (six-day versus lake water: odds ratio (OR) 0.22; 95% confidence interval (CI) 0.1-0.5) and showed increasing preference to lay eggs as soil infusion age increased (six-day versus lake water: OR 2.1; 95% CI 1.4-3.3). Larvae survived in soil infusions equally well as in lake water but died in pellet infusions. Anopheles gambiae s.s. preferred to lay eggs in the non-autoclaved soil (OR 2.6; 95% CI 1.8-3.7) compared with autoclaved soil. There was no change in the avoidance of pellet infusion by individuals reared in the infusion compared with those reared in lake water. Conclusion: Wild and caged An. gambiae s.l. females discriminate between potential aquatic habitats for oviposition. These choices benefit the survival of the offspring. Although the study was not designed to distinguish between stimuli that acted over a distance or on contact, it could be demonstrated that the choice of habitat is mediated by chemical cues based on both preference and avoidance. These cues, if identified, might be developed for 'push-pull' strategies to improve malaria vector monitoring and control.

  • 23. Holtel, Andreas
    et al.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Penas-Jimenez, Inmaculada
    EU-funded malaria research under the 6th and 7th Framework Programmes for research and technological development.2011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, s. 11-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    While malaria research has traditionally been strong in Europe, targeted and sustained support for cooperative malaria research at EU level, namely through the EU's 6th and 7th Framework Programmes for research and technological development, FP6 (2002-2006) and FP7 (2007-2013), has boosted both impact and visibility of European malaria research. Most of the European malaria research community is now organized under a number of comprehensive and complementary research networks and projects, assembled around four key areas: (1) fundamental research on the malaria parasite and the disease, (2) development of new malaria drugs, (3) research and development of a malaria vaccine, and (4) research to control the malaria-transmitting mosquito vector. Considerable efforts were undertaken to ensure adequate participation of research groups from disease-endemic countries, in particular from Africa, with the long-term aim to strengthen cooperative links and research capacities in these countries. The concept of organizing European research through major strategic projects to form a "European Research Area" (ERA) was originally developed in the preparation of FP6, and ERA formation has now turned into a major EU policy objective explicitly inscribed into the Lisbon Treaty. EU-funded malaria research may serve as a showcase to demonstrate how ERA formation can successfully be implemented in a given area of science when several surrounding parameters converge to support implementation of this strategic concept: timely coincidence of political stimuli, responsive programming, a clearly defined--and well confined--area of research, and the readiness of the targeted research community who is well familiar with transnational cooperation at EU level. Major EU-funded malaria projects have evolved into thematic and organizational platforms that can collaborate with other global players. Europe may thus contribute more, and better, to addressing the global research agenda for malaria.

  • 24.
    Ishengoma, Deus S.
    et al.
    Natl Inst Med Res, Tanga Res Ctr, Tanga, Tanzania.
    Mandara, Celine I.
    Natl Inst Med Res, Tanga Res Ctr, Tanga, Tanzania;Kilimanjaro Christian Med Univ Coll, Kilimanjaro Christian Med Ctr, Moshi, Tanzania.
    Francis, Filbert
    Natl Inst Med Res, Tanga Res Ctr, Tanga, Tanzania.
    Talundzic, Eldin
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Lucchi, Naomi W.
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Ngasala, Billy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition. Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Sch Publ Hlth, Dar Es Salaam, Tanzania.
    Kabanywanyi, Abdunoor M.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.
    Mahende, Muhidin K.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.
    Kamugisha, Erasmus
    Catholic Univ Hlth & Allied Sci, Bugando Med Ctr, Mwanza, Tanzania.
    Kavishe, Reginald A.
    Kilimanjaro Christian Med Univ Coll, Kilimanjaro Christian Med Ctr, Moshi, Tanzania.
    Muro, Florida
    Kilimanjaro Christian Med Univ Coll, Kilimanjaro Christian Med Ctr, Moshi, Tanzania.
    Mohamed, Ally
    Natl Malaria Control Programme, Ocean Rd Luthuli Ave NIMR Complex, Dar Es Salaam, Tanzania.
    Mandike, Renata
    Natl Malaria Control Programme, Ocean Rd Luthuli Ave NIMR Complex, Dar Es Salaam, Tanzania.
    Mkude, Sigsbert
    Natl Malaria Control Programme, Ocean Rd Luthuli Ave NIMR Complex, Dar Es Salaam, Tanzania.
    Chacky, Frank
    Natl Malaria Control Programme, Ocean Rd Luthuli Ave NIMR Complex, Dar Es Salaam, Tanzania.
    Paxton, Lynn
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Greer, George
    US Embassy, US Presidents Malaria Initiat, US Agcy Int Dev, Dar Es Salaam, Tanzania.
    Kitojo, Chonge A.
    US Embassy, US Presidents Malaria Initiat, US Agcy Int Dev, Dar Es Salaam, Tanzania.
    Njau, Ritha
    WHO, Country Off, Dar Es Salaam, Tanzania.
    Martin, Troy
    Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, 1124 Columbia St, Seattle, WA 98104 USA.
    Venkatesan, Meera
    US Agcy Int Dev, US Presidents Malaria Initiat, Washington, DC 20523 USA.
    Warsame, Marian
    WHO, Global Malaria Programme, 20 Ave Appia, CH-1211 Geneva 27, Switzerland;Gothenburg Univ, Gothenburg, Sweden.
    Halsey, Eric S.
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA;Ctr Dis Control & Prevent, US Presidents Malaria Initiat, Atlanta, GA USA.
    Udhayakumar, Venkatachalam
    Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin-based combination therapy in mainland Tanzania2019Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 18, artikel-id 88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The World Health Organization recommends regular therapeutic efficacy studies (TES) to monitor the performance of first and second-line anti-malarials. In 2016, efficacy and safety of artemether-lumefantrine (AL) for the treatment of uncomplicated falciparum malaria were assessed through a TES conducted between April and October 2016 at four sentinel sites of Kibaha, Mkuzi, Mlimba, and Ujiji in Tanzania. The study also assessed molecular markers of artemisinin and lumefantrine (partner drug) resistance.

    Methods: Eligible patients were enrolled at the four sites, treated with standard doses of AL, and monitored for 28 days with clinical and laboratory assessments. The main outcomes were PCR corrected cure rates, day 3 positivity rates, safety of AL, and prevalence of single nucleotide polymorphisms in Plasmodium falciparum kelch 13 (Pfk13) (codon positions: 440-600) and P. falciparum multi-drug resistance 1 (Pfmdr1) genes (codons: N86Y, Y184F and D1246Y), markers of artemisinin and lumefantrine resistance, respectively.

    Results: Of 344 patients enrolled, three withdrew, six were lost to follow-up; and results were analysed for 335 (97.4%) patients. Two patients had treatment failure (one early treatment failure and one recrudescent infection) after PCR correction, yielding an adequate clinical and parasitological response of > 98%. Day 3 positivity rates ranged from 0 to 5.7%. Common adverse events included cough, abdominal pain, vomiting, and diarrhoea. Two patients had serious adverse events; one died after the first dose of AL and another required hospitalization after the second dose of AL (on day 0) but recovered completely. Of 344 samples collected at enrolment (day 0), 92.7% and 100% were successfully sequenced for Pfk13 and Pfmdr1 genes, respectively. Six (1.9%) had non-synonymous mutations in Pfk13, none of which had been previously associated with artemisinin resistance. For Pfmdr1, the NFD haplotype (codons N86, 184F and D1246) was detected in 134 (39.0%) samples; ranging from 33.0% in Mlimba to 45.5% at Mkuzi. The difference among the four sites was not significant (p = 0.578). All samples had a single copy of the Pfmdr1 gene.

    Conclusion: The study indicated high efficacy of AL and the safety profile was consistent with previous reports. There were no known artemisinin-resistance Pfk13 mutations, but there was a high prevalence of a Pfmdr1 haplotype associated with reduced sensitivity to lumefantrine (but no reduced efficacy was observed in the subjects). Continued TES and monitoring of markers of resistance to artemisinin and partner drugs is critical for early detection of resistant parasites and to inform evidence-based malaria treatment policies.

  • 25.
    Israelsson, Elisabeth
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Ekström, Mattias
    Nasr, Amre
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Dolo, Amagana
    Kearsley, Susannah
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Arambepola, Gishanthi
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Homann, Manijeh V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Maiga, Bakary
    Doumbo, Ogobara K.
    ElGhazali, Gehad
    Giha, Hayder A.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Berzins, Klavs
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Tornvall, Per
    Marked differences in CRP genotype frequencies between the Fulani and sympatric ethnic groups in Africa2009Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, nr 136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    C-reactive protein (CRP) is an acute phase protein that can activate various immune cells and bind to certain Fcγ receptors. The latter may compete with the binding of IgG antibodies to these receptors and could thereby interfere with the antigen-specific immune response. Polymorphisms in the promoter region of the CRP gene have been strongly associated with the plasma concentration of CRP. The known lower susceptibility to malaria in the Fulani ethnic group, as compared to their sympatric neighbours in Africa, has been linked to different genetic backgrounds. The present study was performed to investigate if polymorphisms in the CRP gene could contribute to the lower susceptibility to malaria seen in the Fulani ethnic group.

    Methods

    The CRP -717 T>C, -286 C>T>A, and +1444 C>T polymorphisms were analysed in asymptomatic Fulani and non-Fulani individuals from Mali and Sudan using Pyrosequencing T and TaqMan r MGB probes.

    Results

    The rare -286 A allele, previously shown to be associated with increased CRP expression and plasma levels, was shown to be more frequent in the non-Fulani ethnic groups as compared to the sympatric Fulani ethnic group both in Mali and Sudan. The common -717 T allele was more prevalent in the non-Fulani ethnic group compared to the sympatric Fulani ethnic group, but only in Mali. The parasite prevalence was increased for the -286 A allele, but not for the -717 T allele. No differences regarding genotype frequency or parasite prevalence were seen for +1444 C>T.

    Conclusion

    This study indicate that CRP may play an important role in the immune responses to malaria, and that the -286 C/T/A CRP polymorphism may be a contributing factor to the lower susceptibility to malaria seen in the Fulani.

  • 26.
    Israelsson, Elisabeth
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Vafa, Manijeh
    Maiga, Bakary
    Lysén, Anna
    Iriemenam, Nnaemeka C.
    Dolo, Amagana
    Doumbo, Ogobara K.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut.
    Berzins, Klavs
    Differences in Fcγ receptor IIa genotypes and IgG subclass pattern of anti-malarial antibodies between sympatric ethnic groups in Mali2008Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 7, nr 175Artikel i tidskrift (Refereegranskat)
  • 27.
    Johansson, Emily White
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Gething, Peter W
    Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, UK.
    Hildenwall, Helena
    Global Health - Health Systems and Policy, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
    Mappin, Bonnie
    Spatial Ecology and Epidemiology Group, Department of Zoology, University of Oxford, UK.
    Petzold, Max
    University of Gothenburg, The Sahlgrenska Academy, Health Metrics, Gothenburg, Sweden.
    Peterson, Stefan Swartling
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Ekholm Selling, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Effect of diagnostic testing on medicines used by febrile children less than five years in 12 malaria-endemic African countries: a mixed-methods study2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, artikel-id 194Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: In 2010, WHO revised guidelines to recommend testing all suspected malaria cases prior to treatment. Yet, evidence to assess programmes is largely derived from limited facility settings in a limited number of countries. National surveys from 12 sub-Saharan African countries were used to examine the effect of diagnostic testing on medicines used by febrile children under five years at the population level, including stratification by malaria risk, transmission season, source of care, symptoms, and age.

    METHODS: Data were compiled from 12 Demographic and Health Surveys in 2010-2012 that reported fever prevalence, diagnostic test and medicine use, and socio-economic covariates (n = 16,323 febrile under-fives taken to care). Mixed-effects logistic regression models quantified the influence of diagnostic testing on three outcomes (artemisinin combination therapy (ACT), any anti-malarial or any antibiotic use) after adjusting for data clustering and confounding covariates. For each outcome, interactions between diagnostic testing and the following covariates were separately tested: malaria risk, season, source of care, symptoms, and age. A multiple case study design was used to understand varying results across selected countries and sub-national groups, which drew on programme documents, published research and expert consultations. A descriptive typology of plausible explanations for quantitative results was derived from a cross-case synthesis.

    RESULTS: Significant variability was found in the effect of diagnostic testing on ACT use across countries (e.g., Uganda OR: 0.84, 95% CI: 0.66-1.06; Mozambique OR: 3.54, 95% CI: 2.33-5.39). Four main themes emerged to explain results: available diagnostics and medicines; quality of care; care-seeking behaviour; and, malaria epidemiology.

    CONCLUSIONS: Significant country variation was found in the effect of diagnostic testing on paediatric fever treatment at the population level, and qualitative results suggest the impact of diagnostic scale-up on treatment practices may not be straightforward in routine conditions given contextual factors (e.g., access to care, treatment-seeking behaviour or supply stock-outs). Despite limitations, quantitative results could help identify countries (e.g., Mozambique) or issues (e.g., malaria risk) where facility-based research or programme attention may be warranted. The mixed-methods approach triangulates different evidence to potentially provide a standard framework to assess routine programmes across countries or over time to fill critical evidence gaps.

  • 28.
    Johansson, Emily White
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Kitutu, Freddy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH). Makerere University School of Public Health, College of Health Sciences.
    Mayora, Chrispus
    Makerere University School of Public Health, College of Health Sciences.
    Awor, Phyllis
    Makerere University School of Public Health, College of Health Sciences.
    Peterson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Wamani, Henry
    Makerere University School of Public Health, College of Health Sciences.
    Hildenwall, Helena
    Karolinska Institutet, Global Health - Health Systems and Policy Research Group.
    "It could be viral, but you don't know. You have not diagnosed it": Health worker challenges in managing non-malaria pediatric fevers in the low transmission area of Mbarara District, Uganda2016Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, artikel-id 197Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In 2012, Uganda initiated nationwide deployment of malaria rapid diagnostic tests (RDT) as recommended by national guidelines. Yet growing concerns about RDT non-compliance in various settings have spurred calls to deploy RDT as part of enhanced support packages. An understanding of how health workers currently manage non-malaria fevers, particularly for children, and challenges faced in this work should also inform efforts.

    Methods: A qualitative study was conducted in the low transmission area of Mbarara District (Uganda). In-depth interviews with 20 health workers at lower level clinics focused on RDT perceptions, strategies to differentiate non-malaria pediatric fevers, influences on clinical decisions, desires for additional diagnostics, and any challenges in this work. Seven focus group discussions were conducted with caregivers of children less than five years in facility catchment areas to elucidate their RDT perceptions, understandings of non-malaria pediatric fevers and treatment preferences. Data were extracted into meaning units to inform codes and themes in order to describe response patterns using a content analysis approach. 

    Findings: Differential diagnosis strategies included studying fever patterns, taking histories, assessing symptoms and analyzing other factors such as child’s age or home environment. If no alternative cause was found, malaria treatment was reportedly often prescribed despite a negative result. Other reasons for malaria over-treatment stemmed from RDT perceptions, system constraints and provider-client interactions. RDT perceptions included mistrust driven largely by expectations of false negative results due to low parasite/antigen loads, previous anti-malarial treatment or test detection of only one species. System constraints included poor referral systems, working alone without opportunity to confer on difficult cases, and lacking skills and/or tools for differential diagnosis. Provider-client interactions included reported caregiver RDT mistrust, demand for certain drugs, and desire to know the ‘exact’ disease cause if not malaria. Many health workers expressed uncertainty about how to manage non-malaria pediatric fevers, feared doing wrong and patient death, worried caregivers would lose trust, or felt unsatisfied without a clear diagnosis.  

    Conclusions: Enhanced support is needed to improve RDT adoption at lower level clinics that focuses on empowering providers to successfully manage non-severe non-malaria pediatric fevers without referral. This includes building trust in negative results, reinforcing integrated care initiatives (e.g. Integrated Management of Childhood Illness) and fostering communities of practice according to the Diffusion of Innovation model.

     

  • 29.
    Johansson, Emily White
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Selling, Katarina Ekholm
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Nsona, Humphreys
    Minist Hlth, Integrated Management Childhood Illness IMCI Unit, Lilongwe, Malawi..
    Mappin, Bonnie
    Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England..
    Gething, Peter W.
    Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England..
    Petzold, Max
    Univ Gothenburg, Ctr Appl Biostat, Sahlgrenska Acad, Gothenburg, Sweden..
    Peterson, Stefan Swartling
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH). Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy Res Grp, Stockholm, Sweden.;Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Kampala, Uganda..
    Hildenwall, Helena
    Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy Res Grp, Stockholm, Sweden..
    Integrated paediatric fever management and antibiotic over-treatment in Malawi health facilities: data mining a national facility census2016Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, artikel-id 396Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: There are growing concerns about irrational antibiotic prescription practices in the era of test-based malaria case management. This study assessed integrated paediatric fever management using malaria rapid diagnostic tests (RDT) and Integrated Management of Childhood Illness (IMCI) guidelines, including the relationship between RDT-negative results and antibiotic over-treatment in Malawi health facilities in 2013-2014.

    Methods: A Malawi national facility census included 1981 observed sick children aged 2-59 months with fever complaints. Weighted frequencies were tabulated for other complaints, assessments and prescriptions for RDT-confirmed malaria, IMCI-classified non-severe pneumonia, and clinical diarrhoea. Classification trees using model-based recursive partitioning estimated the association between RDT results and antibiotic over-treatment and learned the influence of 38 other input variables at patient-, provider- and facility-levels.

    Results: Among 1981 clients, 72 % were tested or referred for malaria diagnosis and 85 % with RDT-confirmed malaria were prescribed first-line anti-malarials. Twenty-eight percent with IMCI-pneumonia were not prescribed antibiotics (under-treatment) and 59 % 'without antibiotic need' were prescribed antibiotics (over-treatment). Few clients had respiratory rates counted to identify antibiotic need for IMCI-pneumonia (18 %). RDT-negative children had 16.8 (95 % CI 8.6-32.7) times higher antibiotic over-treatment odds compared to RDT-positive cases conditioned by cough or difficult breathing complaints.

    Conclusions: Integrated paediatric fever management was sub-optimal for completed assessments and antibiotic targeting despite common compliance to malaria treatment guidelines. RDT-negative results were strongly associated with antibiotic over-treatment conditioned by cough or difficult breathing complaints. A shift from malaria-focused 'test and treat' strategies toward 'IMCI with testing' is needed to improve quality fever care and rational use of both anti-malarials and antibiotics in line with recent global commitments to combat resistance.

  • 30.
    Jovel, Irina T.
    et al.
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Björkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Roper, Cally
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England..
    Mårtensson, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Ursing, Johan
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden.;Danderyd Hosp, Dept Infect Dis, Stockholm, Sweden..
    Unexpected selections of Plasmodium falciparum polymorphisms in previously treatment-naive areas after monthly presumptive administration of three different anti-malarial drugs in Liberia 1976-782017Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, artikel-id 113Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: To assess the effect on malaria prevalence, village specific monthly administrations of pyrimethamine, chlorproguanil, chloroquine or placebo were given to children in four previously treatment-naive Liberian villages, 1976-78. Plasmodium falciparum in vivo resistance developed to pyrimethamine only. Selection of molecular markers of P.falciparum resistance after 2 years of treatment are reported. Methods: Blood samples were collected from 191 study children in a survey in 1978. Polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps, pfmrp1 and pfnhe1 genes were determined using PCR-based methods. Results: Pfcrt 72-76 CVIET was found in one chloroquine village sample, all remaining samples had pfcrt CVMNK. Pfmdr1 N86 prevalence was 100%. A pfmdr1 T1069(ACT -> ACG) synonymous polymorphism was found in 30% of chloroquine village samples and 3% of other samples (P = 0.008). Variations in pfnhe1 block I were found in all except the chloroquine treated village (P < 0.001). Resistance associated pfdhfr 108N prevalence was 2% in the pyrimethamine village compared to 45-65% elsewhere, including the placebo village (P = 0.001). Conclusions: Chloroquine treatment possibly resulted in the development of pfcrt 72-76 CVIET. Selection of pfmdr1 T1069(ACG) and a pfnhe1 block 1 genotypes indicates that chloroquine treatment exerted a selective pressure on P. falciparum. Pyrimethamine resistance associated pfdhfr 108N was present prior to the introduction of any drug. Decreased pfdhfr 108N frequency concurrent with development of pyrimethamine resistance suggests a non-pfdhfr polymorphisms mediated resistance mechanism.

  • 31.
    Kalyango, Joan N
    et al.
    Department of Public Health Sciences, Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Alfven, Tobias
    Department of Public Health Sciences, Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Peterson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Mugenyi, Kevin
    African Field Epidemiology Network (AFENET), Kampala, Uganda.
    Karamagi, Charles
    Clinical Epidemiology Unit, Makerere University College of Health Sciences, Kampala, Uganda.
    Rutebemberwa, Elizeus
    Department of Health Policy, Makerere University College of Health Scineces, Kampala, Uganda.
    Integrated community case management of malaria and pneumonia increases prompt and appropriate treatment for pneumonia symptoms in children under five years in Eastern Uganda2013Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, s. 340-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Efforts to improve access to treatment for common illnesses in children less than five years initially targeted malaria alone under the home management of malaria strategy. However under this strategy, children with other illnesses were often wrongly treated with anti-malarials. Integrated community case management of common childhood illnesses is now recommended but its effect on promptness of appropriate pneumonia treatment is unclear.ObjectivesTo determine the effect of integrated malaria and pneumonia management on receiving prompt and appropriate antibiotics for pneumonia symptoms and treatment outcomes as well as determine associated factors.

    METHODS: A follow-up study was nested within a cluster-randomized trial that compared under-five mortality in areas where community health workers (CHWs) treated children with malaria and pneumonia (intervention areas) and where they treated children with malaria only (control areas). Children treated by CHWs were enrolled on the day of seeking treatment from CHWs (609 intervention, 667 control) and demographic, illness, and treatment seeking information was collected. Further information on illness and treatment outcomes was collected on day four. The primary outcome was prompt and appropriate antibiotics for pneumonia symptoms and the secondary outcome was treatment outcomes on day four.

    RESULTS: Children in the intervention areas were more likely to receive prompt and appropriate antibiotics for pneumonia symptoms compared to children in the control areas (RR = 3.51, 95%CI = 1.75-7.03). Children in the intervention areas were also less likely to have temperature >=37.5[degree sign]C on day four (RR = 0.29, 95%CI = 0.11-0.78). The decrease in fast breathing between day one and four was greater in the intervention (9.2%) compared to the control areas (4.2%, p-value = 0.01).

    CONCLUSIONS: Integrated community management of malaria and pneumonia increases prompt and appropriate treatment for pneumonia symptoms and improves treatment outcomes. Trial registrationISRCTN: ISRCTN52966230.

  • 32.
    Kalyango, Joan N
    et al.
    Dept of Public Health Sciences, Division of Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Rutebemberwa, Elizeus
    Dept of Health Policy, Planning and Management, School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda.
    Alfven, Tobias
    Dept of Public Health Sciences, Division of Global Health (IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Ssali, Sarah
    Dept of Gender and Women Studies, Makerere University College of Health Sciences, Kampala, Uganda.
    Peterson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Karamagi, Charles
    Clinical Epidemiology Unit, Makerere University College of Health Sciences, Kampala, Uganda.
    Performance of community health workers under integrated community case management of childhood illnesses in eastern Uganda2012Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, nr 1, s. 282-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    Curative interventions delivered by community health workers (CHWs) were introduced to increase access to health services for children less than five years and have previously targeted single illnesses. However, CHWs in the integrated community case management of childhood illnesses strategy adopted in Uganda in 2010 will manage multiple illnesses. There is little documentation about the performance of CHWs in the management of multiple illnesses. This study compared the performance of CHWs managing malaria and pneumonia with performance of CHWs managing malaria alone in eastern Uganda and the factors influencing performance.

    METHODS:

    A mixed methods study was conducted among 125 CHWs providing either dual malaria and pneumonia management or malaria management alone for children aged four to 59 months. Performance was assessed using knowledge tests, case scenarios of sick children, review of CHWs' registers, and observation of CHWs in the dual management arm assessing respiratory symptoms. Four focus group discussions with CHWs were also conducted.

    RESULTS:

    CHWs in the dual- and single-illness management arms had similar performance with respect to: overall knowledge of malaria (dual 72 %, single 70 %); eliciting malaria signs and symptoms (50 % in both groups); prescribing anti-malarials based on case scenarios (82 % dual, 80 % single); and correct prescription of anti-malarials from record reviews (dual 99 %, single 100 %). In the dual-illness arm, scores for malaria and pneumonia differed on overall knowledge (72 % vs 40 %, p < 0.001); and correct doses of medicines from records (100 % vs 96 %, p < 0.001). According to records, 82 % of the children with fast breathing had received an antibiotic. From observations 49 % of CHWs counted respiratory rates within five breaths of the physician (gold standard) and 75 % correctly classified the children. The factors perceived to influence CHWs' performance were: community support and confidence, continued training, availability of drugs and other necessary supplies, and cooperation from formal health workers.

    CONCLUSION:

    CHWs providing dual-illness management handled malaria cases as well as CHWs providing single-illness management, and also performed reasonably well in the management of pneumonia. With appropriate training that emphasizes pneumonia assessment, adequate supervision, and provision of drugs and necessary supplies, CHWs can provide integrated treatment for malaria and pneumonia.

  • 33. Kamugisha, Erasmus
    et al.
    Jing, Sun
    Minde, Mercy
    Kataraihya, Johaness
    Kongola, Gilbert
    Kironde, Fred
    Swedberg, Göte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Efficacy of artemether-lumefantrine in treatment of malaria among under-fives and prevalence of drug resistance markers in Igombe-Mwanza, north-western Tanzania2012Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, s. 58-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Drug resistance to anti-malarials is a major public health problem worldwide. This study aimed at establishing the efficacy of artemether-lumefantrine (ACT) in Igombe-Mwanza, north-western Tanzania after a few years of ACT use, and establish the prevalence of mutations in key targets for artemisinin, chloroquine and sulphadoxine/pyrimetamine (SP) drugs. Methods: A prospective single cohort study was conducted at Igombe health centre using artemether-lumefantrine combination therapy between February 2010 and March 2011. The follow-up period was 28 days and outcome measures were according to WHO guidelines. Blood was collected on Whatman filter paper for DNA analysis. DNA extraction was done using TRIS-EDTA method, and mutations in Pfcrt, Pfmdr1, Pfdhfr, Pfdhps and Pfatp6 were detected using PCR-RFLP methods established previously. Results: A total of 103 patients completed the 28 days follow-up. The mean haemoglobin was 8.9 g/dl (range 5.0 to 14.5 g/dl) and mean parasite density was 5,608 parasites/mu l. Average parasite clearance time was 34.7 hours and all patients cleared the parasites by day 3. There was no early treatment failure in this study. Late clinical failure was seen in three (2.9%) patients and late parasitological failure (LPF) was seen in two (1.9%). PCR-corrected LPF was 1% and adequate clinical and parasitological response was 96%. The majority of parasites have wild type alleles on pfcrt 76 and pfmdr1 86 positions being 87.8% and 93.7% respectively. Mutant parasites predominated at pfdhfr gene at the main three positions 108, 51 and 59 with prevalence of 94.8%, 75.3% and 82.5% respectively. Post-treatment parasites had more wild types of pfdhps at position 437 and 540 than pre-treatment parasites. No mutation was seen in pfatp6 769 in re-infecting or recrudescing parasites. Conclusion: The efficacy of artemether-lumefantrine for treatment of uncomplicated malaria is still high in the study area although the rate of re-infection is higher than previously reported. Parasite clearance after 48 hours was lower compared to previous studies. The prevalence of wild type allele pfcrt 76 K and pfmdr1 86 N was high in the study area while markers for SP resistance is still high. Artemether-lumefantrine may be selecting for wild type alleles on both positions (437 and 540) of pfdhps.

  • 34.
    Kitutu, Freddy Eric
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition.
    Kalyango, Joan Nakayaga
    Mayora, Chrispus
    Ekholm Selling, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition.
    Peterson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition.
    Wamani, Henry
    Integrated community case management by drug sellers influences appropriate treatment of paediatric febrile illness in South Western Uganda: a quasi-experimental study.2017Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, nr 1, artikel-id 425Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Fever case management is a major challenge for improved child health globally, despite existence of cheap and effective child survival health technologies. The integrated Community Case Management (iCCM) intervention of paediatric febrile illnesses though adopted by Uganda's Ministry of Health to be implemented by community health workers, has not addressed the inaccess to life-saving medicines and diagnostics. Therefore, the iCCM intervention was implemented in private drug shops and evaluated for its effect on appropriate treatment of paediatric fever in a low malaria transmission setting in South Western Uganda.

    METHODS: From June 2013 to September 2015, the effect of the iCCM intervention on drug seller paediatric fever management and adherence to iCCM guidelines was assessed in a quasi-experimental study in South Western Uganda. A total of 212 care-seeker exit interviews were done before and 285 after in the intervention arm as compared to 216 before and 268 care-seeker interviews at the end of the study period in the comparison arm. The intervention effect was assessed by difference-in-difference analysis of drug seller treatment practices against national treatment recommendations between the intervention and comparison arms. Observed proportions among care-seeker interviews were compared with corresponding proportions from 5795 child visits recorded in patient registries and 49 direct observations of drug seller-care-seeker encounters in intervention drug shops.

    RESULTS: The iCCM intervention increased the appropriate treatment of uncomplicated malaria, pneumonia symptoms and non-bloody diarrhoea by 80.2% (95% CI 53.2-107.2), 65.5% (95% CI 51.6-79.4) and 31.4% (95% CI 1.6-61.2), respectively. Within the intervention arm, drug seller scores on appropriate treatment for pneumonia symptoms and diagnostic test use were the same among care-seeker exit interviews and direct observation. A linear trend (negative slope, - 0.009 p value < 0.001) was observed for proportions of child cases prescribed any antimicrobial medicine in the intervention arm drug shops.

    CONCLUSIONS: The iCCM intervention improved appropriate treatment for uncomplicated malaria, pneumonia symptoms and diarrhoea. Drug seller adherence to iCCM guidelines was high, without causing excessive prescription of antimicrobial medicines in this study. Further research should assess whether this effect is sustained over time and under routine supervision models.

  • 35.
    Kitutu, Freddy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH). Makerere Univ, Coll Hlth Sci, Pharm Dept, Kampala, Uganda.
    Wamani, Henry
    Makerere University School of Public Health.
    Ekholm Selling, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition.
    Katabazi, Fred
    Makerere University College of Health Sciences, Department of Medical Microbiology.
    Kuteesa, Ronald
    Makerere University College of Health Sciences, Infectious Disease Institute.
    Peterson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH). Makerere Univ, Coll Hlth Sci, Pharm Dept, Kampala, Uganda; Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda.
    Kalyango, Joan
    Makerere University College of Health Sciences, Department of Pharmacy.
    Mårtensson, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition.
    Can malaria rapid diagnostic tests by drug sellers under feld conditions classify children 5 years old or less with or without Plasmodium falciparum malaria?: Comparison with nested PCR analysis2018Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, artikel-id 365Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Malaria rapid diagnostic tests (RDTs) available as dipsticks or strips, are simple to perform, easily interpretable and do not require electricity nor infrastructural investment. Correct interpretation of and compliance with the malaria RDT results is a challenge to drug sellers. Thus, drug seller interpretation of malaria RDT strips was compared with laboratory scientist re-reading, and PCR analysis of Plasmodium DNA extracted from malaria RDT nitrocellulose strips and Fast Transient Analysis (FTA) cards. Malaria RDT cassettes are also assessed as potential source of Plasmodium DNA.

    Methods

    A total of 212 children aged between 2 and 60 months, 199 of whom had complete records at two study drug shops in south west Uganda participated in the study. Duplicate 5μL samples of capillary blood were picked from the 212 children, dispensed onto the sample well of the CareStartTM Pf-HRP2 RDT cassette and a fast transient analysis (FTA), WhatmanTM 3MM filter paper in parallel. The malaria RDT strip was interpreted by the drug seller within 15 to 20 minutes, visually re-read centrally by laboratory scientist and from it; Plasmodium DNA was recovered and detected by PCR, and compared with FTA recovered P. falciparum DNA PCR detection.

    Results

    Malaria positive samples were 62/199 (31.2% 95% CI 24.9 - 38.3) by drug seller interpretation of malaria RDT strip, 59/212 (27.8% 95% CI 22.2 – 34.3) by laboratory scientist, 55/212 (25.9% 95% CI 20.0 – 32.6) by RDT nitrocellulose strip PCR and 64/212 (30.2% 95% CI 24.4 – 37.7). The overall agreement between the drug seller interpretation and laboratory scientist re-reading of the malaria RDT strip was 93% with kappa value of 0.8 (95 % CI 0.7, 0.9). The drug seller compliance with the reported malaria RDT results and kappa value were 92.5% and 0.8 (95% CI 0.7, 0.9), respectively. The performance of the three diagnostic strategies compared with FTA PCR as the gold standard had sensitivity between 76.6% and 86.9%, specificity above 90%, positive predictive value ranging from 79% to 89.8% and negative predictive value above 90%.

    Conclusion:

    Drug sellers can use of malaria RDTs in field conditions and achieve acceptable accuracy for malaria diagnosis, and they comply with the malaria RDT results. Plasmodium DNA can be recovered from malaria RDT nitrocellulose strips even in the context of drug shops. Future malaria surveillance and diagnostic quality control studies with malaria RDT cassette as a source of Plasmodium DNA are recommended.

  • 36. Kofoed, Poul-Erik
    et al.
    Ursing, Johan
    Rodrigues, Amabelia
    Rombo, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Paracetamol versus placebo in treatment of non-severe malaria in children in Guinea-Bissau: a randomized controlled trial2011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, s. 148-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    The current guidelines for treatment of malaria include paracetamol to children with fever. No convincing evidence for the beneficial effects of this practice exists. Studies show that time to parasite clearance is significantly longer in children treated with paracetamol, which questions the policy. Whether this is of clinical importance has not been investigated.

    METHODS:

    Children with Plasmodium falciparum monoinfection and ≥20 parasites per 200 leucocytes at the Bandim Health Centre, Guinea-Bissau were randomized to receive paracetamol or placebo together with chloroquine for three days in a double blind randomized study. Temperature and symptoms were recorded twice daily during treatment and on day 3. The participants were interviewed and a malaria film taken once weekly until day 35. The data is in the form of grouped failure-times, the outcome of interest being time until parasitaemia during follow-up. Mantel-Haenszel weighted odds ratios are given. Other differences between and within the two groups have been tested using the Chi-square test and Mann-Whitney U test.

    RESULTS:

    In the evening of the day of inclusion, the temperature was slightly, but statistically insignificant, higher in the placebo group and significantly more children complained of headache. At no other time was a significant difference in temperature or symptoms detected. However, 6 children from the placebo-group as compared to two children from the paracetamol-group were admitted to hospital with high fever and convulsions by day 3. No differences in the cumulative percentages of children with adequate clinical and parasitological response were found in the intention-to-treat analysis or in the per-protocol analysis.

    CONCLUSION:

    Fewer children had early treatment failure and the mean temperature was slightly lower in the afternoon on day 0 in the paracetamol group. However, the cumulative adequate clinical and parasitological cure rates were not significantly different during the period of study. It is doubtful whether adding paracetamol to the treatment of uncomplicated malaria in children is beneficial.

    TRIAL REGISTRATION:

    NCT00137566

  • 37. Lalani, Mirza
    et al.
    Kitutu, Freddy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Clarke, Siân E
    Kaur, Harparkash
    Anti-malarial medicine quality field studies and surveys: a systematic review of screening technologies used and reporting of findings2017Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, nr 1, artikel-id 197Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    BACKGROUND: Assessing the quality of medicines in low-middle income countries (LMICs) relies primarily on human inspection and screening technologies, where available. Field studies and surveys have frequently utilized screening tests to analyse medicines sampled at the point of care, such as health care facilities and medicine outlets, to provide a snap shot of medicine quality in a specific geographical area. This review presents an overview of the screening tests typically employed in surveys to assess anti-malarial medicine quality, summarizes the analytical methods used, how findings have been reported and proposes a reporting template for future studies.

    METHODS: A systematic search of the peer-reviewed and grey literature available in the public domain (including national and multi-national medicine quality surveys) covering the period 1990-2016 was undertaken. Studies were included if they had used screening techniques to assess the quality of anti-malarial medicines. As no standardized set of guidelines for the methodology and reporting of medicine quality surveys exist, the included studies were assessed for their standard against a newly proposed list of criteria.

    RESULTS: The titles and abstracts of 4621 records were screened and only 39 were found to meet the eligibility criteria. These 39 studies utilized visual inspection, disintegration, colorimetry and Thin Layer Chromatography (TLC) either as components of the Global Pharma Health Fund (GPHF) MiniLab(®) or as individual tests. Overall, 30/39 studies reported employing confirmatory testing described in international pharmacopeia to verify the quality of anti-malarials post assessment by a screening test. The authors assigned scores for the 23 criteria for the standard of reporting of each study.

    CONCLUSIONS: There is considerable heterogeneity in study design and inconsistency in reporting of field surveys of medicine quality. A lack of standardization in the design and reporting of studies of medicine quality increases the risk of bias and error, impacting on the generalizability and reliability of study results. The criteria proposed for reporting on the standard of studies in this review can be used in conjunction with existing medicine quality survey guidelines as a checklist for designing and reporting findings of studies. The review protocol has been registered with PROSPERO (CRD42015026782).

  • 38.
    Lemma, Hailemariam
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Löfgren, Curt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    San Sebastian, Miguel
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Adherence to a six-dose regimen of artemether-lumefantrine among uncomplicated Plasmodium falciparum patients in the Tigray Region, Ethiopia2011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, s. 349-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: In 2004, Ethiopia switched its first-line treatment of uncomplicated Plasmodium falciparum malaria from sulphadoxine-pyrimethamine to a fixed artemisinin-based combination therapy (ACT), artemether-lumefantrine (AL). Patient adherence to AL regimen is a major determining factor to achieve the desired therapeutic outcome. The aim of this study was to measure patient adherence levels to the six-dose AL regimen for the treatment of uncomplicated P. falciparum malaria and to identify its determinant factors in rural areas of the Tigray region, Ethiopia

    METHODS: The study was conducted under routine health service delivery at health posts level. Patients/caregivers were not informed about their home visit and were traced on the day after they finished the AL regimen. By combining the response to a structured questionnaire and the tablet count from the blister, adherence level was classified into three categories: definitely non-adherent, probably non-adherent and probably adherent. Reasons for being definitely non-adherent were also assessed. For the purpose of examine risk factors, definitely non-adherent and probably non-adherent was merged into a non-adherent group. Variables found significantly associated (p < 0.05) with the adherence level on the univariate analysis were fitted into a multivariate logistic regression model.

    RESULTS: Out of the total initially enrolled 180 patients, 86.1% completed the follow-up. Out of these, 38.7% were classified as probably adherent, 34.8% as probably non-adherent, and 26.5% were definitely non-adherent. The most common reasons that definitely non-adherents gave for not taking the full dose were "too many tablets" (37.3%) and to "felt better before finished the treatment course" (25.5%). The adherence of the patients was associated with the ownership of a radio (adjusted odd ratio, AOR: 3.8; 95% CI: 1.66-8.75), the belief that malaria can be treated traditionally (AOR: 0.09; 95% CI: 0.01-0.78) and a delay of more than one day in seeking treatment after the onset of fever (AOR: 5.39; 95% CI: 1.83-15.88).

    CONCLUSION: The very low adherence to AL found in this study raises serious concerns for the malaria control in the region. The implementation of a monitoring adherence system is essential to ensure long-term treatment efficacy.

  • 39.
    Lindh, Jenny M.
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi.
    Okal, M. N.
    Herrera-Varela, M.
    Borg-Karlson, Anna Karin
    KTH, Skolan för kemivetenskap (CHE), Kemi.
    Torto, B.
    Lindsay, S. W.
    Fillinger, U.
    Discovery of an oviposition attractant for gravid malaria vectors of the Anopheles gambiae species complex2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, nr 1, artikel-id 119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: New strategies are needed to manage malaria vector populations that resist insecticides and bite outdoors. This study describes a breakthrough in developing 'attract and kill' strategies targeting gravid females by identifying and evaluating an oviposition attractant for Anopheles gambiae s.l. Methods: Previously, the authors found that gravid An. gambiae s.s. females were two times more likely to lay eggs in lake water infused for six days with soil from a natural oviposition site in western Kenya compared to lake water alone or to the same but autoclaved infusion. Here, the volatile chemicals released from these substrates were analysed with a gas-chromatograph coupled to a mass-spectrometer (GC-MS). Furthermore, the behavioural responses of gravid females to one of the compounds identified were evaluated in dual choice egg-count bioassays, in dual-choice semi-field experiments with odour-baited traps and in field bioassays. Results: One of the soil infusion volatiles was readily identified as the sesquiterpene alcohol cedrol. Its widespread presence in natural aquatic habitats in the study area was confirmed by analysing the chemical headspace of 116 water samples collected from different aquatic sites in the field and was therefore selected for evaluation in oviposition bioassays. Twice as many gravid females were attracted to cedrol-treated water than to water alone in two choice cage bioassays (odds ratio (OR) 1.84; 95% confidence interval (CI) 1.16-2.91) and in experiments conducted in large-screened cages with free-flying mosquitoes (OR 1.92; 95% CI 1.63-2.27). When tested in the field, wild malaria vector females were three times more likely to be collected in the traps baited with cedrol than in the traps containing water alone (OR 3.3; 95% CI 1.4-7.9). Conclusion: Cedrol is the first compound confirmed as an oviposition attractant for gravid An. gambiae s.l. This finding paves the way for developing new 'attract and kill strategies' for malaria vector control.

  • 40.
    Lohy Das, Jesmin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kyaw, Myat P.
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Nyunt, Myat
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Chit, Khin
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Aye, Kyin
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Aye, Moe
    Department of Medical Research, Yangon, Republic of the Union of Myanmar..
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bergstrand, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Tarning, Joel
    Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand;Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
    Population Pharmacokinetic and Pharmacodynamic Properties of Artesunate in Patients with Artemisinin Resistant Infections in Southern Myanmar2018Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, artikel-id 126Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Artemisinins are the most effective anti-malarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening the possibility to control and eliminate malaria. This work aimed to evaluate the pharmacokinetic and pharmacodynamic properties of artesunate and its active metabolite, dihydroartemisinin, in patients with sensitive and resistant falciparum infections in Southern Myanmar. In addition, a simple nomogram previously developed to identify artemisinin resistant malaria infections was evaluated. Methods: Fifty-three (n = 53) patients were recruited and received daily oral artesunate monotherapy (4 mg/kg) for 7 days. Frequent artesunate and dihydroartemisinin plasma concentration measurements and parasite microscopy counts were obtained and evaluated using nonlinear mixed-effects modelling. Results: The absorption of artesunate was best characterized by a transit-compartment (n = 3) model, followed by one-compartment disposition models for artesunate and dihydroartemisinin. The drug-dependent parasite killing effect of dihydroartemisinin was described using an Emax function, with a mixture model discriminating between artemisinin sensitive and resistant parasites. Overall, 56% of the studied population was predicted to have resistant malaria infections. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. Conclusion: The pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to differentiate between drug sensitive and resistant infections in these patients. More than half of all patients recruited in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights its potential clinical usefulness.

  • 41. Lokki, A Inkeri
    et al.
    Järvelä, Irma
    Israelsson, Elisabeth
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Maiga, Bakary
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Dolo, Amagana
    Doumbo, Ogobara K
    Meri, Seppo
    Holmberg, Ville
    Lactase persistence genotypes and malaria susceptibility in Fulani of Mali.2011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, s. 9-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Fulani are a widely spread African ethnic group characterized by lower susceptibility to Plasmodium falciparum, clinical malaria morbidity and higher rate of lactase persistence compared to sympatric tribes. Lactase non-persistence, often called lactose intolerance, is the normal condition where lactase activity in the intestinal wall declines after weaning. Lactase persistence, common in Europe, and in certain African people with traditions of raising cattle, is caused by polymorphisms in the enhancer region approximately 14 kb upstream of the lactase gene.

    METHODS: To evaluate the relationship between malaria and lactase persistence genotypes, a 400 bp region surrounding the main European C/T-13910 polymorphism upstream of the lactase gene was sequenced. DNA samples used in the study originated from 162 Fulani and 79 Dogon individuals from Mali.

    RESULTS: Among 79 Dogon only one heterozygote of the lactase enhancer polymorphism was detected, whereas all others were homozygous for the ancestral C allele. Among the Fulani, the main European polymorphism at locus C/T-13910 was by far the most common polymorphism, with an allele frequency of 37%. Three other single-nucleotide polymorphisms were found with allele frequencies of 3.7%, 1.9% and 0.6% each. The novel DNA polymorphism T/C-13906 was seen in six heterozygous Fulani. Among the Fulani with lactase non-persistence CC genotypes at the C/T-13910 locus, 24% had malaria parasites detectable by microscopy compared to 18% for lactase persistent genotypes (P = 0.29). Pooling the lactase enhancer polymorphisms to a common presumptive genotype gave 28% microscopy positives for non-persistent and 17% for others (P = 0.11).

    CONCLUSIONS: Plasmodium falciparum parasitaemia in asymptomatic Fulani is more common in individuals with lactase non-persistence genotypes, but this difference is not statistically significant. The potential immunoprotective properties of dietary cow milk as a reason for the partial malaria resistance of Fulani warrant further investigation.

  • 42. Lover, Andrew A
    et al.
    Sutton, Brett A
    Asy, Angelina J
    Wilder-Smith, Annelies
    Institute of Public Health, University of Heidelberg, Germany.
    An exploratory study of treated-bed nets in Timor-Leste: patterns of intended and alternative usage.2011Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, s. 199-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The Timor-Leste Ministry of Health has recently finalized the National Malaria Control Strategy for 2010-2020. A key component of this roadmap is to provide universal national coverage with long-lasting insecticide-treated nets (LLINs) in support of achieving the primary goal of reducing both morbidity and mortality from malaria by 30% in the first three years, followed by a further reduction of 20% by end of the programme cycle in 2020 1. The strategic plan calls for this target to be supported by a comprehensive information, education and communication (IEC) programme; however, there is limited prior research into household and personal usage patterns to assist in the creation of targeted, effective, and socio-culturally specific behaviour change materials.

    METHODS: Nine separate focus group discussions (FGDs) were carried out in Dili, Manatuto, and Covalima districts, Democratic Republic of Timor-Leste, in July 2010.These focus groups primarily explored themes of perceived malaria risk, causes of malaria, net usage patterns within families, barriers to correct and consistent usage, and the daily experience of users (both male and female) in households with at least one net. Comprehensive qualitative analysis utilized open source analysis software.

    RESULTS: The primary determinants of net usage were a widespread perception that nets could or should only be used by pregnant women and young children, and the availability of sufficient sleeping space under a limited number of nets within households. Both nuisance biting and disease prevention were commonly cited as primary motivations for usage, while seasonality was not a significant factor. Long-term net durability and ease of hanging were seen as key attributes in net design preference. Very frequent washing cycles were common, potentially degrading net effectiveness. Finally, extensive re-purposing of nets (fishing, protecting crops) was both reported and observed, and may significantly decrease availability of nighttime sleeping space for all family members if distributed nets do not remain within the household.

    CONCLUSIONS: Emphasizing that net usage is acceptable and important for all family members regardless of age or gender, and addressing the complex behavioural economics of alternative net usages could have significant impacts on malaria control efforts in Timor-Leste, as the country's programmes make progress towards universal net coverage.

  • 43.
    Low, Matthew
    et al.
    Swedish Univ Agr Sci, Dept Ecol, Box 7044, S-75007 Uppsala, Sweden..
    Tsegaye, Admasu Tassew
    Univ Addis Ababa, Ethiopian Inst Water Resources, Addis Ababa, Ethiopia..
    Ignell, Rickard
    Swedish Univ Agr Sci, Dept Plant Protect Biol, Unit Chem Ecol, Box 102, S-23053 Alnarp, Sweden..
    Hill, Sharon
    Swedish Univ Agr Sci, Dept Plant Protect Biol, Unit Chem Ecol, Box 102, S-23053 Alnarp, Sweden..
    Elleby, Rasmus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Geovetenskapliga sektionen, Institutionen för geovetenskaper. Swedish Univ Agr Sci, Dept Ecol, Box 7044, S-75007 Uppsala, Sweden..
    Feltelius, Vilhelm
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Geovetenskapliga sektionen, Institutionen för geovetenskaper. Swedish Univ Agr Sci, Dept Ecol, Box 7044, S-75007 Uppsala, Sweden..
    Hopkins, Richard
    Univ Greenwich, Nat Resources Inst, London SE18 6PF, England..
    The importance of accounting for larval detectability in mosquito habitat-association studies2016Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, artikel-id 253Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Mosquito habitat-association studies are an important basis for disease control programmes and/or vector distribution models. However, studies do not explicitly account for incomplete detection during larval presence and abundance surveys, with potential for significant biases because of environmental influences on larval behaviour and sampling efficiency.

    Methods: Data were used from a dip-sampling study for Anopheles larvae in Ethiopia to evaluate the effect of six factors previously associated with larval sampling (riparian vegetation, direct sunshine, algae, water depth, pH and temperature) on larval presence and detectability. Comparisons were made between: (i) a presence-absence logistic regression where samples were pooled at the site level and detectability ignored, (ii) a success versus trials binomial model, and (iii) a presence-detection mixture model that separately estimated presence and detection, and fitted different explanatory variables to these estimations.

    Results: Riparian vegetation was consistently highlighted as important, strongly suggesting it explains larval presence (-). However, depending on how larval detectability was estimated, the other factors showed large variations in their statistical importance. The presence-detection mixture model provided strong evidence that larval detectability was influenced by sunshine and water temperature (+), with weaker evidence for algae (+) and water depth (-). For larval presence, there was also some evidence that water depth (-) and pH (+) influenced site occupation. The number of dip-samples needed to determine if larvae were likely present at a site was condition dependent: with sunshine and warm water requiring only two dips, while cooler water and cloud cover required 11.

    Conclusions: Environmental factors influence true larval presence and larval detectability differentially when sampling in field conditions. Researchers need to be more aware of the limitations and possible biases in different analytical approaches used to associate larval presence or abundance with local environmental conditions. These effects can be disentangled using data that are routinely collected (i.e., multiple dip samples at each site) by employing a modelling approach that separates presence from detectability.

  • 44.
    Lwanira, Catherine N.
    et al.
    Makerere Univ, Coll Hlth Sci, Sch Biomed Sci, Kampala, Uganda..
    Mukasa, Mark Kaddu
    Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda..
    Swedberg, Göte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Kironde, Fred
    Makerere Univ, Coll Hlth Sci, Sch Biomed Sci, Kampala, Uganda.;Islamic Univ Uganda IUIU, Fac Hlth Sci, Habib Med Sch, Kampala, Uganda..
    Frequency of RANTES gene polymorphisms and their association with incidence of malaria: a longitudinal study on children in Iganga district, Uganda2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, artikel-id 341Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The severity and outcome of malaria is influenced by host immunity in which chemokines such as Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) play an important role. Previous studies show that variations in the RANTES gene affect RANTES protein production, hence altering host immunity. In this study, the relationship between presence of mutations in RANTES and incidence of malaria in a cohort of children living in a malaria-endemic area of Uganda was determined. Methods: This was a longitudinal study comprising of 423 children aged between 6 months and 9 years, who were actively followed up for 1 year. Malaria episodes occurring in the cohort children were detected and the affected children treated with national policy drug regimen. Mutations in the RANTES gene were determined by PCR-RFLP method and their frequencies were calculated. A multivariate negative binomial regression model was used to estimate the impact of RANTES mutations on malaria incidence. In all statistical tests, a P-value of <0.05 was considered as significant. Results: The frequencies of the -403A and In1.1C allele were 53.7 and 19.2 %, respectively. No mutations were found at the -28 locus. After adjustment of incidence rates for age, blood group, insecticide-treated bed net (ITN) use, malaria history and the sickle cell trait, 1n1.1T/C heterozygotes and homozygotes showed a non-significant trend towards higher incidence rates compared to wild-type individuals (IRR = 1.10; P = 0.55 and IRR = 1.25; P = 0.60, respectively). Similarly, there was no significant difference in malaria incidence rates between RANTES -403G/A heterozygotes or homozygotes and those without mutations (IRR = 1.09; P = 0.66 and IRR = 1.16; P = 0.50, respectively). No relation was seen between RANTES polymorphisms, baseline parasite densities and the time to first re-infection after administration of anti-malaria drugs. Conclusions: This study showed that the -403A mutation occurs in nearly half of the study population and the In1.1C allele occurs in one in every four children. Despite the high frequency of these mutations, there was no clear association with malaria incidence. Other studies evaluating more markers, that could potentially modulate RANTES gene transcription alongside other genetic modifiers of malaria susceptibility, may provide further explanations to these less dramatic findings.

  • 45.
    Lwanira, Catherine Nassozi
    et al.
    Makerere Univ, Coll Hlth Sci, Sch Biomed Sci, Kampala, Uganda..
    Kironde, Fred
    Islamic Univ Uganda IUIU, Fac Hlth Sci, Habib Med Sch, Kampala Campus, Uganda..
    Kaddumukasa, Mark
    Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda..
    Swedberg, Göte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda2017Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, artikel-id 322Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Host genetics play an important role in Plasmodium falciparum malaria susceptibility. However, information on host genetic factors and their relationships with malaria in the vaccine trial site of Iganga, Uganda is limited. The main objective of this study was to determine the prevalence of selected host genetic markers and their relationship to malaria incidence in the vaccine trial site of Iganga, Uganda. In a 1-year longitudinal cohort study, 423 children aged below 9 years were recruited and their malaria episodes were investigated. Host genetic polymorphisms were assessed by PCR-RFLP, haemoglobin electrophoresis and DNA sequencing. Using a multivariate negative binomial regression model, estimates of the impact of human genetic polymorphisms on malaria incidence were performed. In all statistical tests, a P value of < 0.05 was considered as significant. Results: The prevalences of sickle cell haemoglobin trait, G6PD c. 202 G > A (rs 1050828) and NOS2 -954 G > C (rs 1800482) variants were 26.6, 22.7 and 17.3%, respectively. Inducible nitric oxide synthase 2 (NOS2 -954 G>C; rs 1800482) heterozygosity was associated with lower incidence of malaria in all age groups {Adjusted incident rates ratio (aIRR) 0.59; 95% CI [0.386-0.887]; P = 0.012)}. About 4% of study subjects had co-existence of sickle cell Hb trait and G6PD deficiency. Sickle cell Hb heterozygotes (Hb AS) aged less than 1 year experienced significantly more malaria episodes annually than children with normal haemoglobin (Hb AA) {aIRR = 1.98; 95% CI [1.240-3.175]; P = 0.004}. There was no significant influence of the sickle cell trait on malaria incidence among older children of 1-9 years. Conclusions: Mutation (NOS2 -954 G > C; rs 1800482) of nitric oxide synthase 2 gene promoter was associated with a lower incidence of acute malaria. The normal haemoglobin (wild genotype; HbAA) was associated with reduced malaria incidence rates during the first year of life. More understanding of the interplay between host genetics and malaria susceptibility is required.

  • 46.
    Maiga, Bakary
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Universités de Bamako, Bali.
    Dolo, Amagana
    Campino, Susana
    Sepulveda, Nuno
    Corran, Patrick
    Rockett, Kirk A.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Doumbo, Ogobara K.
    Clark, Taane G.
    Glucose-6-phosphate dehydrogenase polymorphisms and susceptibility to mild malaria in Dogon and Fulani, Mali2014Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, s. 270-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. Methods: A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. Results: It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (< 1% versus Dogon 7.9%). The Betica-Selma 968C/376G (similar to 11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. Conclusions: The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency.

  • 47. Marwa, Karol J.
    et al.
    Schmidt, Theresa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sjögren, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Minzi, Omary M. S.
    Kamugisha, Erasmus
    Swedberg, Göte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations2014Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, s. 420-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Artemisinin-based combinations currently recommended for treatment of uncomplicated Plasmodium falciparum malaria in many countries of sub-Saharan Africa are substrates of CYP enzymes. The cytochrome enzyme system is responsible for metabolism of about 80-90% of clinically used drugs. It is, therefore, important to obtain the pharmacogenetics of the population in the region with respect to these combinations and thereby enable practitioners to predict treatment outcomes. The aim of this study was to detect and determine allelic frequencies of CYP2C8*2, CYP2C8*3, CYP3A4*1B, CYP3A5*3 and CYP2B6*6 variant alleles in a Tanzanian indigenous population. Methods: Genomic DNA extraction from blood obtained from 256 participants who escorted patients at Karume Health Centre in Mwanza Tanzania, was carried out using the Gene JET (TM) Genomic DNA purification kit (Thermo Scientific). Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. Amplification was done by PCR while differentiation between alleles was done by restriction fragment length polymorphism (PCR-RFLP) (for CYP2C8*2, CYP2C8*3) and sequencing (for CYP2B6*6, CYP3A5*3 and CYP3A4*1B). Results: CYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A4*1B and CYP2B6*6 variant allelic frequencies were found to be 19,10,16,78 and 36% respectively. Conclusion: Prevalence of CYP2C8*2, CYP3A5*3, CYP3A4*1B and CYP2B6*6 mutations in a Tanzanian population/ subjects are common. The impact of these point mutations on the metabolism of anti-malarial drugs, particularly artemisinin-based combinations, and their potential drug-drug interactions (DDIs) needs to be further evaluated.

  • 48. Minja, Daniel T. R.
    et al.
    Schmiegelow, Christentze
    Oesterholt, Mayke
    Magistrado, Pamela A.
    Boström, Stephanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    John, Davis
    Pehrson, Caroline
    Andersen, Daniel
    Deloron, Philippe
    Salanti, Ali
    Lemnge, Martha
    Luty, Adrian J. F.
    Alifrangis, Michael
    Theander, Thor
    Lusingu, John P. A.
    Reliability of rapid diagnostic tests in diagnosing pregnancy associated malaria in North Eastern Tanzania2012Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, s. 211-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Accurate diagnosis and prompt treatment of pregnancy-associated malaria (PAM) are key aspects in averting adverse pregnancy outcomes. Microscopy is the gold standard in malaria diagnosis, but it has limited detection and availability. When used appropriately, rapid diagnostic tests (RDTs) could be an ideal diagnostic complement to microscopy, due to their ease of use and adequate sensitivity in detecting even sub-microscopic infections. Polymerase chain reaction (PCR) is even more sensitive, but it is mainly used for research purposes. The accuracy and reliability of RDTs in diagnosing PAM was evaluated using microscopy and PCR. Methods: A cohort of pregnant women in north-eastern Tanzania was followed throughout pregnancy for detection of plasmodial infection using venous and placental blood samples evaluated by histidine rich protein 2 (HRP-2) and parasite lactate dehydrogenase (pLDH) based RDTs (Parascreen (TM)) or HRP-2 only (Paracheck Pf (R) and ParaHIT (R) f), microscopy and nested Plasmodium species diagnostic PCR. Results: From a cohort of 924 pregnant women who completed the follow up, complete RDT and microscopy data was available for 5,555 blood samples and of these 442 samples were analysed by PCR. Of the 5,555 blood samples, 49 ((proportion and 95% confidence interval) 0.9% [0.7 - 1.1]) samples were positive by microscopy and 91 (1.6% [1.3-2.0]) by RDT. Forty-six (50.5% [40.5 - 60.6]) and 45 (49.5% [39.4 - 59.5]) of the RDT positive samples were positive and negative by microscopy, respectively, whereas nineteen (42.2% [29.0 - 56.7]) of the microscopy negative, but RDT positive, samples were positive by PCR. Three (0.05% [0.02 - 0.2]) samples were positive by microscopy but negative by RDT. 351 of the 5,461 samples negative by both RDT and microscopy were tested by PCR and found negative. There was no statistically significant difference between the performances of the different RDTs. Conclusions: Microscopy underestimated the real burden of malaria during pregnancy and RDTs performed better than microscopy in diagnosing PAM. In areas where intermittent preventive treatment during pregnancy may be abandoned due to low and decreasing malaria risk and instead replaced with active case management, screening with RDT is likely to identify most infections in pregnant women and out-performs microscopy as a diagnostic tool.

  • 49. Morris, Ulrika
    et al.
    Khamis, Mwinyi
    Aydin-Schmidt, Berit
    Abass, Ali K
    Msellem, Mwinyi I
    Nassor, Majda H
    González, Iveth J
    Mårtensson, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Ali, Abdullah S
    Björkman, Anders
    Cook, Jackie
    Field deployment of loop-mediated isothermal amplification for centralized mass-screening of asymptomatic malaria in Zanzibar: a pre-elimination setting2015Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, artikel-id 205Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Molecular tools for detection of low-density asymptomatic Plasmodium infections are needed in malaria elimination efforts. This study reports results from the hitherto largest implementation of loop-mediated isothermal amplification (LAMP) for centralized mass screening of asymptomatic malaria in Zanzibar.

    METHODS: Healthy individuals present and willing to participate in randomly selected households in 60 villages throughout Zanzibar were screened for malaria by rapid diagnostic tests (RDT). In 50 % of the study households, participants were asked to provide 60 μL of finger-prick blood for additional LAMP screening. LAMP was conducted in two centralized laboratories in Zanzibar, by trained technicians with limited or no previous experience of molecular methods. The LAMP assay was performed with Loopamp(TM) MALARIA Pan/Pf Detection Kit (Eiken Chemical Company, Japan). Samples positive for Plasmodium genus (Pan)-LAMP were re-tested using Plasmodium falciparum-specific LAMP kits.

    RESULTS: Paired RDT and LAMP samples were available from 3983 individuals. The prevalence of asymptomatic malaria was 0.5 % (CI 95 % 0.1-0.8) and 1.6 % (CI 95 % 1.1-2.2) by RDT and Pan-LAMP, respectively. LAMP detected 3.4 (CI 95 % 2.2-5.2) times more Plasmodium positive samples than RDT. DNA contamination was experienced, but solved by repetitive decontamination of all equipment and reagents.

    CONCLUSIONS: LAMP is a simple and sensitive molecular tool, and has potential in active surveillance and mass-screening programmes for detection of low-density asymptomatic malaria in pre-elimination settings. However, in order to deploy LAMP more effectively in field settings, protocols may need to be adapted for processing larger numbers of samples. A higher throughput, affordable closed system would be ideal to avoid contamination.

  • 50.
    Mubi, Marycelina
    et al.
    Department of Medicine, Malaria Research, Karolinska Institutet, Stockholm, Sweden.
    Kakoko, Deodatus
    Department of Behavioural Sciences, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Saalam, Tanzania.
    Ngasala, Billy
    Department of Parasitology and Medical entomology, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Saalam, Tanzania.
    Premji, Zul
    Department of Parasitology and Medical entomology, School of Public Health and Social Sciences, Muhimbili University of Health and Allied Sciences, Dar es Saalam, Tanzania.
    Peterson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Bjorkman, Anders
    Department of Medicine, Malaria Research, Karolinska Institutet, Stockholm, Sweden.
    Martensson, Andreas
    Department of Medicine, Malaria Research, Karolinska Institutet, Stockholm, Sweden.
    Malaria diagnosis and treatment practices following introduction of rapid diagnostic tests in Kibaha District, Coast Region, Tanzania2013Ingår i: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, s. 293-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The success of the universal parasite-based malaria testing policy for fever patients attending primary health care (PHC) facilities in Tanzania will depend highly on health workers' perceptions and practices. The aim of this study was, therefore, to assess the present use of malaria diagnostics (rapid diagnostic tests (RDTs) and microscopy), prescription behaviour and factors affecting adherence to test results at PHC facilities in Kibaha District, Coast Region, Tanzania. Methods: Exit interviews were conducted with fever patients at PHC facilities and information on diagnostic test performed and treatment prescribed were recorded. Interviews with prescribers to assess their understanding, perceptions and practices related to RDTs were conducted, and health facility inventory performed to assess availability of staff, diagnostics and anti-malarial drugs. Results: The survey was undertaken at ten governmental PHC facilities, eight of which had functional diagnostics. Twenty health workers were interviewed and 195 exit interviews were conducted with patients at the PHC facilities. Of the 168 patients seen at facilities with available diagnostics, 105 (63%) were tested for malaria, 31 (30%) of whom tested positive. Anti-malarial drugs were prescribed to all patients with positive test results, 14% of patients with negative results and 28% of patients not tested for malaria. Antibiotics were more likely to be prescribed to patients with negative test results compared to patients with positive results (81 vs 39%, p < 0.01) and among non-tested compared to those tested for malaria (84 vs 69%, p = 0.01). Stock-outs of RDTs and staff shortage accounted for the low testing rate, and health worker perceptions were the main reason for non-adherence to test results. Conclusions: Anti-malarial prescription to patients with negative test results and those not tested is still practiced in Tanzania despite the universal malaria testing policy of fever patients. The use of malaria diagnostics was also associated with higher prescription of antibiotics among patients with negative results. Strategies to address health system factors and health worker perceptions associated with these practices are needed.

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