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IgG antibodies to synthetic GPI are biomarkers of immune-status to both Plasmodium falciparum and Plasmodium vivax malaria in young children

  • França, Camila T.
  • Li Wai Suen, Connie S. N.
  • Carmagnac, Amandine
  • Lin, Enmoore
  • Kiniboro, Benson
  • Siba, Peter
  • Schofield, Louis
  • Mueller, Ivo
BACKGROUND: Further reduction in malaria prevalence and its eventual elimination would be greatly facilitated by the development of biomarkers of exposure and/or acquired immunity to malaria, as well as the deployment of effective vaccines against Plasmodium falciparum and Plasmodium vivax. A better understanding of the acquisition of immunity in naturally-exposed populations is essential for the identification of antigens useful as biomarkers, as well as to inform rational vaccine development. METHODS: ELISA was used to measure total IgG to a synthetic form of glycosylphosphatidylinositol from P. falciparum (PfGPI) in a cohort of 1-3 years old Papua New Guinea children with well-characterized individual differences in exposure to P. falciparum and P. vivax blood-stage infections. The relationship between IgG levels to PfGPI and measures of recent and past exposure to P. falciparum and P. vivax infections was investigated, as well as the association between antibody levels and prospective risk of clinical malaria over 16 months of follow-up. RESULTS: Total IgG levels to PfGPI were low in the young children tested. Antibody levels were higher in the presence of P. falciparum or P. vivax infections, but short-lived. High IgG levels were associated with higher risk of P. falciparum malaria (IRR 1.33-1.66, P = 0.008-0.027), suggesting that they are biomarkers of increased exposure to P. falciparum infections. Given the cross-reactive nature of antibodies to PfGPI, high IgG levels were also associated with reduced risk of P. vivax malaria (IRR 0.65-0.67, P = 0.039-0.044), indicating that these antibodies are also markers of acquired immunity to P. vivax. CONCLUSIONS: This study highlights that in young children, IgG to PfGPI might be a useful marker of immune-status to both P. falciparum and P. vivax infections, and potentially useful to help malaria control programs to identify populations at-risk. Further functional studies are necessary to confirm the potential of PfGPI as a target for vaccine development.
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Assessment of the Combined Effect of Epstein-Barr Virus and Plasmodium falciparum Infections on Endemic Burkitt Lymphoma Using a Multiplex Serological Approach

  • Aguilar, Ruth
  • Casabonne, Delphine
  • O'Callaghan Gordo, Cristina
  • Vidal, Marta
  • Campo, Joseph J.
  • Mutalima, Nora
  • Angov, Evelina
  • Dutta, Sheetij
  • Gaur, Deepak
  • Chitnis, Chetan E.
  • Chauhan, Virander Singh
  • Michel, Angelika
  • Sanjosé Llongueras, Silvia de
  • Waterboer, Tim
  • Kogevinas, Manolis
  • Newton, Rob
  • Dobaño, Carlota, 1969-
Epstein–Barr virus (EBV) is a necessary cause of endemic Burkitt lymphoma (eBL), while the role of Plasmodium falciparum in eBL remains uncertain. This study aimed to generate new hypotheses on the interplay between both infections in the development of eBL by investigating the IgG and IgM profiles against several EBV and P. falciparum antigens. Serum samples collected in a childhood study in Malawi (2005–2006) from 442 HIV-seronegative children (271 eBL cases and 171 controls) between 1.4 and 15 years old were tested by quantitative suspension array technology against a newly developed multiplex panel combining 4 EBV antigens [Z Epstein–Barr replication activator protein (ZEBRA), early antigen-diffuse component (EA-D), EBV nuclear antigen 1, and viral capsid antigen p18 subunit (VCA-p18)] and 15 P. falciparum antigens selected for their immunogenicity, role in malaria pathogenesis, and presence in different parasite stages. Principal component analyses, multivariate logistic models, and elastic-net regressions were used. As expected, elevated levels of EBV IgG (especially against the lytic antigens ZEBRA, EA-D, and VCA-p18) were strongly associated with eBL [high vs low tertile odds ratio (OR) = 8.67, 95% confidence interval (CI) = 4.81–15.64]. Higher IgG responses to the merozoite surface protein 3 were observed in children with eBL compared with controls (OR = 1.29, 95% CI = 1.02–1.64), showing an additive interaction with EBV IgGs (OR = 10.6, 95% CI = 5.1–22.2, P = 0.05). Using elastic-net regression models, eBL serological profile was further characterized by lower IgM levels against P. falciparum preerythrocytic-stage antigen CelTOS and EBV lytic antigen VCA-p18 compared with controls. In a secondary analysis, abdominal Burkitt lymphoma had lower IgM to EBV and higher IgG to EA-D levels than cases with head involvement. Overall, this exploratory study confirmed the strong role of EBV in eBL and identified differential IgG and IgM patterns to erythrocytic vs preerythrocytic P. falciparum antigens that suggest a more persistent/chronic malaria exposure and a weaker IgM immune response in children with eBL compared with controls. Future studies should continue exploring how the malaria infection status and the immune response to P. falciparum interact with EBV infection in the development of eBL.
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Stillbirth With Group B Streptococcus Disease Worldwide: Systematic Review and Meta-analyses

  • Seale, Anna C.
  • Blencowe, Hannah
  • Bianchi-Jassir, Fiorella
  • Embleton, Nicholas
  • Bassat Orellana, Quique
  • Ordi i Majà, Jaume
  • Menéndez, Clara
  • Cutland, Clare L.
  • Briner, Carmen
  • Berkley, James A.
  • Lawn, Joy E.
  • Baker, Carol J.
  • Bartlett, Linda
  • Gravett, Michael G.
  • Heath, Paul T.
  • Ip, Margaret
  • Le Doare, Kirsty
  • Rubens, Craig E.
  • Saha, Samir K.
  • Schrag, Stephanie
  • Meulen, Ajoke Sobanjo-ter
  • Vekemans, Johan
  • Madhi, Shabir A.
Background: There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease. Methods: We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciencias da Saude, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly >/=28 weeks' gestation or >/=1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets. Results: We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval [CI], 0-2%) of all stillbirths in developed countries and 4% (95% CI, 2%-6%) in Africa were associated with GBS. Conclusions: GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination.
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Maternal Colonization With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses

  • Russell, Neal J.
  • Seale, Anna C.
  • O'Driscoll, Megan
  • O'Sullivan, Catherine
  • Bianchi-Jassir, Fiorella
  • Gonzalez Guarin, Juan
  • Lawn, Joy E.
  • Baker, Carol J.
  • Bartlett, Linda
  • Cutland, Clare L.
  • Gravett, Michael G.
  • Heath, Paul T.
  • Le Doare, Kirsty
  • Madhi, Shabir A.
  • Rubens, Craig E.
  • Schrag, Stephanie
  • Sobanjo Ter Meulen, Ajoke
  • Vekemans, Johan
  • Saha, Samir K.
  • Ip, Margaret
  • GBS Maternal Colonization Investigator Group
Background Maternal rectovaginal colonization with group B Streptococcus (GBS) is the most common pathway for GBS disease in mother, fetus, and newborn. This article, the second in a series estimating the burden of GBS, aims to determine the prevalence and serotype distribution of GBS colonizing pregnant women worldwide. Methods We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus), organized Chinese language searches, and sought unpublished data from investigator groups. We applied broad inclusion criteria to maximize data inputs, particularly from low- and middle-income contexts, and then applied new meta-analyses to adjust for studies with less-sensitive sampling and laboratory techniques. We undertook meta-analyses to derive pooled estimates of maternal GBS colonization prevalence at national and regional levels. Results The dataset regarding colonization included 390 articles, 85 countries, and a total of 299924 pregnant women. Our adjusted estimate for maternal GBS colonization worldwide was 18% (95% confidence interval [CI], 17%–19%), with regional variation (11%–35%), and lower prevalence in Southern Asia (12.5% [95% CI, 10%–15%]) and Eastern Asia (11% [95% CI, 10%–12%]). Bacterial serotypes I–V account for 98% of identified colonizing GBS isolates worldwide. Serotype III, associated with invasive disease, accounts for 25% (95% CI, 23%–28%), but is less frequent in some South American and Asian countries. Serotypes VI–IX are more common in Asia. Conclusions GBS colonizes pregnant women worldwide, but prevalence and serotype distribution vary, even after adjusting for laboratory methods. Lower GBS maternal colonization prevalence, with less serotype III, may help to explain lower GBS disease incidence in regions such as Asia. High prevalence worldwide, and more serotype data, are relevant to prevention efforts.
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Economic evaluations of HBV testing and treatment strategies and applicability to low and middle-income countries

  • Nayagam, Shevanthi
  • Sicuri, Elisa
  • Lemoine, Maud
  • Easterbrook, Philippa
  • Conteh, Lesong
  • Hallett, Timothy B.
  • Thursz, Mark
BACKGROUND: Many people living with chronic HBV infection remain undiagnosed until later stages of disease. Increasing testing and treatment rates form part of the strategy to respond to the WHO goal of eliminating viral hepatitis as a public health threat by 2030. However, achieving these ambitious targets is dependent on finding effective and cost-effective methods of scale up strategies. The aim of this study was to undertake a narrative review of the literature on economic evaluations of testing and treatment for HBV infection, to help inform the development of the 2017 WHO Hepatitis Testing Guidelines. METHODS: We undertook a focussed literature review for economic evaluations on testing for HBV accompanied by antiviral treatment. The search was carried out in Pubmed and included only articles published after 2000 and written in English. We narratively synthesise the results and discuss the key drivers of cost-effectiveness and their applicability to low and middle-income countries (LMICs). RESULTS: Nine published studies were included in this review, only one of which was performed in a low or middle-income setting in West Africa. Eight studies were performed in high-income settings, seven among high risk groups and one among the general population. The studies were heterogeneous in many respects including the population and testing strategy under consideration, model structure and baselines parameters, willingness to pay thresholds and outcome measures used. However, most studies found HBV testing and treatment to be cost-effective, even at low HBsAg prevalence levels. CONCLUSIONS: Currently economic evaluations of HBV testing and treatment strategies in LMICs is lacking, therefore limiting the ability to provide formal recommendations on the basis of cost-effectiveness alone. Further implementation research is needed in order to help guide national policy planning.
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Blood Interferon Signatures Putatively Link Lack of Protection Conferred by the RTS,S Recombinant Malaria Vaccine to an Antigen-specific IgE Response

  • Rinchai, Darawan
  • Presnell, Scott
  • Vidal, Marta
  • Dutta, Sheetij
  • Chauhan, Virander Singh
  • Cavanagh, David
  • Moncunill, Gemma
  • Dobaño, Carlota, 1969-
  • Chaussabel, Damien
Malaria remains a major cause of mortality and morbidity worldwide. Progress has been made in recent years with the development of vaccines that could pave the way towards protection of hundreds of millions of exposed individuals. Here we used a modular repertoire approach to re-analyze a publically available microarray blood transcriptome dataset monitoring the response to malaria vaccination. We report the seminal identification of interferon signatures in the blood of subjects on days 1, 3 and 14 following administration of the third dose of the RTS,S recombinant malaria vaccine. These signatures at day 1 correlate with protection, and at days 3 and 14 to susceptibility to subsequent challenge of study subjects with live parasites. In addition we putatively link the decreased abundance of interferon-inducible transcripts observed at days 3 and 14 post-vaccination with the elicitation of an antigen-specific IgE response in a subset of vaccine recipients that failed to be protected by the RTS,S vaccine. Furthermore, profiling of antigen-specific levels of IgE in a Mozambican cohort of malaria-exposed children vaccinated with RTS,S identified an association between elevated baseline IgE levels and subsequent development of naturally acquired malaria infection during follow up. Taken together these findings warrant further investigation of the role of antigen-specific IgE in conferring susceptibility to malaria infection.
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Burden of invasive pneumococcal disease among children in rural Mozambique: 2001-2012

  • Sigaúque, Betuel
  • Verani, Jennifer R.
  • Massora, Sérgio
  • Vubil, Delfino
  • Quintó, Llorenç
  • Acácio, Sozinho
  • Mandomando, Inácio
  • Bassat Orellana, Quique
  • Nhampossa, Tacilta
  • Pimenta, Fabiana
  • Sacoor, Charfudin
  • Carvalho, Maria da Gloria
  • Macete, Eusébio
  • Alonso, Pedro
BACKGROUND: Invasive pneumococcal disease (IPD) is a major cause of illness and death among children worldwide. 10-valent pneumococcal conjugate vaccine (PCV10) was introduced as part of the Mozambican routine immunization program in April 2013. We characterized the IPD burden in a rural area of Mozambique before PCV introduction and estimated the potential impact of this intervention. METHODS: We conducted population-based surveillance for IPD, defined as S. pneumoniae isolated from blood or cerebrospinal fluid, among children <5 years old admitted to Manhica District Hospital, a referral hospital in a rural area with high prevalence of human immunodiciency virus infection. S. pneumoniae was identified using standard microbiologic methods and serotyped using sequential multiplex PCR or Quellung. IPD incidence was calculated among cases from a defined catchment area. RESULTS: From January 2001 through December 2012, we isolated 768 cases of IPD, 498 (65%) of which were bacteraemic pneumonia episodes. A total of 391 (51%) were from the catchment area, yielding IPD incidence rates of 479, 390 and 107 episodes per 100,000 children-years at risk among children <12, 12-23 and 24-<60 months old, respectively. The overall IPD incidence fluctuated and showed a downward trend over time. In these same age groups, in-hospital death occurred in 48 (17%), 26 (12%), and 21 (13%) of all IPD cases, respectively. Overall 90% (543/603) of IPD isolates were available for serotyping; of those, 65% were covered by PCV10 and 83% by PCV13. Among 77 hospital deaths associated with serotyped IPD, 49% and 69% were caused by isolates included in the PCV10 and PCV13, respectively. CONCLUSIONS: We describe very high rates of IPD among children in rural Mozambique that were declining before PCV introduction. Children <1 year old have the greatest incidence and case fatality; although the rates remain high among older groups as well. Most IPD episodes and many deaths among children <5 years old will likely be prevented through PCV10 introduction in Mozambique.
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Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer.

  • Garcia Recio, Susana
  • Fuster Orellana, Gemma
  • Fernandez-Nogueira, Patricia
  • Pastor Arroyo, Eva M.
  • Yeong Park, So
  • Mayordomo, Cristina
  • Ametller, Elisabet
  • Mancino, Mario
  • Gonzalez-Farre, Xavier
  • Russnes, Hage G.
  • Engel Rocamora, Pablo
  • Costamagna, Domiziana
  • Fernandez, Pedro L.
  • Gascón, Pere
  • Almendro Navarro, Vanessa
ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored.
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Comparison of methods for the isolation of human breast epithelial and myoepithelial cells.

  • Zubeldia Plazaola, Arantzazu
  • Ametller, Elisabet
  • Mancino, Mario
  • Prats de Puig, Miquel
  • López Plana, Anna
  • Guzman, Flavia
  • Vinyals, Laia
  • Pastor Arroyo, Eva M.
  • Almendro Navarro, Vanessa
  • Fuster Orellana, Gemma
  • Gascón, Pere
Two lineages, epithelial, and myoepithelial cells are the main cell populations in the normal mammary gland and in breast cancer. Traditionally, cancer research has been performed using commercial cell lines, but primary cell cultures obtained from fresh breast tissue are a powerful tool to study more reliably new aspects of mammary gland biology, including normal and pathological conditions. Nevertheless, the methods described to date have some technical problems in terms of cell viability and yield, which hamper work with primary mammary cells. Therefore, there is a need to optimize technology for the proper isolation of epithelial and myoepithelial cells. For this reason, we compared four methods in an effort to improve the isolation and primary cell culture of different cell populations of human mammary epithelium. The samples were obtained from healthy tissue of patients who had undergone mammoplasty or mastectomy surgery. We based our approaches on previously described methods, and incorporated additional steps to ameliorate technical efficiency and increase cell survival. We determined cell growth and viability by phase-contrast images, growth curve analysis and cell yield, and identified cell-lineage specific markers by flow cytometry and immunofluorescence in 3D cell cultures. These techniques allowed us to better evaluate the functional capabilities of these two main mammary lineages, using CD227/K19 (epithelial cells) and CD10/K14 (myoepithelial cells) antigens. Our results show that slow digestion at low enzymatic concentration combined with the differential centrifugation technique is the method that best fits the main goal of the present study: protocol efficiency and cell survival yield. In summary, we propose some guidelines to establish primary mammary epithelial cell lines more efficiently and to provide us with a strong research instrument to better understand the role of different epithelial cell types in the origin of breast cancer.
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Invasive bacterial disease trends and characterization of group B streptococcal isolates among young infants in southern Mozambique, 2001-2015

  • Sigauque, Betuel
  • Kobayashi, Miwako
  • Vubil, Delfino
  • Nhacolo, Ariel
  • Chauque, Alberto
  • Moaine, Benild
  • Massora, Sérgio
  • Mandomando, Inácio
  • Nhampossa, Tacilta
  • Bassat Orellana, Quique
  • Pimenta, Fabiana
  • Menéndez, Clara
  • Carvalho, Maria da Gloria
  • Macete, Eusébio
  • Schrag, Stephanie
BACKGROUND: Maternal group B streptococcal (GBS) vaccines under development hold promise to prevent GBS disease in young infants. Sub-Saharan Africa has the highest estimated disease burden, although data on incidence and circulating strains are limited. We described invasive bacterial disease (IBD) trends among infants <90 days in rural Mozambique during 2001-2015, with a focus on GBS epidemiology and strain characteristics. METHODS: Community-level birth and mortality data were obtained from Manhica's demographic surveillance system. IBD cases were captured through ongoing surveillance at Manhica district hospital. Stored GBS isolates from cases underwent serotyping by multiplex PCR, antimicrobial susceptibility testing, and whole genome sequencing. RESULTS: There were 437 IBD cases, including 57 GBS cases. Significant declines in overall IBD, neonatal mortality, and stillbirth rates were observed (P<0.0001), but not for GBS (P = 0.17). In 2015, GBS was the leading cause of young infant IBD (2.7 per 1,000 live births). Among 35 GBS isolates available for testing, 31 (88.6%) were highly related serotype III isolates within multilocus sequence types (STs) 17 (68.6%) or 109 (20.0%). All seven ST109 isolates (21.9%) had elevated minimum inhibitory concentration (MIC) to penicillin (>/=0.12 mug/mL) associated with penicillin-binding protein (PBP) 2x substitution G398A. Epidemiologic and molecular data suggest this is a well-established clone. CONCLUSION: A notable young infant GBS disease burden persisted despite improvements in overall maternal and neonatal health. We report an established strain with pbp2x point mutation, a first-step mutation associated with reduced penicillin susceptibility within a well-known virulent lineage in rural Mozambique. Our findings further underscores the need for non-antibiotic GBS prevention strategies.
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