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  • 1.
    Abate, Ebba
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Gondar, Ethiopia.
    Belayneh, Meseret
    University of Addis Ababa, Ethiopia.
    Idh, Jonna
    Vastervik Hospital, Sweden.
    Diro, Ermias
    University of Gondar, Ethiopia.
    Elias, Daniel
    University of Southern Denmark, Denmark.
    Britton, Sven
    Karolinska Hospital, Sweden.
    Aseffa, Abraham
    Armauer Hansen Research Institute, Ethiopia.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar County Hospital, Sweden.
    Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity2015In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 9, no 8, article id e0003994Article in journal (Refereed)
    Abstract [en]

    Background The impact of intestinal helminth infection on the clinical presentation and immune response during active tuberculosis (TB) infection is not well characterized. Our aim was to investigate whether asymptomatic intestinal helminth infection alters the clinical signs and symptoms as well as the cell mediated immune responses in patients with active TB.

    Methodology Consecutive, newly diagnosed TB patients and healthy community controls (CCs) were recruited in North-west Ethiopia. TB-score, body mass index and stool samples were analyzed. Cells from HIV-negative TB patients (HIV-/TB) and from CCs were analyzed for regulatory T-cells (Tregs) and cytokine responses using flow cytometry and ELISPOT, respectively.

    Results A significantly higher ratio of helminth co-infection was observed in TB patients without HIV (Helm+/HIV-/TB) compared to HIV negative CCs, (40% (121/306) versus 28% (85/306), p = 0.003). Helm+/HIV-/TB patients showed significantly increased IL-5 secreting cells compared to Helm-/HIV-/TB (37 SFU (IQR:13-103) versus 2 SFU (1-50); p = 0.02, n = 30). Likewise, levels of absolute Tregs (9.4 (3.2-16.7) cells/mu l versus 2.4 (1.1-4.0) cells/mu l; p = 0.041) and IL-10 secreting cells (65 SFU (7-196) versus 1 SFU (0-31); p = 0.014) were significantly higher in Helm+/HIV-/TB patients compared to Helm-/HIV-/TB patients. In a multivariate analysis, a lower rate of sputum smear positivity for acid fast bacilli, lower body temperature, and eosinophilia were independently associated with helminth infection in TB patients.

    Conclusions Asymptomatic helminth infection is associated with increased regulatory T-cell and Th2-type responses and a lower rate of sputum smear positivity. Further studies are warranted to investigate the clinical and immunological impact of helminth infection in TB patients.

  • 2.
    Abioye, Ajibola I.
    et al.
    Brown Univ, RI 02912 USA.
    McDonald, Emily A.
    Brown Univ, RI 02912 USA.
    Park, Sangshin
    Brown Univ, RI 02912 USA; Univ Seoul, South Korea.
    Joshi, Ayush
    Brown Univ, RI 02912 USA.
    Kurtis, Jonathan D.
    Brown Univ, RI 02912 USA.
    Wu, Hannah
    Brown Univ, RI 02912 USA.
    Pond-Tor, Sunthorn
    Brown Univ, RI 02912 USA.
    Sharma, Surendra
    Brown Univ, RI 02912 USA; Women and Infants Hosp Rhode Isl, RI 02908 USA.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Baltazar, Palmera
    Remedios Trinidad Romualdez Hosp, Philippines.
    Acosta, Luz P.
    Res Inst Trop Med, Philippines.
    Olveda, Remigio M.
    Res Inst Trop Med, Philippines.
    Tallo, Veronica
    Res Inst Trop Med, Philippines.
    Friedman, Jennifer F.
    Brown Univ, RI 02912 USA.
    Maternal, placental and cord blood cytokines and the risk of adverse birth outcomes among pregnant women infected with Schistosoma japonicum in the Philippines2019In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 13, no 6, article id e0007371Article in journal (Refereed)
    Abstract [en]

    Background The objectives of this study were to 1) evaluate the influence of treatment with praziquantel on the inflammatory milieu in maternal, placental, and cord blood, 2) assess the extent to which proinflammatory signatures in placental and cord blood impacts birth outcomes, and 3) evaluate the impact of other helminths on the inflammatory micro environment. Methods/Findings This was a secondary analysis of samples from 369 mother-infant pairs participating in a randomized controlled trial of praziquantel given at 12-16 weeks gestation. We performed regression analysis to address our study objectives. In maternal peripheral blood, the concentrations of CXCL8, and TNF receptor I and II decreased from 12 to 32 weeks gestation, while IL-13 increased. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Hookworm infection was associated with elevated placental IL-1, CXCL8 and IFN-gamma. The risk of small-for-gestational age increased with elevated IL-6, IL-10, and CXCL8 in cord blood. The risk of prematurity was increased when cord blood sTNFRI and placental IL-5 were elevated. Conclusions Our study suggests that fetal cytokines, which may be related to infectious disease exposures, contribute to poor intrauterine growth. Additionally, hookworm infection influences cytokine concentrations at the maternal-fetal interface. Clinical Trial Registry number and website ClinicalTrials.gov (NCT00486863). Author summary Schistosomiasis is one of the most prevalent parasitic tropical diseases, and it is primarily treated with the drug praziquantel. This study examined the effects of praziquantel treatment for schistosomiasis and the presence of geohelminth infections during pregnancy on cytokines in maternal, placental, and cord blood, and examined the effects of pro-inflammatory signatures at the maternal-fetal interface on perinatal outcomes. We analyzed the data of 369 mother-infant pairs obtained from a randomized controlled trial of praziquantel given at 12-16 weeks gestation. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Elevated levels of both Th1 and Th2 cytokines were associated with the risk of adverse perinatal outcomes (small-for-gestational age and prematurity). Hookworm coinfection at 12 weeks gestation was, however, related to elevated levels of certain cytokines in the placenta (IL-1, IL-5, CXCL8 and IFN-gamma).

  • 3. Affognon, Hippolyte
    et al.
    Mburu, Peter
    Hassan, Osama Ahmed
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kingori, Sarah
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sang, Rosemary
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ethnic groups' knowledge, attitude and practices and Rift Valley fever exposure in Isiolo County of Kenya2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 3, article id e0005405Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever (RVF) is an emerging mosquito-borne viral hemorrhagic fever in Africa and the Arabian Peninsula, affecting humans and livestock. For spread of infectious diseases, including RVF, knowledge, attitude and practices play an important role, and the understanding of the influence of behavior is crucial to improve prevention and control efforts. The objective of the study was to assess RVF exposure, in a multiethnic region in Kenya known to experience RVF outbreaks, from the behavior perspective. We investigated how communities in Isiolo County, Kenya were affected, in relation to their knowledge, attitude and practices, by the RVF outbreak of 2006/2007. A cross-sectional study was conducted involving 698 households selected randomly from three different ethnic communities. Data were collected using a structured questionnaire regarding knowledge, attitudes and practices that could affect the spread of RVF. In addition, information was collected from the communities regarding the number of humans and livestock affected during the RVF outbreak. This study found that better knowledge about a specific disease does not always translate to better practices to avoid exposure to the disease. However, the high knowledge, attitude and practice score measured as a single index of the Maasai community may explain why they were less affected, compared to other investigated communities (Borana and Turkana), by RVF during the 2006/2007 outbreak. We conclude that RVF exposure in Isiolo County, Kenya during the outbreak was likely determined by the behavioral differences of different resident community groups. We then recommend that strategies to combat RVF should take into consideration behavioral differences among communities.

  • 4.
    Aira, Naomi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Anna-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Singh, Susmita K.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Mckay, Derek M.
    University of Calgary, Canada.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Species dependent impact of helminth-derived antigens on human macrophages infected with Mycobacterium tuberculosis: Direct effect on the innate anti-mycobacterial response2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 3, article id e0005390Article in journal (Refereed)
    Abstract [en]

    Background In countries with a high prevalence of tuberculosis there is high coincident of helminth infections that might worsen disease outcome. While Mycobacterium tuberculosis (Mtb) gives rise to a pro-inflammatory Th1 response, a Th2 response is typical of helminth infections. A strong Th2 response has been associated with decreased protection against tuberculosis. Principal findings We investigated the direct effect of helminth-derived antigens on human macrophages, hypothesizing that helminths would render macrophages less capable of controlling Mtb. Measuring cytokine output, macrophage surface markers with flow cytometry, and assessing bacterial replication and phagosomal maturation revealed that antigens from different species of helminth directly affect macrophage responses to Mtb. Antigens from the tapeworm Hymenolepis diminuta and the nematode Trichuris muris caused an anti-inflammatory response with M2-type polarization, reduced macrophage phagosome maturation and ability to activate T cells, along with increased Mtb burden, especially in T. muris exposed cells which also induced the highest IL-10 production upon co-infection. However, antigens from the trematode Schistosoma mansoni had the opposite effect causing a decrease in IL-10 production, M1-type polarization and increased control of Mtb. Conclusion We conclude that, independent of any adaptive immune response, infection with helminth parasites, in a species-specific manner can influence the outcome of tuberculosis by either enhancing or diminishing the bactericidal function of macrophages.

  • 5. Alm, Erik
    et al.
    Lesko, Birgitta
    Lindegren, Gunnel
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Soderholm, Sandra
    Falk, Kerstin I.
    Lagerqvist, Nina
    Universal Single-Probe RT-PCR Assay for Diagnosis of Dengue Virus Infections2014In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 8, no 12, p. e3416-Article in journal (Refereed)
    Abstract [en]

    Background: Dengue is a mosquito-borne viral disease that has become more prevalent in the last few decades. Most patients are viremic when they present with symptoms, and early diagnosis of dengue is important in preventing severe clinical complications associated with this disease and also represents a key factor in differential diagnosis. Here, we designed and validated a hydrolysis-probe-based one-step real-time RT-PCR assay that targets the genomes of dengue virus serotypes 1-4. Methodology/Principal Findings: The primers and probe used in our RT-PCR assay were designed to target the 39 untranslated region of all complete genome sequences of dengue virus available in GenBank (n=3,305). Performance of the assay was evaluated using in vitro transcribed RNA, laboratory-adapted virus strains, external control panels, and clinical specimens. The linear dynamic range was found to be 10(4)-10(11) GCE/mL, and the detection limit was between 6.0x10(2) and 1.1x10(3) GCE/mL depending on target sequence. The assay did not cross-react with human RNA, nor did it produce false-positive results for other human pathogenic flaviviruses or clinically important etiological agents of febrile illnesses. We used clinical serum samples obtained from returning travelers with dengue-compatible symptomatology (n = 163) to evaluate the diagnostic relevance of our assay, and laboratory diagnosis performed by the RT-PCR assay had 100% positive agreement with diagnosis performed by NS1 antigen detection. In a retrospective evaluation including 60 archived serum samples collected from confirmed dengue cases 1-9 days after disease onset, the RT-PCR assay detected viral RNA up to 9 days after appearance of symptoms. Conclusions/Significance: The validation of the RT-PCR assay presented here indicates that this technique can be a reliable diagnostic tool, and hence we suggest that it be introduced as the method of choice during the first 5 days of dengue symptoms.

  • 6.
    Ansell, Brendan R. E.
    et al.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    McConville, Malcolm J.
    Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic 3052, Australia..
    Baker, Louise
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Korhonen, Pasi K.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Young, Neil D.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Hall, Ross S.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Rojas, Cristian A. A.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Gasser, Robin B.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Jex, Aaron R.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Time-Dependent Transcriptional Changes in Axenic Giardia duodenalis Trophozoites2015In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 9, no 12, article id e0004261Article in journal (Refereed)
    Abstract [en]

    Giardia duodenalis is the most common gastrointestinal protozoan parasite of humans and a significant contributor to the global burden of both diarrheal disease and post-infectious chronic disorders. Although G. duodenalis can be cultured axenically, significant gaps exist in our understanding of the molecular biology and metabolism of this pathogen. The present study employed RNA sequencing to characterize the mRNA transcriptome of G. duodenalis trophozoites in axenic culture, at log (48 h of growth), stationary (60 h), and declining (96 h) growth phases. Using similar to 400-times coverage of the transcriptome, we identified 754 differentially transcribed genes (DTGs), mainly representing two large DTG groups: 438 that were down-regulated in the declining phase relative to log and stationary phases, and 281 that were up-regulated. Differential transcription of prominent antioxidant and glycolytic enzymes implicated oxygen tension as a key factor influencing the transcriptional program of axenic trophozoites. Systematic bioinformatic characterization of numerous DTGs encoding hypothetical proteins of unknown function was achieved using structural homology searching. This powerful approach greatly informed the differential transcription analysis and revealed putative novel antioxidant-coding genes, and the presence of a nearcomplete two-component-like signaling system that may link cytosolic redox or metabolite sensing to the observed transcriptional changes. Motif searching applied to promoter regions of the two large DTG groups identified different putative transcription factor-binding motifs that may underpin global transcriptional regulation. This study provides new insights into the drivers and potential mediators of transcriptional variation in axenic G. duodenalis and provides context for static transcriptional studies.

  • 7.
    Bowman, Leigh
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Kroeger, Axel
    Olliaro, Piero
    Skewes, Ronald
    A comparison of Zika and dengue outbreaks using national surveillance data in the Dominican Republic2018In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 12, no 11, article id e0006876Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Aedes-borne arboviruses continue to precipitate epidemics worldwide. In Dominican Republic, the appearance of Zika virus cases that closely followed a large dengue epidemic provided an opportunity to study the different transmission drivers behind these two flaviviruses. Retrospective datasets were used to collect information on the populations at risk and descriptive statistics were used to describe the outbreaks on a national scale.

    METHODOLOGY/ PRINCIPAL FINDINGS: Expectedly, box plots showed that 75% of dengue was reported in those aged <20 years while Zika infections were more widely dispersed among the population. Dengue attack rates were marginally higher among males at 25.9 per 10,000 population vs. 21.5 per 10,000 population for females. Zika infections appeared to be highly clustered among females (73.8% (95% CI 72.6%, 75.0%; p<0.05)); age-adjusted Zika attack rates among females were 7.64 per 10,000 population compared with 2.72 per 10,000 population among males. R0 calculations stratified by sex also showed a significantly higher metric among females: 1.84 (1.82, 1.87; p<0.05) when compared to males at 1.72 (1.69, 1.75; p<0.05). However, GBS attack rates stratified by sex revealed slightly higher risk in males vs. females, at 0.62 and 0.57 per 10,000 population respectively.

    CONCLUSIONS/ SIGNIFICANCE: Evidence suggests little impact of existing dengue immunity on reported attack rates of Zika at the population level. Confounding of R0 and incident risk calculations by sex-specific over-reporting can alter the reliability of epidemiological metrics, which could be addressed using associated proxy syndromes or conditions to explore seemingly sex-skewed incidence. The findings indicate that community awareness campaigns, through influencing short-term health seeking behaviour, remain the most plausible mechanism behind increased reporting among women of reproductive age, although biological susceptibility cannot yet be ruled out. Media campaigns and screening are therefore recommended for women of reproductive age during Zika outbreaks. Future research should focus on clinical Zika outcomes among dengue seropositive individuals.

  • 8. Capasso, Ariadna
    et al.
    Ompad, Danielle C.
    Vieira, Dorice L.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Department of Disease Control, London School of Hygiene and Tropical Medicine, London, United Kingdom.
    Tozan, Yesim
    Incidence of Guillain-Barre Syndrome (GBS) in Latin America and the Caribbean before and during the 2015-2016 Zika virus epidemic: A systematic review and meta-analysis2019In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 13, no 8, article id e0007622Article, review/survey (Refereed)
    Abstract [en]

    Background: A severe neurological disorder, Guillain-Barré syndrome (GBS) is the leading cause of acute flaccid paralysis. Enhanced surveillance of GBS in Latin America and the Caribbean (LAC) following the 2015–2016 Zika virus (ZIKV) epidemic presents an opportunity to estimate, for the first time, the regional incidence of GBS.

    Methods and findings: For this systematic review and meta-analysis, we searched nine scientific databases and grey literature from January 1, 1980 to October 1, 2018. Sources with primary data on incident GBS cases in LAC within a well-defined population and timeframe, published in English, Spanish, Portuguese, or French, were included. We calculated the annual GBS incidence rates (IRs) and 95% confidence intervals (CIs) for each source based on published data. Following an assessment of heterogeneity, we used random-effects meta-analysis to calculate the pooled annual IR of GBS. The study is registered with PROSPERO, number CRD42018086659. Of the 6568 initial citation hits, 31 were eligible for inclusion. Background annual GBS IRs in Latin America ranged from 0.40 in Brazil to 2.12/100,000 in Chile. The pooled annual IR in the Caribbean was 1.64 (95% CI 1.29–2.12, I2<0.01, p = 0.44). During the ZIKV epidemic, GBS IRs ranged from 0.62 in Mexico to 9.35/100,000 in Martinique. GBS increased 2.6 (95% CI 2.3–2.9) times during ZIKV and 1.9 (95% CI 1.1–3.4) times during chikungunya outbreaks over background rates. A limitation of this review is that the studies included employed different methodologies to find and ascertain cases of GBS, which could contribute to IR heterogeneity. In addition, it is important to consider that data on GBS are lacking for many countries in the region.

    Conclusions: Background IRs of GBS appear to peak during arboviral disease outbreaks. The current review contributes to an understanding of the epidemiology of GBS in the LAC region, which can inform healthcare system planning and preparedness, particularly during arboviral epidemics.

  • 9.
    de Glanville, William A.
    et al.
    Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland;Int Livestock Res Inst, Nairobi, Kenya;Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Glasgow, Lanark, Scotland.
    Conde-Alvarez, Raquel
    Univ Navarra, Inst Trop Hlth, Navarra Inst Sanitary Res, Pamplona, Spain;Univ Navarra, Med Sch, Dept Microbiol & Parasitol, Pamplona, Spain.
    Moriyon, Ignacio
    Univ Navarra, Inst Trop Hlth, Navarra Inst Sanitary Res, Pamplona, Spain;Univ Navarra, Med Sch, Dept Microbiol & Parasitol, Pamplona, Spain.
    Njeru, John
    Friedrich Loeffler Inst, Inst Bacterial Infect & Zoonoses, Berlin, Germany;Kenya Govt Med Res Ctr, Ctr Microbiol Res, Nairobi, Kenya.
    Diaz, Ramon
    Univ Navarra, Inst Trop Hlth, Navarra Inst Sanitary Res, Pamplona, Spain;Univ Navarra, Med Sch, Dept Microbiol & Parasitol, Pamplona, Spain.
    Cook, Elizabeth A. J.
    Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland;Int Livestock Res Inst, Nairobi, Kenya.
    Morin, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bronsvoort, Barend M. de C.
    Univ Edinburgh, Roslin Inst, Epidemiol Econ & Risk Assessment Grp, Edinburgh, Midlothian, Scotland.
    Thomas, Lian F.
    Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland;Int Livestock Res Inst, Nairobi, Kenya.
    Kariuki, Samuel
    Kenya Govt Med Res Ctr, Ctr Microbiol Res, Nairobi, Kenya.
    Fevre, Eric M.
    Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England;Int Livestock Res Inst, Nairobi, Kenya.
    Poor performance of the rapid test for human brucellosis in health facilities in Kenya2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 4, article id e0005508Article in journal (Refereed)
    Abstract [en]

    Human brucellosis is considered to be an important but typically under-diagnosed cause of febrile illness in many low and middle-income countries. In Kenya, and throughout East Africa, laboratory diagnosis for the disease is based primarily on the febrile antigen Brucella agglutination test (FBAT), yet few studies of the diagnostic accuracy of this test exist. Assessment of the performance of the FBAT is essential for its appropriate clinical use, as well as for evaluating surveillance data reported by public health systems. To assess FBAT performance, we collected sera from people with symptoms compatible with brucellosis attending two health facilities in Busia County, Kenya. Sera were tested using the FBAT and results compared with those from the Rose Bengal Test (RBT), an assay with well-known performance characteristics. Positives on either test were confirmed using the classical serum agglutination test (SAT)-Coombs test combination and a rapid IgM/IgG lateral flow immunochromatography assay (LFA). A questionnaire focussing on known risk factors for exposure to Brucella spp. was also conducted, and relationships with FBAT positivity examined using logistic regression. Out of 825 recruited individuals, 162 (19.6%) were classified as positive using the FBAT. In contrast, only eight (1.0%) were positive using the RBT. Of the 162 FBAT positives, one (0.62%) had an atypical agglutination in SAT and three (1.9%) showed low Coombs titres. Out of 148 FBAT positive individuals tested using the LFA, five (3.4%) were IgM positive and none were IgG positive. Poor or no correlation was observed between FBAT results and most established risk factors for Brucella infection. We observed substantial disagreement between the FBAT and a number of well-known serological tests, with the majority of reactive FBAT results appearing to be false positives. Poor FBAT specificity, combined with a lack of confirmatory testing, strongly suggests overdiagnosis of brucellosis is common in this low prevalence setting. This is expected to have important economic impacts on affected patients subjected to the long and likely unnecessary courses of multiple antibiotics required for treatment of the disease.

  • 10. DeRaedt Banks, Sarah
    et al.
    Orsborne, James
    Gezan, Salvador A
    Kaur, Harparkash
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
    Lindsey, Steve W
    Logan, James G
    Permethrin-Treated Clothing as Protection against the Dengue Vector, Aedes aegypti: Extent and Duration of Protection2015In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 9, no 10, article id e0004109Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Dengue transmission by the mosquito vector, Aedes aegypti, occurs indoors and outdoors during the day. Personal protection of individuals, particularly when outside, is challenging. Here we assess the efficacy and durability of different types of insecticide-treated clothing on laboratory-reared Ae. aegypti.

    METHODS: Standardised World Health Organisation Pesticide Evaluation Scheme (WHOPES) cone tests and arm-in-cage assays were used to assess knockdown (KD) and mortality of Ae. aegypti tested against factory-treated fabric, home-dipped fabric and microencapsulated fabric. Based on the testing of these three different treatment types, the most protective was selected for further analysis using arm-in cage assays with the effect of washing, ultra-violet light, and ironing investigated using high pressure liquid chromatography.

    RESULTS: Efficacy varied between the microencapsulated and factory dipped fabrics in cone testing. Factory-dipped clothing showed the greatest effect on KD (3 min 38.1%; 1 hour 96.5%) and mortality (97.1%) with no significant difference between this and the factory dipped school uniforms. Factory-dipped clothing was therefore selected for further testing. Factory dipped clothing provided 59% (95% CI = 49.2%- 66.9%) reduction in landing and a 100% reduction in biting in arm-in-cage tests. Washing duration and technique had a significant effect, with insecticidal longevity shown to be greater with machine washing (LW50 = 33.4) compared to simulated hand washing (LW50 = 17.6). Ironing significantly reduced permethrin content after 1 week of simulated use, with a 96.7% decrease after 3 months although UV exposure did not reduce permethrin content within clothing significantly after 3 months simulated use.

    CONCLUSION: Permethrin-treated clothing may be a promising intervention in reducing dengue transmission. However, our findings also suggest that clothing may provide only short-term protection due to the effect of washing and ironing, highlighting the need for improved fabric treatment techniques.

  • 11. Durrant, Jacob D.
    et al.
    Keränen, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Wilson, Benjamin A.
    McCammon, J. Andrew
    Computational Identification of Uncharacterized Cruzain Binding Sites2010In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 4, no 5, p. e676-Article in journal (Refereed)
    Abstract [en]

    Chagas disease, caused by the unicellular parasite Trypanosoma cruzi, claims 50,000 lives annually and is the leading cause of infectious myocarditis in the world. As current antichagastic therapies like nifurtimox and benznidazole are highly toxic, ineffective at parasite eradication, and subject to increasing resistance, novel therapeutics are urgently needed. Cruzain, the major cysteine protease of Trypanosoma cruzi, is one attractive drug target. In the current work, molecular dynamics simulations and a sequence alignment of a non-redundant, unbiased set of peptidase C1 family members are used to identify uncharacterized cruzain binding sites. The two sites identified may serve as targets for future pharmacological intervention.

  • 12.
    Eid Rodríguez, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Department of Biomedical Sciences Research, Faculty of Medicine, San Simon University, Cochabamba, Bolivia.
    San Sebastian, Miguel
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Pulkki-Brännström, Anni-Maria
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    "Cheaper and better": Societal cost savings and budget impact of changing from systemic to intralesional pentavalent antimonials as the first-line treatment for cutaneous leishmaniasis in Bolivia2019In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 13, no 11, article id e0007788Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Cutaneous leishmaniasis (CL), endemic in Bolivia, mostly affects poor people in rainforest areas. The current first-line treatment consists of systemic pentavalent antimonials (SPA) for 20 days and is paid for by the Ministry of Health (MoH). Long periods of drug shortages and a lack of safe conditions to deliver treatment are challenges to implementation. Intralesional pentavalent antimonials (ILPA) are an alternative to SPA. This study aims to compare the cost of ILPA and SPA, and to estimate the health and economic impacts of changing the first-line treatment for CL in a Bolivian endemic area.

    METHODS: The cost-per-patient treated was estimated for SPA and ILPA from the perspectives of the MoH and society. The quantity and unit costs of medications, staff time, transportation and loss of production were obtained through a health facility survey (N = 12), official documents and key informants. A one-way sensitivity analysis was conducted on key parameters to evaluate the robustness of the results. The annual number of patients treated and the budget impact of switching to ILPA as the first-line treatment were estimated under different scenarios of increasing treatment utilization. Costs were reported in 2017 international dollars (1 INT$ = 3.10 BOB).

    RESULTS: Treating CL using ILPA was associated with a cost-saving of $248 per-patient-treated from the MoH perspective, and $688 per-patient-treated from the societal perspective. Switching first-line treatment to ILPA while maintaining the current budget would allow two-and-a-half times the current number of patients to be treated. ILPA remained cost-saving compared to SPA in the sensitivity analysis.

    CONCLUSIONS: The results of this study support a shift to ILPA as the first-line treatment for CL in Bolivia and possibly in other South American countries.

  • 13.
    Einarsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Troell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Vet Inst, Dept Microbiol, S-75007 Uppsala, Sweden.
    Höppner, Marc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Kiel, Inst Clin Mol Biol, Kiel, Germany.
    Grabherr, Mannfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ribacke, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Coordinated Changes in Gene Expression Throughout Encystation of Giardia intestinalis2016In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 3, article id e0004571Article in journal (Refereed)
    Abstract [en]

    Differentiation into infectious cysts through the process of encystation is crucial for transmission and survival of the intestinal protozoan parasite Giardia intestinalis. Hitherto the majority of studies have focused on the early events, leaving late encystation poorly defined. In order to further study encystation, focusing on the later events, we developed a new encystation protocol that generates a higher yield of mature cysts compared to standard methods. Transcriptome changes during the entire differentiation from trophozoites to cysts were thereafter studied using RNA sequencing (RNA-seq). A high level of periodicity was observed for up-and down-regulated genes, both at the level of the entire transcriptome and putative regulators. This suggests the trajectory of differentiation to be coordinated through developmentally linked gene regulatory activities. Our study identifies a core of 13 genes that are consistently up-regulated during initial encystation. Of these, two constitute previously uncharacterized proteins that we were able to localize to a new type of encystation-specific vesicles. Interestingly, the largest transcriptional changes were seen in the late phase of encystation with the majority of the highly up-regulated genes encoding hypothetical proteins. Several of these were epitope-tagged and localized to further characterize these previously unknown genetic components of encystation and possibly excystation. Finally, we also detected a switch of variant specific surface proteins (VSPs) in the late phase of encystation. This occurred at the same time as nuclear division and DNA replication, suggesting a potential link between the processes.

  • 14.
    Hassan, Osama Ahmed
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Public Health Institute, Khartoum, Sudan.
    Affognon, Hippolyte
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Mburu, Peter
    Sang, Rosemary
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    The One Health approach to identify knowledge, attitudes and practices that affect community involvement in the control of Rift Valley fever outbreaks2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 2, article id e0005383Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever (RVF) is a viral mosquito-borne disease with the potential for global expansion, causes hemorrhagic fever, and has a high case fatality rate in young animals and in humans. Using a cross-sectional community-based study design, we investigated the knowledge, attitudes and practices of people living in small village in Sudan with respect to RVF outbreaks. A special One Health questionnaire was developed to compile data from 235 heads of household concerning their knowledge, attitudes, and practices with regard to controlling RVF. Although the 2007 RVF outbreak in Sudan had negatively affected the participants' food availability and livestock income, the participants did not fully understand how to identify RVF symptoms and risk factors for both humans and livestock. For example, the participants mistakenly believed that avoiding livestock that had suffered spontaneous abortions was the least important risk factor for RVF. Although the majority noticed an increase in mosquito population during the 2007 RVF outbreak, few used impregnated bed nets as preventive measures. The community was reluctant to notify the authorities about RVF suspicion in livestock, a sentinel for human RVF infection. Almost all the respondents stressed that they would not receive any compensation for their dead livestock if they notified the authorities. In addition, the participants believed that controlling RVF outbreaks was mainly the responsibility of human health authorities rather than veterinary authorities. The majority of the participants were aware that RVF could spread from one region to another within the country. Participants received most their information about RVF from social networks and the mass media, rather than the health system or veterinarians. Because the perceived role of the community in controlling RVF was fragmented, the probability of RVF spread increased.

  • 15.
    Hassan, Osama Ahmed
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Federal Ministry of Health, Khartoum, Sudan.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sang, Rosemary
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    The 2007 rift valley Fever outbreak in Sudan2011In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 5, no 9, article id e1229Article, review/survey (Refereed)
    Abstract [en]

    Rift Valley fever (RVF) is a neglected, emerging, mosquito-borne disease with severe negative impact on human and animal health and economy. RVF is caused by RVF virus (RVFV) affecting humans and a wide range of animals. The virus is transmitted through bites from mosquitoes and exposure to viremic blood, body fluids, or tissues of infected animals. During 2007 a large RVF outbreak occurred in Sudan with a total of 747 confirmed human cases including 230 deaths (case fatality 30.8%); although it has been estimated 75,000 were infected. It was most severe in White Nile, El Gezira, and Sennar states near to the White Nile and the Blue Nile Rivers. Notably, RVF was not demonstrated in livestock until after the human cases appeared and unfortunately, there are no records or reports of the number of affected animals or deaths. Ideally, animals should serve as sentinels to prevent loss of human life, but the situation here was reversed. Animal contact seemed to be the most dominant risk factor followed by animal products and mosquito bites. The Sudan outbreak followed an unusually heavy rainfall in the country with severe flooding and previous studies on RVF in Sudan suggest that RVFV is endemic in parts of Sudan. An RVF outbreak results in human disease, but also large economic loss with an impact beyond the immediate influence on the directly affected agricultural producers. The outbreak emphasizes the need for collaboration between veterinary and health authorities, entomologists, environmental specialists, and biologists, as the best strategy towards the prevention and control of RVF.

  • 16.
    Hii, Yien Ling
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wall, Stig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ng, Lee Ching
    Tang, Choon Siang
    Ng, Nawi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Optimal lead time for dengue forecast2012In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 6, no 10, p. e1848-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A dengue early warning system aims to prevent a dengue outbreak by providing an accurate prediction of a rise in dengue cases and sufficient time to allow timely decisions and preventive measures to be taken by local authorities. This study seeks to identify the optimal lead time for warning of dengue cases in Singapore given the duration required by a local authority to curb an outbreak.

    METHODOLOGY AND FINDINGS: We developed a Poisson regression model to analyze relative risks of dengue cases as functions of weekly mean temperature and cumulative rainfall with lag times of 1-5 months using spline functions. We examined the duration of vector control and cluster management in dengue clusters > = 10 cases from 2000 to 2010 and used the information as an indicative window of the time required to mitigate an outbreak. Finally, we assessed the gap between forecast and successful control to determine the optimal timing for issuing an early warning in the study area. Our findings show that increasing weekly mean temperature and cumulative rainfall precede risks of increasing dengue cases by 4-20 and 8-20 weeks, respectively. These lag times provided a forecast window of 1-5 months based on the observed weather data. Based on previous vector control operations, the time needed to curb dengue outbreaks ranged from 1-3 months with a median duration of 2 months. Thus, a dengue early warning forecast given 3 months ahead of the onset of a probable epidemic would give local authorities sufficient time to mitigate an outbreak.

    CONCLUSIONS: Optimal timing of a dengue forecast increases the functional value of an early warning system and enhances cost-effectiveness of vector control operations in response to forecasted risks. We emphasize the importance of considering the forecast-mitigation gaps in respective study areas when developing a dengue forecasting model.

  • 17.
    Hii, Yien Ling
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Zhu, Huaiping
    Ng, Nawi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ng, Lee Ching
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Forecast of dengue incidence using temperature and rainfall2012In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 6, no 11, p. e1908-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: An accurate early warning system to predict impending epidemics enhances the effectiveness of preventive measures against dengue fever. The aim of this study was to develop and validate a forecasting model that could predict dengue cases and provide timely early warning in Singapore.

    METHODOLOGY AND PRINCIPAL FINDINGS: We developed a time series Poisson multivariate regression model using weekly mean temperature and cumulative rainfall over the period 2000-2010. Weather data were modeled using piecewise linear spline functions. We analyzed various lag times between dengue and weather variables to identify the optimal dengue forecasting period. Autoregression, seasonality and trend were considered in the model. We validated the model by forecasting dengue cases for week 1 of 2011 up to week 16 of 2012 using weather data alone. Model selection and validation were based on Akaike's Information Criterion, standardized Root Mean Square Error, and residuals diagnoses. A Receiver Operating Characteristics curve was used to analyze the sensitivity of the forecast of epidemics. The optimal period for dengue forecast was 16 weeks. Our model forecasted correctly with errors of 0.3 and 0.32 of the standard deviation of reported cases during the model training and validation periods, respectively. It was sensitive enough to distinguish between outbreak and non-outbreak to a 96% (CI = 93-98%) in 2004-2010 and 98% (CI = 95%-100%) in 2011. The model predicted the outbreak in 2011 accurately with less than 3% possibility of false alarm.

    SIGNIFICANCE: We have developed a weather-based dengue forecasting model that allows warning 16 weeks in advance of dengue epidemics with high sensitivity and specificity. We demonstrate that models using temperature and rainfall could be simple, precise, and low cost tools for dengue forecasting which could be used to enhance decision making on the timing, scale of vector control operations, and utilization of limited resources.

  • 18.
    Horstick, Olaf
    et al.
    Institute of Public Health, University of Heidelberg, Heidelberg, Germany.
    Tozan, Yesim
    Institute of Public Health, University of Heidelberg, Heidelberg, Germany ; Steinhardt School of Culture, Education and Human Development and Global Institute of Public Health, New York University, New York, New York, United States of America.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Institute of Public Health, University of Heidelberg, Heidelberg, Germany ; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
    Reviewing dengue: still a neglected tropical disease?2015In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 9, no 4, article id e0003632Article, review/survey (Refereed)
    Abstract [en]

    Dengue is currently listed as a "neglected tropical disease" (NTD). But is dengue still an NTD or not? Classifying dengue as an NTD may carry advantages, but is it justified? This review considers the criteria for the definition of an NTD, the current diverse lists of NTDs by different stakeholders, and the commonalities and differences of dengue with other NTDs. We also review the current research gaps and research activities and the adequacy of funding for dengue research and development (R&D) (2003-2013). NTD definitions have been developed to a higher precision since the early 2000s, with the following main features: NTDs are characterised as a) poverty related, b) endemic to the tropics and subtropics, c) lacking public health attention, d) having poor research funding and shortcomings in R&D, e) usually associated with high morbidity but low mortality, and f) often having no specific treatment available. Dengue meets most of these criteria, but not all. Although dengue predominantly affects resource-limited countries, it does not necessarily only target the poor and marginalised in those countries. Dengue increasingly attracts public health attention, and in some affected countries it is now a high profile disease. Research funding for dengue has increased exponentially in the past two decades, in particular in the area of dengue vaccine development. However, despite advances in dengue research, dengue epidemics are increasing in frequency and magnitude, and dengue is expanding to new areas. Specific treatment and a highly effective vaccine remain elusive. Major research gaps exist in the area of integrated surveillance and vector control. Hence, although dengue differs from many of the NTDs, it still meets important criteria commonly used for NTDs. The current need for increased R& D spending, shared by dengue and other NTDs, is perhaps the key reason why dengue should continue to be considered an NTD.

  • 19. Jaenisch, Thomas
    et al.
    Sakuntabhai, Anavaj
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Dengue research funded by the European commission: scientific strategies of three European dengue research consortia2013In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 7, no 12, article id e2320Article in journal (Refereed)
  • 20. Jin, Jing
    et al.
    Sherman, Michael B.
    Chafets, Daniel
    Dinglasan, Nuntana
    Lu, Kai
    Lee, Tzong-Hae
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Muench, Marcus O.
    Simmons, Graham
    An attenuated replication-competent chikungunya virus with a fluorescently tagged envelope2018In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 12, no 7, article id e0006693Article in journal (Refereed)
    Abstract [en]

    Background: Chikungunya virus (CHIKV) is the most common alphavirus infecting humans worldwide, causing acute and chronically debilitating arthralgia at a great economic expense.

    Methodology/Principal findings: To facilitate our study of CHIKV, we generated a mCherry tagged replication-competent chimeric virus, CHIKV 37997-mCherry. Single particle cryoEM demonstrated icosahedral organization of the chimeric virus and the display of mCherry proteins on virus surface. CHIKV 37997-mCherry is attenuated in both IFN alpha R knockout and wild-type mice. Strong antiCHIKV and anti-mCherry antibody responses were induced in CHIKV 37997-mCherry infected mice.

    Conclusions/Significance: Our work suggests that chimeric alphaviruses displaying foreign antigen can serve as vaccines against both aphaviruses and other pathogens and diseases.

  • 21.
    Kamuyu, Gathoni
    et al.
    Studies Epidemiol Epilepsy Demog Surveillance Sys, Accra, Ghana.
    Bottomley, Christian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England.
    Mageto, James
    Egerton Univ, Nakuru, Kenya.
    Lowe, Brett
    Studies Epidemiol Epilepsy Demog Surveillance Sys, Accra, Ghana.
    Wilkins, Patricia P.
    Ctr Dis Control & Prevent CDC, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Noh, John C.
    Ctr Dis Control & Prevent CDC, Div Parasit Dis & Malaria, Atlanta, GA USA.
    Nutman, Thomas B.
    National Institute of Allergy & Infectious Diseases (NIAID) .
    Ngugi, Anthony K.
    Studies Epidemiol Epilepsy Demog Surveillance Sys, Accra, Ghana.
    Odhiambo, Rachael
    KEMRI Wellcome Trust Res Programme, Ctr Geog Med Res Coast, Kilifi, Kenya.
    Wagner, Ryan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health & Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Kakooza-Mwesige, Angelina
    Owusu-Agyei, Seth
    Ae-Ngibise, Kenneth
    Masanja, Honorati
    Osier, Faith H. A.
    Odermatt, Peter
    Newton, Charles R.
    Exposure to Multiple Parasites Is Associated with the Prevalence of Active Convulsive Epilepsy in Sub-Saharan Africa2014In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 8, no 5, article id e2908Article in journal (Refereed)
    Abstract [en]

    Background: Epilepsy is common in developing countries, and it is often associated with parasitic infections. We investigated the relationship between exposure to parasitic infections, particularly multiple infections and active convulsive epilepsy (ACE), in five sites across sub-Saharan Africa. Methods and Findings: A case-control design that matched on age and location was used. Blood samples were collected from 986 prevalent cases and 1,313 age-matched community controls and tested for presence of antibodies to Onchocerca volvulus, Toxocara canis, Toxoplasma gondii, Plasmodium falciparum, Taenia solium and HIV. Exposure (seropositivity) to Onchocerca volvulus (OR = 1.98; 95% CI: 1.52-2.58, p<0.001), Toxocara canis (OR = 1.52; 95% CI: 1.23-1.87, p<0.001), Toxoplasma gondii (OR = 1.28; 95% CI: 1.04-1.56, p=0.018) and higher antibody levels (top tertile) to Toxocara canis (OR = 1.70; 95% CI: 1.30-2.24, p<0.001) were associated with an increased prevalence of ACE. Exposure to multiple infections was common (73.8% of cases and 65.5% of controls had been exposed to two or more infections), and for T. gondii and O. volvulus co-infection, their combined effect on the prevalence of ACE, as determined by the relative excess risk due to interaction (RERI), was more than additive (T. gondii and O. volvulus, RERI = 1.19). The prevalence of T. solium antibodies was low (2.8% of cases and 2.2% of controls) and was not associated with ACE in the study areas. Conclusion: This study investigates how the degree of exposure to parasites and multiple parasitic infections are associated with ACE and may explain conflicting results obtained when only seropositivity is considered. The findings from this study should be further validated.

  • 22.
    Kesik-Brodacka, Malgorzata
    et al.
    Institute Biotechnol and Antibiot, Poland.
    Lipiec, Agnieszka
    Warsaw University of Life Science, Poland.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Polish Academic Science, Poland.
    Jedlina, Luiza
    Polish Academic Science, Poland.
    Miedzinska, Katarzyna
    Polish Academic Science, Poland; Queens Medical Research Institute, Scotland.
    Mikolajczak, Magdalena
    Polish Academic Science, Poland.
    Plucienniczak, Andrzej
    Institute Biotechnol and Antibiot, Poland.
    Legocki, Andrzej B.
    Polish Academic Science, Poland.
    Wedrychowicz, Halina
    Polish Academic Science, Poland.
    Immune response of rats vaccinated orally with various plant-expressed recombinant cysteine proteinase constructs when challenged with Fasciola hepatica metacercariae2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 3Article in journal (Refereed)
    Abstract [en]

    Background Cysteine proteinases of Fasciola hepatica are important candidates for vaccine antigens because of their role in fluke biology and host-parasite relationships. In our previous experiments, we found that a recombinant cysteine proteinase cloned from adult F. hepatica ( CPFhW) can protect rats against liver fluke infections when it is administered intramuscularly or intranasally in the form of cDNA. We also observed considerable protection upon challenge following mucosal vaccination with inclusion bodies containing recombinant CPFhW produced in Escherichia coli. In this study, we explore oral vaccination, which may be the desired method of delivery and is potentially capable of preventing infections at the site of helminth entry. To provide antigen encapsulation and to protect the vaccine antigen from degradation in the intestinal tract, transgenic plant-based systems are used. Methodology Conclusions We obtained substantial protection after oral administration of the plant-produced hybrids of CPFhW and HBcAg. The highest level of protection (65.4%)was observed in animals immunised with transgenic plants expressing the mature CPFhW enzyme flanked by Gly-rich linkers and inserted into c/e1 epitope of truncated HBcAg. The immunised rats showed clear IgG1 and IgM responsesIn the present study, we aimed to evaluate the protective ability of mucosal vaccinations of 12-week- old rats with CPFhW produced in a transgenic-plant-based system. To avoid inducing tolerance and to maximise the immune response induced by oral immunisation, we used the hepatitis B virus (HBV) core protein ( HBcAg) as a carrier. Animals were immunised with two doses of the antigen and challenged with 25 or 30 metacercariae of F. hepatica. Conclusions We obtained substantial protection after oral administration of the plant-produced hybrids of CPFhW and HBcAg. The highest level of protection (65.4%) was observed in animals immunised with transgenic plants expressing the mature CPFhW enzyme flanked by Gly- rich linkers and inserted into c/e1 epitope of truncated HBcAg. The immunised rats showed clear IgG1 and IgM responses to CPFhW for 4 consecutive weeks after the challenge.

  • 23.
    Kinsman, John
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    de Bruijne, Kars
    Jalloh, Alpha M.
    Harris, Muriel
    Abdullah, Hussainatu
    Boye-Thompson, Titus
    Sankoh, Osman
    Jalloh, Abdul K.
    Jalloh-Vos, Heidi
    Development of a set of community-informed Ebola messages for Sierra Leone2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 8, article id e0005742Article in journal (Refereed)
    Abstract [en]

    The West African Ebola epidemic of 2013-2016 was by far the largest outbreak of the disease on record. Sierra Leone suffered nearly half of the 28,646 reported cases. This paper presents a set of culturally contextualized Ebola messages that are based on the findings of qualitative interviews and focus group discussions conducted in 'hotspot' areas of rural Bombali District and urban Freetown in Sierra Leone, between January and March 2015. An iterative approach was taken in the message development process, whereby (i) data from formative research was subjected to thematic analysis to identify areas of community concern about Ebola and the national response; (ii) draft messages to address these concerns were produced; (iii) the messages were field tested; (iv) the messages were refined; and (v) a final set of messages on 14 topics was disseminated to relevant national and international stakeholders. Each message included details of its rationale, audience, dissemination channels, messengers, and associated operational issues that need to be taken into account. While developing the 14 messages, a set of recommendations emerged that could be adopted in future public health emergencies. These included the importance of embedding systematic, iterative qualitative research fully into the message development process; communication of the subsequent messages through a two-way dialogue with communities, using trusted messengers, and not only through a one-way, top-down communication process; provision of good, parallel operational services; and engagement with senior policy makers and managers as well as people in key operational positions to ensure national ownership of the messages, and to maximize the chance of their being utilised. The methodological approach that we used to develop our messages along with our suggested recommendations constitute a set of tools that could be incorporated into international and national public health emergency preparedness and response plans.

  • 24. Kittayapong, Pattamaporn
    et al.
    Olanratmanee, Phanthip
    Maskhao, Pongsri
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Logan, James
    Tozan, Yesim
    Louis, Valérie
    Gubler, Duane J
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. London School of Hygiene and Tropical Medicine, London, United Kingdom; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Public Health, University of Heidelberg, Heidelberg, Germany.
    Mitigating Diseases Transmitted by Aedes Mosquitoes: A Cluster-Randomised Trial of Permethrin-Impregnated School Uniforms2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 1, article id e0005197Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Viral diseases transmitted via Aedes mosquitoes are on the rise, such as Zika, dengue, and chikungunya. Novel tools to mitigate Aedes mosquitoes-transmitted diseases are urgently needed. We tested whether commercially insecticide-impregnated school uniforms can reduce dengue incidence in school children.

    METHODS: We designed a cluster-randomised controlled trial in Thailand. The primary endpoint was laboratory-confirmed dengue infections. Secondary endpoints were school absenteeism; and impregnated uniforms' 1-hour knock-down and 24 hour mosquito mortality as measured by standardised WHOPES bioassay cone tests at baseline and after repeated washing. Furthermore, entomological assessments inside classrooms and in outside areas of schools were conducted.

    RESULTS: We enrolled 1,811 pupils aged 6-17 from 5 intervention and 5 control schools. Paired serum samples were obtained from 1,655 pupils. In the control schools, 24/641 (3.7%) and in the intervention schools 33/1,014 (3.3%) students had evidence of new dengue infections during one school term (5 months). There was no significant difference in proportions of students having incident dengue infections between the intervention and control schools, with adjustment for clustering by school. WHOPES cone tests showed a 100% knock down and mortality of Aedes aegypti mosquitoes exposed to impregnated clothing at baseline and up to 4 washes, but this efficacy rapidly declined to below 20% after 20 washes, corresponding to a weekly reduction in knock-down and mosquito mortality by 4.7% and 4.4% respectively. Results of the entomological assessments showed that the mean number of Aedes aegypti mosquitoes caught inside the classrooms of the intervention schools was significantly reduced in the month following the introduction of the impregnated uniforms, compared to those collected in classrooms of the control schools (p = 0.04).

    CONCLUSIONS: Entomological assessments showed that the intervention had some impact on the number of Aedes mosquitoes inside treatment schools immediately after impregnation and before insecticidal activity declined. However, there was no serological evidence of protection against dengue infections over the five months school term, best explained by the rapid washing-out of permethrin after 4 washes. If rapid washing-out of permethrin could be overcome by novel technological approaches, insecticide-treated clothes might become a potentially cost-effective and scalable intervention to protect against diseases transmitted by Aedes mosquitoes such as dengue, Zika, and chikungunya.

    TRIAL REGISTRATION: ClinicalTrials.gov NCT01563640.

  • 25.
    Larsson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundqvist, Jenny
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    van Rooijen, Nico
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice2009In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 3, no 9, p. e522-Article in journal (Refereed)
    Abstract [en]

    Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection.

  • 26.
    Lindahl-Rajala, Elisabeth
    et al.
    Swedish Univ Agr Sci, Div Reprod, Dept Clin Sci, Uppsala, Sweden..
    Hoffman, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Zoonosis Science Center.
    Fretin, David
    Vet & Agrochem Res Ctr, Unit Bacterial Zoonoses Livestock, Operat Direct Bacterial Dis, Brussels, Belgium..
    Godfroid, Jacques
    Arctic Univ Norway, Univ Tromso, Fac Biosci Fisheries & Econ, Dept Arctic & Marine Biol, Tromso, Norway..
    Sattorov, Nosirjon
    Tajik Acad Agr Sci, Inst Biosafety Problems, Ctr Natl Collect Pathogen Microorganisms, Dushanbe, Tajikistan..
    Boqvist, Sofia
    Swedish Univ Agr Sci, Div Food Safety & Bacteriol, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Zoonosis Science Center.
    Magnusson, Ulf
    Swedish Univ Agr Sci, Div Reprod, Dept Clin Sci, Uppsala, Sweden..
    Detection and characterization of Brucella spp. in bovine milk in small-scale urban and peri-urban farming in Tajikistan2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 3, article id e0005367Article in journal (Refereed)
    Abstract [en]

    Brucellosis is one of the most common zoonoses globally, and Central Asia remains a Brucella hotspot. The World Health Organization classifies brucellosis as a neglected zoonotic disease that is rarely in the spotlight for research and mainly affects poor, marginalized people. Urban and peri-urban farming is a common practice in many low-income countries, and it increases the incomes of families that are often restrained by limited economic resources. However, there is a concern that the growing number of people and livestock living close together in these areas will increase the transmission of zoonotic pathogens such as Brucella. This study investigates the presence of Brucella DNA in bovine milk in the urban and peri-urban area of Dushanbe, Tajikistan. Brucella DNA was detected in 10.3% of 564 cow milk samples by IS711-based real-time PCR. This finding is concerning because consumption of unpasteurized dairy products is common in the region. Furthermore, Brucella DNA was detected in the milk of all seropositive cows, but 8.3% of the seronegative cows also showed the presence of Brucella DNA. In addition, sequence analysis of the rpoB gene suggests that one cow was infected with B. abortus and another cow was most likely infected with B. melitensis. The discrepancies between the serology and real-time PCR results highlight the need to further investigate whether there is a need for implementing complementary diagnostic strategies to detect false serological negative individuals in Brucella surveillance, control, and eradication programmes. Furthermore, vaccination of cattle with S19 in addition to vaccination of small ruminants with Rev 1 might be needed in order to control Brucella infections in the livestock population but further research focusing on the isolation of Brucella is required to obtain a comprehensive understanding of the Brucella spp. circulating among the livestock in this region.

  • 27.
    Lundström, Jan O
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Nedre Dalalven Utvecklings AB, Biol Mosquito Control, Gysinge, Sweden.
    Hesson, Jenny C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Liverpool, Inst Infect & Global Hlth, Dept Epidemiol & Populat Hlth, Liverpool, Merseyside, England.
    Schafer, Martina L.
    Nedre Dalalven Utvecklings AB, Biol Mosquito Control, Gysinge, Sweden.
    Ostman, Orjan
    Swedish Univ Agr Sci, Inst Coastal Res, Dept Aquat Resources, Oregrund, Sweden.
    Semmler, Torsten
    Robert Koch Inst, NG Microbial Genom 1, Berlin, Germany.
    Bekaert, Michael
    Univ Stirling, Inst Aquaculture, Stirling, Scotland.
    Weidmann, Manfred
    Univ Stirling, Inst Aquaculture, Stirling, Scotland.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala Univ Hosp, Lab Clin Microbiol, Uppsala, Sweden.
    Pfeffer, Martin
    Univ Leipzig, Inst Anim Hyg & Vet Publ Hlth, Leipzig, Germany.
    Sindbis virus polyarthritis outbreak signalled by virus prevalence in the mosquito vectors2019In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 13, no 8, article id e0007702Article in journal (Refereed)
    Abstract [en]

    Polyarthritis and rash caused by Sindbis virus (SINV), was first recognised in northern Europe about 50 years ago and is known as Ockelbo disease in Sweden and Pogosta disease in Finland. This mosquito-borne virus occurs mainly in tropical and sub-tropical countries, and in northern Europe it is suggested to cause regularly reoccurring outbreaks. Here a seven-year cycle of SINV outbreaks has been referred to in scientific papers, although the hypothesis is based solely on reported human cases. In the search for a more objective outbreak signal, we evaluated mosquito abundance and SINV prevalence in vector mosquitoes from an endemic area in central Sweden. Vector mosquitoes collected in the River Dalalven floodplains during the years before, during, and after the hypothesised 2002 outbreak year were assayed for virus on cell culture. Obtained isolates were partially sequenced, and the nucleotide sequences analysed using Bayesian maximum clade credibility and median joining network analysis. Only one SINV strain was recovered in 2001, and 4 strains in 2003, while 15 strains were recovered in 2002 with significantly increased infection rates in both the enzootic and the bridge-vectors. In 2002, the Maximum Likelihood Estimated infection rates were 10.0/1000 in the enzootic vectors Culex torrentium/pipiens, and 0.62/1000 in the bridge-vector Aedes cinereus, compared to 4.9/1000 and 0.0/1000 in 2001 and 0.0/1000 and 0.32/1000 in 2003 Sequence analysis showed that all isolates belonged to the SINV genotype I (SINV-I). The genetic analysis revealed local maintenance of four SINV-I clades in the River Dalalven floodplains over the years. Our findings suggest that increased SINV-I prevalence in vector mosquitoes constitutes the most valuable outbreak marker for further scrutinising the hypothesized seven-year cycle of SINV-I outbreaks and the mechanisms behind.

  • 28.
    Ma'ayeh, Showgy Y.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Liu, Jingyi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Peirasmaki, Dimitra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Hörnaeus, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergström Lind, Sara K.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Svärd, Staffan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Characterization of the Giardia intestinalis secretome during interaction with human intestinal epithelial cells: The impact on host cells2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 12, article id e0006120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Giardia intestinalis is a non-invasive protozoan parasite that causes giardiasis in humans, the most common form of parasite-induced diarrhea. Disease mechanisms are not completely defined and very few virulence factors are known.

    METHODOLOGY:

    To identify putative virulence factors and elucidate mechanistic pathways leading to disease, we have used proteomics to identify the major excretory-secretory products (ESPs) when Giardia trophozoites of WB and GS isolates (assemblages A and B, respectively) interact with intestinal epithelial cells (IECs) in vitro.

    FINDINGS:

    The main parts of the IEC and parasite secretomes are constitutively released proteins, the majority of which are associated with metabolism but several proteins are released in response to their interaction (87 and 41 WB and GS proteins, respectively, 76 and 45 human proteins in response to the respective isolates). In parasitized IECs, the secretome profile indicated effects on the cell actin cytoskeleton and the induction of immune responses whereas that of Giardia showed anti-oxidation, proteolysis (protease-associated) and induction of encystation responses. The Giardia secretome also contained immunodominant and glycosylated proteins as well as new candidate virulence factors and assemblage-specific differences were identified. A minor part of Giardia ESPs had signal peptides (29% for both isolates) and extracellular vesicles were detected in the ESPs fractions, suggesting alternative secretory pathways. Microscopic analyses showed ESPs binding to IECs and partial internalization. Parasite ESPs reduced ERK1/2 and P38 phosphorylation and NF-κB nuclear translocation. Giardia ESPs altered gene expression in IECs, with a transcriptional profile indicating recruitment of immune cells via chemokines, disturbances in glucose homeostasis, cholesterol and lipid metabolism, cell cycle and induction of apoptosis.

    CONCLUSIONS:

    This is the first study identifying Giardia ESPs and evaluating their effects on IECs. It highlights the importance of host and parasite ESPs during interactions and reveals the intricate cellular responses that can explain disease mechanisms and attenuated inflammatory responses during giardiasis.

  • 29.
    Macleod, Colin
    et al.
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Yalen, Chelsea
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Butcher, Robert
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Mudaliar, Umesh
    Lautoka Hosp, Dept Ophthalmol, Lautoka, Fiji..
    Natutusau, Kinisimere
    Lautoka Hosp, Dept Ophthalmol, Lautoka, Fiji..
    Rainima-Qaniuci, Mere
    WHO, Fiji Country Off, Suva, Fiji..
    Haffenden, Chris
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of History of Science and Ideas.
    Watson, Conall
    London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London, England..
    Cocks, Naomi
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Cikamatana, Luisa
    Lautoka Hosp, Dept Ophthalmol, Lautoka, Fiji.;Minist Hlth, Dept Communicable Dis, Suva, Fiji..
    Roberts, Chrissy H.
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Marks, Michael
    London Sch Hyg & Trop Med, Dept Clin Res, London, England.;Hosp Trop Dis, London, England..
    Rafai, Eric
    Minist Hlth, Dept Communicable Dis, Suva, Fiji..
    Mabey, David C. W.
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Kama, Mike
    Minist Hlth, Dept Communicable Dis, Suva, Fiji..
    Solomon, Anthony W.
    London Sch Hyg & Trop Med, Dept Clin Res, London, England.;Hosp Trop Dis, London, England..
    Eyelash Epilation in the Absence of Trichiasis: Results of a Population-Based Prevalence Survey in the Western Division of Fiji2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 1, article id e0005277Article in journal (Refereed)
    Abstract [en]

    Background The WHO definition of trachomatous trichiasis (TT) is "at least one eyelash touching the globe, or evidence of recent epilation of in-turned eyelashes ", reflecting the fact that epilation is used as a self-management tool for TT. In Fiji's Western Division, a high TT prevalence (8.7% in those aged >= 15 years) was reported in a 2012 survey, yet a 2013 survey found no TT and Fijian ophthalmologists rarely see TT cases. Local anecdote suggests that eyelash epilation is a common behaviour, even in the absence of trichiasis. Epilators may have been identified as TT cases in previous surveys. Methods We used a preliminary focus group to design an interview questionnaire, and subsequently conducted a population-based prevalence survey to estimate the prevalence of epilation in the absence of trichiasis, and factors associated with this behaviour, in the Western Division of Fiji. Results We sampled 695 individuals aged >= 15 years from a total of 457 households in 23 villages. 125 participants (18%) reported epilating their eyelashes at least once within the past year. Photographs were obtained of the eyes of 121/125 (97%) individuals who epilated, and subsequent analysis by an experienced trachoma grader found no cases of trachomatous conjunctival scarring or trichiasis. The age-and sex-adjusted prevalence of epilation in those aged >= 15 years was 8.6% ( 95% Cl 5.7-11.3%). iTaukei ethnicity, female gender, and a higher frequency of drinking kava root were independently associated with epilation. Conclusion Epilation occurs in this population in the absence of trichiasis, with sufficient frequency to have markedly inflated previous estimates of local TT prevalence. Individuals with epilated eyelashes should be confirmed as having epilated in-turned eyelashes in an eye with scarring of the conjunctiva before being counted as cases of TT.

  • 30. Matiko, Mirende Kichuki
    et al.
    Salekwa, Linda Peniel
    Kasanga, Christopher Jacob
    Kimera, Sharadhuli Idd
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nyangi, Wambura Philemon
    Serological evidence of inter-epizootic/interepidemic circulation of Rift Valley fever virus in domestic cattle in Kyela and Morogoro, Tanzania2018In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 12, no 11, article id e0006931Article in journal (Refereed)
    Abstract [en]

    Background: Tanzania is among the Rift Valley fever (RVF) epizootic/endemic countries in sub Saharan Africa, where RVF disease outbreaks occur within a range of 3 to 17-year intervals. Detection of Rift Valley fever virus (RVFV) antibodies in animals in regions with no previous history of outbreaks raises the question of whether the disease is overlooked due to lack-of effective surveillance systems, or if there are strains of RVFV with low pathogenicity. Furthermore, which vertebrate hosts are involved in the inter-epidemic and inter-epizootic maintenance of RVFV? In our study region, the Kyela and Morogoro districts in Tanzania, no previous RVF outbreaks have been reported.

    Methodology: The study was conducted from June 2014 to October 2015 in the Kyela and Morogoro districts, Tanzania. Samples (n = 356) were retrieved from both the local breed of zebu cattle (Bos indicus) and Bos indicus/Bos Taurus cross breed. RVFV antibodies were analyzed by two enzyme-linked immunosorbent assay (ELISA) approaches. Initially, samples were analyzed by a RVFV multi-species competition ELISA (cELISA), which detected both RVFV IgG and IgM antibodies. All serum samples that were positive with the cELISA method were specifically analysed for the presence of RVFV IgM antibodies to trace recent infection. A plaque reduction neutralization assay (PRNT80) was performed to determine presence of RVFV neutralizing antibodies in all cELISA positive samples.

    Findings: Overall RVFV seroprevalence rate in cattle by cELISA in both districts was 29.2% (104 of 356) with seroprevalence rates of 33% (47/147) in the Kyela district and 27% (57/209) in the Morogoro district. In total, 8.4% (30/356) of all cattle sampled had RVFV IgM antibodies, indicating current disease transmission. When segregated by districts, the IgM antibody seroprevalence was 2.0% (3/147) and 12.9% (27/209) in Kyela and Morogoro districts respectively. When the 104 cELISA positive samples were analyzed by PRNT80 to confirm that RVFV-specific antibodies were present, the majority (89%, 93/104) had RVFV neutralising antibodies.

    Conclusion: The results provided evidence of widespread prevalence of RVFV antibody among cattle during an inter-epizootic/inter-epidemic period in Tanzania in regions with no previous history of outbreaks. There is a need for further investigations of RVFV maintenance and transmission in vertebrates and vectors during the long inter-epizootic/inter-epidemic periods.

  • 31.
    Näsström, Elin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Dongol, Sabina
    Karkey, Abhilasha
    Basnyat, Buddha
    Thieu, Nga Tran Vu
    Van, Tan Trinh
    Thwaites, Guy E.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Baker, Stephen
    Diagnostic metabolite biomarkers of chronic typhoid carriage2018In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 12, no 1, article id e0006215Article in journal (Refereed)
    Abstract [en]

    Background: Salmonella Typhi and Salmonella Paratyphi A are the agents of enteric (typhoid) fever; both can establish chronic carriage in the gallbladder. Chronic Salmonella carriers are typically asymptomatic, intermittently shedding bacteria in the feces, and contributing to disease transmission. Detecting chronic carriers is of public health relevance in areas where enteric fever is endemic, but there are no routinely used methods for prospectively identifying those carrying Salmonella in their gallbladder.

    Methodology/Principal findings: Here we aimed to identify biomarkers of Salmonella carriage using metabolite profiling. We performed metabolite profiling on plasma from Nepali patients undergoing cholecystectomy with confirmed S. Typhi or S. Paratyphi A gallbladder carriage (and non-carriage controls) using two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) and supervised pattern recognition modeling. We were able to significantly discriminate Salmonella carriage samples from non-carriage control samples. We were also able to detect differential signatures between S. Typhi and S. Paratyphi A carriers. We additionally compared carriage metabolite profiles with profiles generated during acute infection; these data revealed substantial heterogeneity between metabolites associated with acute enteric fever and chronic carriage. Lastly, we found that Salmonella carriers could be significantly distinguished from non-carriage controls using only five metabolites, indicating the potential of these metabolites as diagnostic markers for detecting chronic Salmonella carriers.

    Conclusions/Significance: Our novel approach has highlighted the potential of using metabolomics to search for diagnostic markers of chronic Salmonella carriage. We suggest further epidemiological investigations of these potential biomarkers in alternative endemic enteric fever settings.

  • 32.
    Ramadona, Aditya Lia
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health. Center for Environmental Studies, Universitas Gadjah Mada, Yogyakarta, Indonesia.
    Tozan, Yesim
    Lazuardi, Lutfan
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    A combination of incidence data and mobility proxies from social media predicts the intra-urban spread of dengue in Yogyakarta, Indonesia2019In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 13, no 4, article id e0007298Article in journal (Refereed)
    Abstract [en]

    Only a few studies have investigated the potential of using geotagged social media data for predicting the patterns of spatio-temporal spread of vector-borne diseases. We herein demonstrated the role of human mobility in the intra-urban spread of dengue by weighting local incidence data with geo-tagged Twitter data as a proxy for human mobility across 45 neighborhoods in Yogyakarta city, Indonesia. To estimate the dengue virus importation pressure in each study neighborhood monthly, we developed an algorithm to estimate a dynamic mobility-weighted incidence index (MI), which quantifies the level of exposure to virus importation in any given neighborhood. Using a Bayesian spatio-temporal regression model, we estimated the coefficients and predictiveness of the MI index for lags up to 6 months. Specifically, we used a Poisson regression model with an unstructured spatial covariance matrix. We compared the predictability of the MI index to that of the dengue incidence rate over the preceding months in the same neighborhood (autocorrelation) and that of the mobility information alone. We based our estimates on a volume of 1·302·405 geotagged tweets (from 118·114 unique users) and monthly dengue incidence data for the 45 study neighborhoods in Yogyakarta city over the period from August 2016 to June 2018. The MI index, as a standalone variable, had the highest explanatory power for predicting dengue transmission risk in the study neighborhoods, with the greatest predictive ability at a 3-months lead time. The MI index was a better predictor of the dengue risk in a neighborhood than the recent transmission patterns in the same neighborhood, or just the mobility patterns between neighborhoods. Our results suggest that human mobility is an important driver of the spread of dengue within cities when combined with information on local circulation of the dengue virus. The geotagged Twitter data can provide important information on human mobility patterns to improve our understanding of the direction and the risk of spread of diseases, such as dengue. The proposed MI index together with traditional data sources can provide useful information for the development of more accurate and efficient early warning and response systems.

  • 33. Sang, Rosemary
    et al.
    Arum, Samwel
    Chepkorir, Edith
    Mosomtai, Gladys
    Tigoi, Caroline
    Sigei, Faith
    Lwande, Olivia Wesula
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Landmann, Tobias
    Affognon, Hippolyte
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Distribution and abundance of key vectors of Rift Valley fever and other arboviruses in two ecologically distinct counties in Kenya2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 2, article id e0005341Article in journal (Refereed)
    Abstract [en]

    Background Rift Valley fever (RVF) is a mosquito-borne viral zoonosis of ruminants and humans that causes outbreaks in Africa and the Arabian Peninsula with significant public health and economic consequences. Humans become infected through mosquito bites and contact with infected livestock. The virus is maintained between outbreaks through vertically infected eggs of the primary vectors of Aedes species which emerge following rains with extensive flooding. Infected female mosquitoes initiate transmission among nearby animals, which amplifies virus, thereby infecting more mosquitoes and moving the virus beyond the initial point of emergence. With each successive outbreak, RVF has been found to expand its geographic distribution to new areas, possibly driven by available vectors. The aim of the present study was to determine if RVF virus (RVFV) transmission risk in two different ecological zones in Kenya could be assessed by looking at the species composition, abundance and distribution of key primary and secondary vector species and the level of virus activity. Methodology Mosquitoes were trapped during short and long rainy seasons in 2014 and 2015 using CO2 baited CDC light traps in two counties which differ in RVF epidemic risk levels(high risk Tana-River and low risk Isiolo), cryo-preserved in liquid nitrogen, transported to the laboratory, and identified to species. Mosquito pools were analyzed for virus infection using cell culture screening and molecular analysis. Findings Over 69,000 mosquitoes were sampled and identified as 40 different species belonging to 6 genera (Aedes, Anopheles, Mansonia, Culex, Aedeomyia, Coquillettidia). The presence and abundance of Aedes mcintoshi and Aedes ochraceus, the primary mosquito vectors associated with RVFV transmission in outbreaks, varied significantly between Tana-River and Isiolo. Ae. mcintoshi was abundant in Tana-River and Isiolo but notably, Aedes ochraceus found in relatively high numbers in Tana-River (n = 1,290), was totally absent in all Isiolo sites. Fourteen virus isolates including Sindbis, Bunyamwera, and West Nile fever viruses were isolated mostly from Ae. mcintoshi sampled in Tana-River. RVFV was not detected in any of the mosquitoes. Conclusion This study presents the geographic distribution and abundance of arbovirus vectors in two Kenyan counties, which may assist with risk assessment for mosquito borne diseases.

  • 34. Sang, Shaowei
    et al.
    Liu-Helmersson, Jing
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Quam, Mikkel B. M.
    Zhou, Hongning
    Guo, Xiaofang
    Wu, Haixia
    Liu, Qiyong
    The evolutionary dynamics of DENV 4 genotype I over a 60-year period2019In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 13, no 7, article id e0007592Article in journal (Refereed)
    Abstract [en]

    Dengue virus serotype 4 (DENV 4) has had a relatively low prevalence worldwide for decades; however, likely due to data paucity, no study has investigated the epidemiology and evolutionary dynamics of DENV 4 genotype I (DENV 4-I). This study aims to understand the diversity, epidemiology and dynamics of DENV 4-I. We collected 404 full length DENV4-1 envelope (E) gene sequences from 14 countries using two sources: Yunnan Province in China (15 strains during 2013-2016) and GenBank (489 strains up to 2018-01-11). Conducting phylogenetic and phylogeographical analyses, we estimated the virus spread, population dynamics, and selection pressures using different statistical analysis methods (substitution saturation, likelihood mapping, Bayesian coalescent inference, and maximum likelihood estimation). Our results show that during the last 60 years (1956-2016), DENV 4-I was present in mainland and maritime Southeast Asia, the Indian subcontinent, the southern provinces of China, parts of Brazil and Australia. The recent spread of DENV 4-I likely originated in the Philippines and later spread to Thailand. From Thailand, it spread to adjacent countries and eventually the Indian subcontinent. Apparently diverging around years 1957, 1963, 1976 and 1990, the different Clades (Clade I-V) were defined. The mean overall evolution rate of DENV 4-I was 9.74 (95% HPD: 8.68-10.82) x 10(-4) nucleotide substitutions/site/year. The most recent common ancestor for DENV 4-I traces back to 1956. While the demographic history of DENV 4-I fluctuated, peaks appeared around 1982 and 2006. While purifying selection dominated the majority of E-gene evolution of DENV 4-I, positive selection characterized Clade III (Vietnam). DENV 4-I evolved in situ in Southeast Asia and the Indian subcontinent. Thailand and Indian acted as the main and secondary virus distribution hubs globally and regionally. Our phylogenetic analysis highlights the need for strengthened regional cooperation on surveillance and sharing of sample sequences to improve global dengue control and cross-border transmission prevention efforts. Author summary Dengue virus (DENV) can be classified into four serotypes, DENV 1, 2, 3 and 4. Although DENV 4 is the first dengue serotype to diverge in phylogenetic analyses of the genus Flavivirus, this serotype occurs at a low prevalence worldwide and spreads the least rapidly. Similar to other serotypes, DENV 4 can also cause severe dengue (SD) disease manifestations, such as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). To date, no study has investigated the epidemiology and dynamics of DENV 4 genotype I comprehensively. In this study, we seek to address this gap. Our study shows that the distribution of DENV 4-I is mainly restricted to Southeast Asia and the Indian subcontinent. The most recent spread of DENV 4-I likely originated from Southeast Asia-initially circulating in the Philippines, then Thailand and later on the Indian subcontinent. Viruses evolved in situ in Southeast Asia and the Indian subcontinent, respectively. Although DENV 4-I occasionally spread elsewhere, this genotype did not become widely established. The overall evolution rate of DENV 4-I was comparable with that of DENV 2-4. The nucleotide sequences indicates that the demographic history of DENV 4-I fluctuated with peaks apparent during parts of the 1980s and 2000s. Although a weak positive selection existed in Clade III -predominately in Vietnam, purifying selection dominated the E-gene evolution of DENV 4-I.

  • 35.
    Thalagala, Neil
    et al.
    Colombo, Sri Lanka.
    Tissera, Hasitha
    Colombo, Sri Lanka.
    Palihawadana, Paba
    Colombo, Sri Lanka.
    Amarasinghe, Ananda
    Colombo, Sri Lanka.
    Ambagahawita, Anuradha
    Colombo, Sri Lanka.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
    Shepard, Donald S
    Waltham, Massachusetts, United States of America.
    Tozan, Yeşim
    Heidelberg, Germany; New York, United States of America.
    Costs of Dengue Control Activities and Hospitalizations in the Public Health Sector during an Epidemic Year in Urban Sri Lanka2016In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 10, no 2, article id e0004466Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Reported as a public health problem since the 1960s in Sri Lanka, dengue has become a high priority disease for public health authorities. The Ministry of Health is responsible for controlling dengue and other disease outbreaks and associated health care. The involvement of large numbers of public health staff in dengue control activities year-round and the provision of free medical care to dengue patients at secondary care hospitals place a formidable financial burden on the public health sector.

    METHODS: We estimated the public sector costs of dengue control activities and the direct costs of hospitalizations in Colombo, the most heavily urbanized district in Sri Lanka, during the epidemic year of 2012 from the Ministry of Health's perspective. The financial costs borne by public health agencies and hospitals are collected using cost extraction tools designed specifically for the study and analysed retrospectively using a combination of activity-based and gross costing approaches.

    RESULTS: The total cost of dengue control and reported hospitalizations was estimated at US$3.45 million (US$1.50 per capita) in Colombo district in 2012. Personnel costs accounted for the largest shares of the total costs of dengue control activities (79%) and hospitalizations (46%). The results indicated a per capita cost of US$0.42 for dengue control activities. The average costs per hospitalization ranged between US$216-609 for pediatric cases and between US$196-866 for adult cases according to disease severity and treatment setting.

    CONCLUSIONS: This analysis is a first attempt to assess the economic burden of dengue response in the public health sector in Sri Lanka. Country-specific evidence is needed for setting public health priorities and deciding about the deployment of existing or new technologies. Our results suggest that dengue poses a major economic burden on the public health sector in Sri Lanka.

  • 36.
    Thielecke, Marlene
    et al.
    Institute of Microbiology and Hygiene, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.
    Nordin, Per
    Skaraborg Institute for Research and Development, Skövde, Sweden.
    Ngomi, Nicholas
    African Population and Health Research Center, Nairobi, Kenya.
    Feldmeier, Hermann
    Institute of Microbiology and Hygiene, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany.
    Treatment of Tungiasis with dimeticone: a proof-of-principle study in rural Kenya2014In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 8, no 7, article id e3058Article in journal (Refereed)
    Abstract [en]

    Tungiasis (sand flea disease) is a neglected tropical disease, prevalent in resource-poor communities in South America and sub-Saharan Africa. It is caused by an inflammatory response against penetrated female sand fleas (Tunga penetrans) embedded in the skin of the host. Although associated with debilitating acute and chronic morbidity, there is no proven effective drug treatment. By consequence patients attempt to remove embedded sand fleas with non-sterile sharp instruments, such as safety pins, a procedure that represents a health threat by itself. In this proof-of-principle study we compared the topical application of a mixture of two dimeticones of low viscosity (NYDA) to the topical application of a 0.05% solution of KMnO4 in 47 school children in an endemic area in rural Kenya. The efficacy of the treatment was assessed during a follow up period of seven days using viability signs of the embedded parasites, alterations in the natural development of lesion morphology and the degree of local inflammation as outcome measures. Seven days after treatment, in the dimeticone group 78% (95% CI 67-86%) of the parasites had lost all signs of viability as compared to 39% (95% CI 28-52%) in the KMnO4 group (p<0.001). In the dimeticone group 90% (95% CI 80-95%) of the penetrated sand fleas showed an abnormal development already after 5 days, compared to 53% (95% CI 40-66%; p<0.001) in the KMnO4 group. Seven days after treatment, signs of local skin inflammation had significantly decreased in the dimeticone group (p<0.001). This study identified the topical application of dimeticones of low viscosity (NYDA) as an effective means to kill embedded sand fleas. In view of the efficacy and safety of the topical treatment with dimeticone, the mechanical extraction of embedded sand fleas using hazardous instruments is no longer warranted.

  • 37.
    Tissera, Hasitha
    et al.
    Colombo, Sri Lanka.
    Amarasinghe, Ananda
    Colombo, Sri Lanka.
    Gunasena, Sunethra
    Colombo, Sri Lanka.
    DeSilva, Aruna Dharshan
    Colombo, Sri Lanka.
    Yee, Leong Wei
    Singapore, Singapore.
    Sessions, October
    Singapore, Singapore.
    Muthukuda, Chanaka
    Colombo, Sri Lanka.
    Palihawadana, Paba
    Colombo, Sri Lanka.
    Lohr, Wolfgang
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Gubler, Duane J
    Singapore, Singapore.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
    Laboratory-Enhanced Dengue Sentinel Surveillance in Colombo District, Sri Lanka: 2012-20142016In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 10, no 2, article id e0004477Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Dengue has emerged as a significant public health problem in Sri Lanka. Historically surveillance was passive, with mandatory dengue notifications based on clinical diagnosis with only limited laboratory confirmation. To obtain more accurate data on the disease burden of dengue, we set up a laboratory-based enhanced sentinel surveillance system in Colombo District. Here we describe the study design and report our findings of enhanced surveillance in the years 2012-2014.

    METHODS: Three outpatient clinics and three government hospitals in Colombo District that covered most of the Colombo metropolitan area were selected for the sentinel surveillance system. Up to 60 patients per week presenting with an undifferentiated fever were enrolled. Acute blood samples from each patient were tested by dengue specific PCR, NS1 ELISA and IgM ELISA. A sub-set of samples was sent to Duke-NUS Singapore for quality assurance, virus isolation and serotyping. Trained medical research assistants used a standardized case report form to record clinical and epidemiological data. Clinical diagnoses by the clinicians-in-charge were recorded for hospitalized cases.

    RESULTS: Of 3,127 febrile cases, 43.6% were PCR and/or NS1 positive for dengue. A high proportion of lab confirmed dengue was observed from inpatients (IPD) (53.9%) compared to outpatient (clinics in hospitals and general practice) (7.6%). Dengue hemorrhagic fever (DHF) was diagnosed in 11% of patients at the time of first contact, and the median day of illness at time of presentation to the sentinel sites was 4. Dengue serotype 1 was responsible for 85% of the cases and serotype 4 for 15%. The sensitivity and specificity of the clinicians' presumptive diagnosis of dengue was 84% and 34%, respectively.

    CONCLUSION: DENV-1, and to a lesser degree DENV-4, infection were responsible for a high proportion of febrile illnesses in Colombo in the years 2012 to 2014. Clinicians' diagnoses were associated with high sensitivity, but laboratory confirmation is required to enhance specificity.

  • 38. Tozan, Yesim
    et al.
    Ratanawong, Pitcha
    Sewe, Maquines Odhiambo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wilder-Smith, Annelies
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Heidelberg Univ, Med Sch, Inst Publ Hlth, Heidelberg, Germany; Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore.
    Kittayapong, Pattamaporn
    Household costs of hospitalized dengue illness in semi-rural Thailand2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 9, article id e005961Article in journal (Refereed)
    Abstract [en]

    Background

    Dengue-related illness is a leading cause of hospitalization and death in Thailand and other Southeast Asian countries, imposing a major economic burden on households, health systems, and governments. This study aims to assess the economic impact of hospitalized dengue cases on households in Chachoengsao province in eastern Thailand.

    Methods

    We conducted a prospective cost-of-illness study of hospitalized pediatric and adult dengue patients at three public hospitals. We examined all hospitalized dengue cases regardless of disease severity. Patients or their legal guardians were interviewed using a standard questionnaire to determine household-level medical and non-medical expenditures and income losses during the illness episode.

    Results

    Between March and September 2015, we recruited a total of 224 hospitalized patients (< 5 years, 4%; 5-14 years, 20%, 15-24 years, 36%, 25-34 years, 15%; 35-44 years, 10%; 45+ years, 12%), who were clinically diagnosed with dengue. The total cost of a hospitalized dengue case was higher for adult patients than pediatric patients, and was US$153.6 and US$166.3 for pediatric DF and DHF patients, respectively, and US$171.2 and US$226.1 for adult DF and DHF patients, respectively. The financial burden on households increased with the severity of dengue illness.

    Conclusions

    Although 74% of the households reported that the patient received free medical care, hospitalized dengue illness cost approximately 19-23% of the monthly household income. These results indicated that dengue imposed a substantial financial burden on households in Thailand where a great majority of the population was covered by the Universal Coverage Scheme for health care.

  • 39.
    Tyson, Jasmine
    et al.
    Univ Hawaii Manoa, HI 96822 USA.
    Tsai, Wen-Yang
    Univ Hawaii Manoa, HI 96822 USA.
    Tsai, Jih-Jin
    Kaohsiung Med Univ, Taiwan.
    Massgard, Ludvig
    Linköping University, Faculty of Medicine and Health Sciences.
    Stramer, Susan L.
    Amer Red Cross Sci Support Off, MD USA.
    Lehrer, Axel T.
    Univ Hawaii Manoa, HI 96822 USA.
    Nerurkar, Vivek R.
    Univ Hawaii Manoa, HI 96822 USA.
    Wang, Wei-Kung
    Univ Hawaii Manoa, HI 96822 USA.
    A high-throughput and multiplex microsphere immunoassay based on non-structural protein 1 can discriminate three flavivirus infections2019In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 13, no 8, article id e0007649Article in journal (Refereed)
    Abstract [en]

    The explosive spread of Zika virus (ZIKV) and associated complications in flavivirus-endemic regions underscore the need for sensitive and specific serodiagnostic tests to distinguish ZIKV, dengue virus (DENV) and other flavivirus infections. Compared with traditional envelope protein-based assays, several nonstructural protein 1 (NS1)-based assays showed improved specificity, however, none can detect and discriminate three flaviviruses in a single assay. Moreover, secondary DENV infection and ZIKV infection with previous DENV infection, both common in endemic regions, cannot be discriminated. In this study, we developed a high-throughput and multiplex IgG microsphere immunoassay (MIA) using the NS1 proteins of DENV1-DENV4, ZIKV and West Nile virus (WNV) to test samples from reverse-transcription-polymerase-chain reaction-confirmed cases, including primary DENV1, DENV2, DENV3, WNV and ZIKV infections, secondary DENV infection, and ZIKV infection with previous DENV infection. Combination of four DENV NS1 IgG MIAs revealed a sensitivity of 94.3% and specificity of 97.2% to detect DENV infection. The ZIKV and WNV NS1 IgG MIAs had a sensitivity/specificity of 100%/87.9% and 86.1%/78.4%, respectively. A positive correlation was found between the readouts of enzyme-linked immunosorbent assay and MIA for different NS1 tested. Based on the ratio of relative median fluorescence intensity of ZIKV NS1 to DENV1 NS1, the IgG MIA can distinguish ZIKV infection with previous DENV infection and secondary DENV infection with a sensitivity of 88.9-90.0% and specificity of 91.7-100.0%. The multiplex and high-throughput assay could be applied to serodiagnosis and serosurveillance of DENV, ZIKV and WNV infections in endemic regions.

  • 40.
    Vikeved, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Alsmark, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Natl Vet Inst SVA, Dept Microbiol, Uppsala, Sweden..
    The Dynamics of Lateral Gene Transfer in Genus Leishmania - A Route for Adaptation and Species Diversification2016In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 10, no 1, article id e0004326Article in journal (Refereed)
    Abstract [en]

    Background The genome of Leishmania major harbours a comparably high proportion of genes of prokaryote origin, acquired by lateral gene transfer (LGT). Some of these are present in closely related trypanosomatids, while some are detected in Leishmania only. We have evaluated the impact and destiny of LGT in genus Leishmania. Methodology/Principal Findings To study the dynamics and fate of LGTs we have performed phylogenetic, as well as nucleotide and amino acid composition analyses within orthologous groups of LGTs detected in Leishmania. A set of universal trypanosomatid LGTs was added as a reference group. Both groups of LGTs have, to some extent, ameliorated to resemble the recipient genomes. However, while virtually all of the universal trypanosomatid LGTs are distributed and conserved in the entire genus Leishmania, the LGTs uniquely present in genus Leishmania are more prone to gene loss and display faster rates of evolution. Furthermore, a PCR based approach has been employed to ascertain the presence of a set of twenty LGTs uniquely present in genus Leishmania, and three universal trypanosomatid LGTs, in ten additional strains of Leishmania. Evolutionary rates and predicted expression levels of these LGTs have also been estimated. Ten of the twenty LGTs are distributed and conserved in all species investigated, while the remainder have been subjected to modifications, or undergone pseudogenization, degradation or loss in one or more species. Conclusions/Significance LGTs unique to the genus Leishmania have been acquired after the divergence of Leishmania from the other trypanosomatids, and are evolving faster than their recipient genomes. This implies that LGT in genus Leishmania is a continuous and dynamic process contributing to species differentiation and speciation. This study also highlights the importance of carefully evaluating these dynamic genes, e.g. as LGTs have been suggested as potential drug targets.

  • 41. Wasunna, Monique
    et al.
    Njenga, Simon
    Balasegaram, Manica
    Alexander, Neal
    Omollo, Raymond
    Edwards, Tansy
    Dorlo, Thomas P C
    Musa, Brima
    Ali, Mohammed Hassan Sharaf
    Elamin, Mohammed Yasein
    Kirigi, George
    Juma, Rashid
    Kip, Anke E
    Schoone, Gerard J
    Hailu, Asrat
    Olobo, Joseph
    Ellis, Sally
    Kimutai, Robert
    Wells, Susan
    Khalil, Eltahir Awad Gasim
    Strub Wourgaft, Nathalie
    Alves, Fabiana
    Musa, Ahmed
    Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial.2016In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 10, no 9, article id e0004880Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa.

    METHODS: A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments.

    RESULTS: In sequential analyses with 49-51 patients per arm, initial cure was 85% (95% CI: 73-92) in all arms. At D210, definitive cure was 87% (95% CI: 77-97) for AmBisome + SSG, 77% (95% CI 64-90) for AmBisome + miltefosine and 72% (95% CI 60-85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults.

    CONCLUSION: No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated.

    TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov, number NCT01067443.

  • 42.
    Yman, Victor
    et al.
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.
    Wandell, Grace
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden;Univ Washington, Dept Otolaryngol, Med Ctr, Seattle, WA 98195 USA.
    Mutemi, Doreen D.
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden;Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Miglar, Aurelie
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.
    Asghar, Muhammad
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.
    Hammar, Ulf
    Karolinska Inst, Dept Environm Med, Unit Biostat, Stockholm, Sweden.
    Karlsson, Mattias
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.
    Lind, Ingrid
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.
    Nordfjell, Cleis
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.
    Rooth, Ingegerd
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.
    Ngasala, Billy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Homann, Manijeh Vafa
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.
    Farnert, Anna
    Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.
    Persistent transmission of Plasmodium malariae and Plasmodium ovale species in an area of declining Plasmodium falciparum transmission in eastern Tanzania2019In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 13, no 5, article id e0007414Article in journal (Refereed)
    Abstract [en]

    A reduction in the global burden of malaria over the past two decades has encouraged efforts for regional malaria elimination. Despite the need to target all Plasmodium species, current focus is mainly directed towards Plasmodium falciparum, and to a lesser extent P. vivax. There is a substantial lack of data on both global and local transmission patterns of the neglected malaria parasites P. malariae and P. ovale spp. We used a species-specific real-time PCR assay targeting the Plasmodium 18s rRNA gene to evaluate temporal trends in the prevalence of all human malaria parasites over a 22-year period in a rural village in Tanzania.We tested 2897 blood samples collected in five cross-sectional surveys conducted between 1994 and 2016. Infections with P. falciparum, P. malariae, and P. ovale spp. were detected throughout the study period, while P. vivax was not detected. Between 1994 and 2010, we found a more than 90% reduction in the odds of infection with all detected species. The odds of P. falciparum infection was further reduced in 2016, while the odds of P. malariae and P. ovale spp. infection increased 2- and 6-fold, respectively, compared to 2010. In 2016, non-falciparum species occurred more often as mono-infections. The results demonstrate the persistent transmission of P. ovale spp., and to a lesser extent P. malariae despite a continued decline in P. falciparum transmission. This illustrates that the transmission patterns of the non-falciparum species do not necessarily follow those of P. falciparum, stressing the need for attention towards non-falciparum malaria in Africa. Malaria elimination will require a better understanding of the epidemiology of P. malariae and P. ovale spp. and improved tools for monitoring the transmission of all Plasmodium species, with a particular focus towards identifying asymptomatic carriers of infection and designing appropriate interventions to enhance malaria control. Author summary The reduction in the global burden of malaria has encouraged efforts for elimination. Attempts to control and monitor transmission have mainly focused on the predominant malaria parasites Plasmodium falciparum and P. vivax. However, eliminating malaria requires the elimination of all human malaria parasites and limited interest has been directed towards estimating the disease burden attributable to the neglected malaria parasites P. ovale spp. and P. malariae. The authors used molecular methods to analyse 2897 blood samples collected in five cross-sectional surveys over a period of 22 years, and described the transmission patterns of all human malaria parasites in a Tanzanian village. They demonstrate a persistent transmission of P. malariae and P. ovale spp. despite a substantial reduction in transmission of P. falciparum, highlighting the need for more attention towards non-falciparum malaria. The authors discuss the implications of these findings in the context of current efforts for regional malaria elimination.

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