Publications by authors named "Simon Correa"

27 Publications

  • Page 1 of 1

Predialysis serum phosphate and intradialytic hypotension.

Hemodial Int 2021 Jul 8. Epub 2021 Jul 8.

Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Introduction: Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD) and is associated with excess morbidity and mortality. Higher serum phosphate is associated with adverse cardiovascular outcomes in maintenance HD patients; however, its association with IDH has not previously been assessed.

Methods: This is an analysis of a prospective cohort of 969 HD patients (80,968 HD sessions) receiving HD at a large dialysis organization (LDO) and a post-hoc analysis of 1838 HD patients (10,594 HD sessions) in the Hemodialysis study (HEMO), a multicenter randomized controlled trial that examined standard or high-dose HD and low-flux or high-flux membranes. Unadjusted and adjusted mixed effects regression models were fit to determine the association of pre-HD serum phosphate with IDH, defined as a nadir intra-HD systolic blood pressure (SBP) <90 mmHg.

Findings: In the LDO cohort, baseline mean pre-HD serum phosphate was 5.2 ± 1.7 mg/dl. IDH occurred in 15.6% of HD sessions. In the adjusted model, higher pre-HD serum phosphate (per 1 mg/dl) was associated with a 12% increased risk of IDH (aOR 1.12, 95% CI 1.10-1.13, p <0.001). In exploratory models where pre-HD laboratory values were available, the effect estimate was attenuated but remained statistically significant (aOR 1.05; 95% CI 1.02-1.08; p <0.01). Participants in the highest (compared with the lowest) quartile of pre-HD serum phosphate had a 56% greater risk of IDH in the adjusted model (aOR Q4:Q1 1.56; 95% CI 1.44-1.68, p <0.001). The association of higher phosphate with IDH was consistent in the HEMO data.

Discussion: Higher pre-HD serum phosphate is independently associated with an increased risk of IDH. As HD may cause an acute decline in serum phosphate, future studies to investigate the mechanisms of this association are warranted.
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http://dx.doi.org/10.1111/hdi.12971DOI Listing
July 2021

Specific Electrocardiograph Intervals Predict Hospitalization with Atrial Fibrillation in Those with Chronic Kidney Disease.

Am J Nephrol 2021 5;52(5):412-419. Epub 2021 May 5.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Introduction: Atrial fibrillation (AF) is common in patients with chronic kidney disease (CKD) and is associated with higher rates of hospitalization compared to those without AF. Whether routine electrocardiographic parameters are predictive of future hospitalizations with AF is not clear.

Methods: The present study is an analysis of a prospective cohort of 2,759 patients without baseline AF from the Chronic Renal Insufficiency Cohort, a large prospective multicenter study of patients with nondialysis-dependent CKD. Unadjusted and adjusted Cox regression models were fit to examine the association of baseline categories of QTc, QRS, and PR intervals with time to first hospitalization with AF. Restricted cubic splines were used to display nonlinear associ-ations.

Results: The mean age of subjects at baseline was 58 ± 11 years, 55% were male, and 44% were Black. The mean follow-up was 6.6 years during which 224 participants experienced a hospitalization with AF. The association of baseline QTc interval with risk of AF hospitalization was nonlinear, such that the lowest and highest quartiles of QTc (<407 and >431 ms, respectively) had higher adjusted risk of AF hospitalization, compared with the second quartile (407-416 ms) (aHR Q1:Q2 1.58, 95% CI 1.03-2.41; p = 0.03; aHR Q4:Q2 1.84, 95% CI 1.22-2.78; p < 0.01). Longer QRS was associated with a higher risk of hospitalization with AF among the subgroup of patients with a history of heart failure (HF). PR interval was not associated with AF hospitalization.

Discussion/conclusion: The association of QTc with risk for hospitalization with AF among patients with CKD is nonlinear, while the association of longer QRS with AF hospitalization is restricted to patients with baseline HF. Electrocardiography may represent a simple and widely accessible method for risk stratification of future AF in patients with CKD.
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http://dx.doi.org/10.1159/000515670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263478PMC
May 2021

Serum Myeloperoxidase, Uric Acid, and the Risk of Atrial Fibrillation in Chronic Kidney Disease.

Circ Arrhythm Electrophysiol 2021 Apr 16;14(4):e009483. Epub 2021 Apr 16.

Division of Renal Medicine, Brigham and Women's Hospital (S.C., K.A.C., F.R.M.C.), Boston University School of Medicine, Boston Medical Center, MA.

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http://dx.doi.org/10.1161/CIRCEP.120.009483DOI Listing
April 2021

Improved housing versus usual practice for additional protection against clinical malaria in The Gambia (RooPfs): a household-randomised controlled trial.

Lancet Planet Health 2021 04;5(4):e220-e229

Department of Biosciences, Durham University, Durham, UK; Department of Disease Control, London School of Hygiene & Tropical Medicine, London, UK. Electronic address:

Background: In malaria-endemic areas, residents of modern houses have less malaria than those living in traditional houses. We aimed to assess whether children in The Gambia received an incremental benefit from improved housing, where current best practice of insecticide-treated nets, indoor residual spraying, seasonal malaria chemoprevention in children younger than 5 years, and prompt treatment against clinical malaria was in place.

Methods: In this randomised controlled study, 800 households with traditional thatched-roofed houses were randomly selected from 91 villages in the Upper River Region of The Gambia. Within each village, equal numbers of houses were randomly allocated to the control and intervention groups using a sampling frame. Houses in the intervention group were modified with metal roofs and screened doors and windows, whereas houses in the control group received no modifications. In each group, clinical malaria in children aged 6 months to 13 years was monitored by active case detection over 2 years (2016-17). We did monthly collections from indoor light traps to estimate vector densities. Primary endpoints were the incidence of clinical malaria in study children with more than 50% of observations each year and household vector density. The trial is registered at ISRCTN02622179.

Findings: In June, 2016, 785 houses had one child each recruited into the study (398 in unmodified houses and 402 in modified houses). 26 children in unmodified houses and 28 children in modified houses did not have at least 50% of visits in a year and so were excluded from analysis. 38 children in unmodified houses were recruited after study commencement, as were 21 children in modified houses, meaning 410 children in unmodified houses and 395 in modified houses were included in the parasitological analyses. At the end of the study, 659 (94%) of 702 children were reported to have slept under an insecticide-treated net; 662 (88%) of 755 children lived in houses that received indoor residual spraying; and 151 (90%) of 168 children younger than 5 years had seasonal malaria chemoprevention. Incidence of clinical malaria was 0·12 episodes per child-year in children in the unmodified houses and 0·20 episodes per child-year in the modified houses (unadjusted incidence rate ratio [RR] 1·68 [95% CI 1·11-2·55], p=0·014). Household vector density was 3·30 Anopheles gambiae per house per night in the unmodified houses compared with 3·60 in modified houses (unadjusted RR 1·28 [0·87-1·89], p=0·21).

Interpretation: Improved housing did not provide protection against clinical malaria in this area of low seasonal transmission with high coverage of insecticide-treated nets, indoor residual spraying, and seasonal malaria chemoprevention.

Funding: Global Health Trials funded by Medical Research Council, UK Department for International Development, and Wellcome Trust.
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http://dx.doi.org/10.1016/S2542-5196(21)00002-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051018PMC
April 2021

Leveraging Deep Learning to Improve Safety of Outpatient Hemodialysis.

Clin J Am Soc Nephrol 2021 03 11;16(3):343-344. Epub 2021 Feb 11.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, and Harvard Medical School, Boston, Massachusetts

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http://dx.doi.org/10.2215/CJN.00450121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011011PMC
March 2021

Sero-epidemiological evaluation of malaria transmission in The Gambia before and after mass drug administration.

BMC Med 2020 11 13;18(1):331. Epub 2020 Nov 13.

Faculty of Infectious Tropical Diseases, Department of Infection Biology, London School of Hygiene and Tropical Medicine (LSHTM), London, WC1E 7HT, UK.

Background: As The Gambia aims to achieve malaria elimination by 2030, serological assays are a useful surveillance tool to monitor trends in malaria incidence and evaluate community-based interventions.

Methods: Within a mass drug administration (MDA) study in The Gambia, where reduced malaria infection and clinical disease were observed after the intervention, a serological sub-study was conducted in four study villages. Spatio-temporal variation in transmission was measured with a panel of recombinant Pf antigens on a multiplexed bead-based assay. Village-level antibody levels were quantified as under-15 sero-prevalence, sero-conversion rates, and age-adjusted antibody acquisition rates. Antibody levels prior to MDA were assessed for association with persistent malaria infection after community chemoprophylaxis.

Results: Seasonal changes in antibodies to Etramp5.Ag1 were observed in children under 15 years in two transmission settings-the West Coast and Upper River Regions (4.32% and 31.30% Pf prevalence, respectively). At the end of the malaria season, short-lived antibody responses to Etramp5.Ag1, GEXP18, HSP40.Ag1, EBA175 RIII-V, and Rh2.2030 were lower amongst 1-15 year olds in the West Coast compared to the Upper River, reflecting known differences in transmission. Prior to MDA, individuals in the top 50th percentile of antibody levels had two-fold higher odds of clinical malaria during the transmission season, consistent with previous findings from the Malaria Transmission Dynamics Study, where individuals infected before the implementation of MDA had two-fold higher odds of re-infection post-MDA.

Conclusions: Serological markers can serve dual functions as indicators of malaria exposure and incidence. By monitoring age-specific sero-prevalence, the magnitude of age-stratified antibody levels, or identifying groups of individuals with above-average antibody responses, these antigens have the potential to complement conventional malaria surveillance tools. Further studies, particularly cluster randomised trials, can help establish standardised serological protocols to reliably measure transmission across endemic settings.
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http://dx.doi.org/10.1186/s12916-020-01785-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664049PMC
November 2020

Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19.

JAMA Intern Med 2021 01;181(1):41-51

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness.

Objective: To test whether tocilizumab decreases mortality in this population.

Design, Setting, And Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding.

Exposures: Treatment with tocilizumab in the first 2 days of ICU admission.

Main Outcomes And Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences.

Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%).

Conclusions And Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.
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http://dx.doi.org/10.1001/jamainternmed.2020.6252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577201PMC
January 2021

Antibody responses to a suite of novel serological markers for malaria surveillance demonstrate strong correlation with clinical and parasitological infection across seasons and transmission settings in The Gambia.

BMC Med 2020 09 25;18(1):304. Epub 2020 Sep 25.

Faculty of Infectious Tropical Diseases, Department of Infection Biology, London School of Hygiene and Tropical Medicine (LSHTM), London, WC1E 7HT, UK.

Background: As malaria transmission declines, sensitive diagnostics are needed to evaluate interventions and monitor transmission. Serological assays measuring malaria antibody responses offer a cost-effective detection method to supplement existing surveillance tools.

Methods: A prospective cohort study was conducted from 2013 to 2015 in 12 villages across five administrative regions in The Gambia. Serological analysis included samples from the West Coast Region at the start and end of the season (July and December 2013) and from the Upper River Region in July and December 2013 and April and December 2014. Antigen-specific antibody responses to eight Plasmodium falciparum (P. falciparum) antigens-Etramp5.Ag1, GEXP18, HSP40.Ag1, Rh2.2030, EBA175 RIII-V, PfMSP1, PfAMA1, and PfGLURP.R2-were quantified using a multiplexed bead-based assay. The association between antibody responses and clinical and parasitological endpoints was estimated at the individual, household, and population level.

Results: Strong associations were observed between clinical malaria and concurrent sero-positivity to Etramp5.Ag1 (aOR 4.60 95% CI 2.98-7.12), PfMSP1 (aOR 4.09 95% CI 2.60-6.44), PfAMA1 (aOR 2.32 95% CI 1.40-3.85), and PfGLURP.R2 (aOR 3.12, 95% CI 2.92-4.95), while asymptomatic infection was associated with sero-positivity to all antigens. Village-level sero-prevalence amongst children 2-10 years against Etramp5.Ag1, HSP40.Ag1, and PfMSP1 showed the highest correlations with clinical and P. falciparum infection incidence rates. For all antigens, there were increased odds of asymptomatic P. falciparum infection in subjects residing in a compound with greater than 50% sero-prevalence, with a 2- to 3-fold increase in odds of infection associated with Etramp5.Ag1, GEXP18, Rh2.2030, PfMSP1, and PfAMA1. For individuals residing in sero-positive compounds, the odds of clinical malaria were reduced, suggesting a protective effect.

Conclusions: At low transmission, long-lived antibody responses could indicate foci of malaria transmission that have been ongoing for several seasons or years. In settings where sub-patent infections are prevalent and fluctuate below the detection limit of polymerase chain reaction (PCR), the presence of short-lived antibodies may indicate recent infectivity, particularly in the dry season when clinical cases are rare. Serological responses may reflect a persistent reservoir of infection, warranting community-targeted interventions if individuals are not clinically apparent but have the potential to transmit. Therefore, serological surveillance at the individual and household level may be used to target interventions where there are foci of asymptomatically infected individuals, such as by measuring the magnitude of age-stratified antibody levels or identifying areas with clustering of above-average antibody responses across a diverse range of serological markers.
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http://dx.doi.org/10.1186/s12916-020-01724-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517687PMC
September 2020

Optimisation and standardisation of a multiplex immunoassay of diverse antigens to assess changes in malaria transmission using sero-epidemiology.

Wellcome Open Res 2019 23;4:26. Epub 2020 Apr 23.

Department of Infection Biology, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.

Antibody responses have been used to characterise transmission and exposure history in malaria-endemic settings for over a decade. Such studies have typically been conducted on well-standardised enzyme-linked immunosorbent assays (ELISAs). However, recently developed quantitative suspension array technologies (qSAT) are now capable of high-throughput and multiplexed screening of up to hundreds of analytes at a time. This study presents a customised protocol for the Luminex MAGPIX qSAT using a diverse set of malaria antigens. The aim is to develop a standardised assay for routine serological surveillance that is implementable across laboratories and epidemiological settings. A panel of eight recombinant antigens, associated with long- and short-lived antibody responses, was designed for the Luminex MAGPIX platform. The assay was optimised for key steps in the protocol: antigen-bead coupling concentration, buffer composition, serum sample dilution, and bead storage conditions. Quality control procedures and data normalisation methods were developed to address high-throughput assay processing.  Antigen-specific limits of quantification (LOQs) were also estimated using both in-house and WHO reference serum as positive controls. Antigen-specific bead coupling was optimised across five serum dilutions and two positive controls, resulting in concentrations operational within stable analytical ranges. Coupled beads were stable after storage at room temperature (22⁰C) for up to eight weeks. High sensitivity and specificity for distinguishing positive and negative controls at serum sample dilutions of 1:500 (AUC 0.94 95%CI 0.91-0.96) and 1:1000 (AUC 0.96 95%CI 0.94-0.98) were observed. LOQs were also successfully estimated for all analytes but varied by antigen and positive control. This study demonstrates that developing a standardised malaria-specific qSAT protocol for a diverse set of antigens is achievable, though further optimisations may be required. Quality control and data standardisation methods may also be useful for future analysis of large sero-epidemiological surveys.
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http://dx.doi.org/10.12688/wellcomeopenres.14950.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255915PMC
April 2020

Predictors of Intradialytic Symptoms: An Analysis of Data From the Hemodialysis Study.

Am J Kidney Dis 2020 09 21;76(3):331-339. Epub 2020 Apr 21.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA.

Background: Most patients receiving maintenance hemodialysis (HD) experience adverse symptoms, which are associated with decreased quality of life. Despite decades of experience, our understanding of causes of HD symptoms remains limited. We aimed to identify modifiable patient- and HD-related predictors of intradialytic symptoms.

Study Design: Prospective cohort.

Setting & Participants: We leveraged patient-level (n=1,838) and HD session-level (n=64,797) data from the Hemodialysis Trial.

Exposure: Pre-HD serum urea nitrogen (SUN) level, pre-HD systolic blood pressure (SBP), intradialytic SBP decline, and ultrafiltration rate (UFR).

Outcomes: Intra-HD symptoms, including cramps, nausea, chest pain, headache, and lightheadedness.

Analytical Approach: Random-effects logistic regression models.

Results: Overall, symptoms occurred in 10.7% of HD sessions. Higher pre-HD SUN level (per 10 mg/dL) was associated with higher adjusted odds of muscle cramping and lightheadedness (adjusted ORs [aORs] of 1.20 [95% CI, 1.17-1.22] and 1.13 [95% CI, 1.08-1.18], respectively). SBP decline (from the predialysis value to the dialysis session nadir, per each 10-mm Hg decrease) was associated with greater risk for muscle cramping, headache, chest pain, vomiting, and lightheadedness (the largest aORs were for the 2 latter symptoms: 1.24 [95% CI, 1.20-1.28] and 1.37 [95% CI, 1.33-1.42], respectively). Higher UFR (per 1 mL/kg/h) was associated with greater odds of cramping (aOR, 1.03; 95% CI, 1.02-1.03). Conversely, higher pre-HD SBP (per 10 mm Hg) was associated with reduced risk for vomiting (aOR, 0.88; 95% CI, 0.85-0.92) and lightheadedness (aOR, 0.82; 95% CI, 0.80-0.85).

Limitations: Measured osmolality, dialysate prescription data, and time stamps for symptom occurrence were not available. Clinical trial data may not be broadly generalizable.

Conclusions: Higher pre-HD SUN level, UFR, pre-HD SBP, and SBP decline are independently associated with different patterns of adverse intradialytic symptoms. Recognition that different symptoms may have variable causes may allow tailoring of personalized treatments in future interventional studies.
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http://dx.doi.org/10.1053/j.ajkd.2020.01.004DOI Listing
September 2020

Association of Prediabetes With CKD Progression and Adverse Cardiovascular Outcomes: An Analysis of the CRIC Study.

J Clin Endocrinol Metab 2020 04;105(4)

Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Purpose: Despite our understanding of diabetes as an established risk factor for progressive kidney disease and cardiac complications, the prognostic significance of prediabetes in patients with chronic kidney disease (CKD) remains largely unknown.

Methods: Participants of the Chronic Renal Insufficiency Cohort (CRIC) were categorized as having normoglycemia, prediabetes, or diabetes according to fasting plasma glucose, glycated hemoglobin A1c (HbA1c), and treatment with antidiabetic drugs at baseline. Unadjusted and adjusted proportional hazards models were fit to estimate the association of prediabetes and diabetes (versus normoglycemia) with: (1) composite renal outcome (end-stage renal disease, 50% decline in estimated glomerular filtration rate to ≤ 15 mL/min/1.73 m2, or doubling of urine protein-to-creatinine ratio to ≥ 0.22 g/g creatinine); (2) composite cardiovascular (CV) outcome (congestive heart failure, myocardial infarction or stroke); and (3) all-cause mortality.

Results: Of the 3701 individuals analyzed, 945 were normoglycemic, 847 had prediabetes and 1909 had diabetes. The median follow-up was 7.5 years. Prediabetes was not associated with the composite renal outcome (adjusted hazard ratio [aHR] 1.13; 95% confidence interval [CI], 0.96-1.32; P = 0.14), but was associated with proteinuria progression (aHR 1.23; 95% CI, 1.03-1.47; P = 0.02). Prediabetes was associated with a higher risk of the composite CV outcome (aHR 1.38; 95% CI, 1.05-1.82; P = 0.02) and a trend towards all-cause mortality (aHR 1.28; 95% CI, 0.99-1.66; P = 0.07). Participants with diabetes had an increased risk of the composite renal outcome, the composite CV outcome, and all-cause mortality.

Conclusions: In individuals with CKD, prediabetes was not associated with composite renal outcome, but was associated with an increased risk of proteinuria progression and adverse CV outcomes.
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http://dx.doi.org/10.1210/clinem/dgaa017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069215PMC
April 2020

Myeloperoxidase and the Risk of CKD Progression, Cardiovascular Disease, and Death in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis 2020 07 19;76(1):32-41. Epub 2019 Dec 19.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA.

Background: Myeloperoxidase (MPO) catalyzes the formation of reactive nitrogen species and levels are elevated in patients with chronic kidney disease (CKD). Although increased oxidative stress and inflammation are associated with progression of CKD and cardiovascular disease (CVD), relationships between MPO concentration, CKD progression, CVD, and death remain unclear.

Study Design: Prospective cohort.

Setting & Participants: 3,872 participants from the Chronic Renal Insufficiency Cohort (CRIC) who had MPO measured at baseline.

Exposure: Baseline MPO concentration.

Outcomes: CKD progression (kidney transplantation, dialysis initiation, or 50% decline in baseline estimated glomerular filtration rate [eGFR] and eGFR≤15mL/min/1.73m), CVD (heart failure, myocardial infarction, or stroke), and death.

Analytical Approach: Cox proportional hazards models.

Results: In adjusted analyses, higher MPO level (per 1-SD increase in log-transformed MPO) was associated with 10% higher risk for CKD progression (adjusted HR, 1.10; 95% CI, 1.01-1.19; P=0.03), 12% higher risk for CVD (adjusted HR, 1.12; 95% CI, 1.03-1.22; P<0.01), and 13% increased risk for death (adjusted HR, 1.13; 95% CI, 1.04-1.22; P<0.01). There was evidence for effect modification of the association of MPO level with CKD progression by baseline eGFR (P interaction=0.02), but not for CVD (P interaction=0.2) or death (P interaction=0.1). In stratified analyses, MPO level (per 1-SD increase in log-transformed MPO) was associated with greater risk for CKD progression among participants with eGFR>45mL/min/1.73m (adjusted HR, 1.23; 95% CI, 1.03-1.46; P=0.02) compared with those with eGFR≤45mL/min/1.73m (adjusted HR, 1.10; 95% CI, 1.02-1.20; P=0.02). The association of MPO level with CVD and death was no longer significant after adjustment for cardiac biomarkers.

Limitations: Potential residual confounding, lack of repeated measurements of MPO.

Conclusions: Higher MPO level was associated with increased risk for CKD progression, but not with CVD and death in patients with CKD from CRIC. Whether therapies aimed at reducing MPO activity can result in improved clinical outcomes is yet to be determined.
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http://dx.doi.org/10.1053/j.ajkd.2019.09.006DOI Listing
July 2020

Efficacy and safety of more potent antiplatelet therapy with vorapaxar in patients with impaired renal function.

J Thromb Thrombolysis 2019 Apr;47(3):353-360

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Rd., Suite 7022, Boston, MA, 02115, USA.

Patients with renal disease are often undertreated with antiplatelet therapy due to concerns about bleeding. Vorapaxar blocks platelet activation via the PAR-1 receptor and reduces cardiovascular events in patients with stable atherosclerosis, but with increased bleeding. We examined the efficacy and safety of vorapaxar in patients with impaired renal function. TRA2°P-TIMI 50 randomized patients with stable atherosclerosis to vorapaxar or. We analyzed patients with eGFR assessed who qualified with a history of MI or PAD (without stroke or TIA) (n = 19,932). Cox models assessed the risk of CV events and bleeding by quartile of baseline eGFR in the placebo arm and then by randomized assignment. Net clinical outcome (NCO) was predefined as CV death, MI, stroke, or GUSTO severe bleeding. Patients with lower eGFR tended to be older, female, have hypertension, hyperlipidemia or prior PAD. In the placebo arm, baseline eGFR in the lowest quartile was associated with a 26% higher risk of CV death, MI or stroke (Q1:Q4 HR 1.26, 1.03-1.55) and 73% higher risk of GUSTO moderate or severe bleeding (HR 1.73, 1.12-2.65). Vorapaxar reduced the risk of MACE to a similar extent (14-26%) across quartiles of baseline eGFR (P interaction = 0.70) and increased the relative risk of GUSTO moderate or severe bleeding (P interaction = 0.54). NCO was similar across quartiles of eGFR (P interaction = 0.65). Intensification of antiplatelet therapy with vorapaxar offers comparable net clinical benefit regardless of baseline renal function. These data support the use of more potent antiplatelet regimens in patients with renal dysfunction.
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http://dx.doi.org/10.1007/s11239-018-1779-yDOI Listing
April 2019

Cystatin C for Risk Stratification in Patients After an Acute Coronary Syndrome.

J Am Heart Assoc 2018 10;7(20):e009077

1 TIMI Study Group Division of Cardiovascular Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA.

Background Cystatin C (Cys-C) is a marker of renal function that has shown prognostic value for cardiovascular risk stratification across different patient populations. The incremental value of Cys-C beyond established cardiac and renal biomarkers remains incompletely explored. Methods and Results SOLID - TIMI 52 (Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52; www.clinicaltrials.gov , NCT01000727) randomized patients ≤30 days post-acute coronary syndrome were treated with darapladib or placebo. The association between Cys-C and long-term risk (median follow-up 2.5 years) was assessed in 4965 individuals with adjustments made for clinical variables and other risk markers (eg, estimated glomerular filtration rate, high-sensitivity troponin I, brain-type natriuretic peptide, and fibroblast growth factor-23). The prespecified outcome of interest was cardiovascular death (CVD) or heart failure hospitalization. Cys-C was strongly correlated with creatinine ( r=0.60) and estimated glomerular filtration rate ( r=-0.68), moderately correlated with fibroblast growth factor-23 ( r=0.39), and weakly correlated with brain-type natriuretic peptide ( r=0.28) and high-sensitivity troponin I ( r=0.06) (all P<0.0001). After multivariate adjustment, increasing concentration of Cys-C (per SD of log-transformed Cys-C) was significantly associated with a 28% higher hazard of CVD or heart failure hospitalization (hazard ratio [ HR ] 1.28, 95% confidence interval [ CI ] 1.12-1.46, P<0.001), including CVD ( HR 1.24, 95% CI 1.04-1.47, P=0.01) and heart failure hospitalization ( HR 1.42, 95% CI 1.19-1.69, P<0.001). Cys-C was also associated with a higher hazard of CVD, myocardial infarction, or stroke ( HR 1.15, 95% CI 1.04-1.28, P<0.01), including myocardial infarction ( HR 1.17, 95% CI 1.02-1.33, P=0.02). The addition of Cys-C to a fully adjusted model without estimated glomerular filtration rate improved the C-statistic from 0.80 to 0.81 ( P=0.03) for CVD or heart failure hospitalization. In contrast, the addition of estimated glomerular filtration rate to a fully adjusted model without Cys-C failed to improve model discrimination ( P=0.17). Conclusions Cys-C is associated with the risk of adverse outcomes in patients after acute coronary syndrome. This relationship is independent of established and novel biomarkers of the cardiorenal axis.
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http://dx.doi.org/10.1161/JAHA.118.009077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474969PMC
October 2018

Complement Factor H Levels Associate With Malaria Susceptibility and Severity.

Open Forum Infect Dis 2018 Jul 20;5(7):ofy166. Epub 2018 Jul 20.

Section of Paediatrics, Imperial College London, London, United Kingdom.

Background: may evade complement-mediated host defense by hijacking complement Factor H (FH), a negative regulator of the alternative complement pathway. Plasma levels of FH vary between individuals and may therefore influence malaria susceptibility and severity.

Methods: We measured convalescent FH plasma levels in 149 Gambian children who had recovered from uncomplicated or severe malaria and in 173 healthy control children. We compared FH plasma levels between children with malaria and healthy controls, and between children with severe (n = 82) and uncomplicated malaria (n = 67). We determined associations between FH plasma levels and laboratory features of severity and used multivariate analyses to examine associations with FH when accounting for other determinants of severity.

Results: FH plasma levels differed significantly between controls, uncomplicated malaria cases, and severe malaria cases (mean [95% confidence interval], 257 [250 to 264], 288 [268 to 309], and 328 [313 to 344] µg/mL, respectively; analysis of variance < .0001). FH plasma levels correlated with severity biomarkers, including lactate, parasitemia, and parasite density, but did not correlate with levels of PfHRP2, which represent the total body parasite load. Associations with severity and lactate remained significant when adjusting for age and parasite load.

Conclusions: Natural variation in FH plasma levels is associated with malaria susceptibility and severity. A prospective study will be needed to strengthen evidence for causation, but our findings suggest that interfering with FH binding by might be useful for malaria prevention or treatment.
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http://dx.doi.org/10.1093/ofid/ofy166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059171PMC
July 2018

The Gametocytocidal Efficacy of Different Single Doses of Primaquine with Dihydroartemisinin-piperaquine in Asymptomatic Parasite Carriers in The Gambia: A Randomized Controlled Trial.

EBioMedicine 2016 Nov 23;13:348-355. Epub 2016 Oct 23.

Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia; Department of Disease Control, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium. Electronic address:

Background: Asymptomatic low-density gametocyte carriers represent the majority of malaria-infected individuals. However, the impact of recommended treatment with single low dose of primaquine and an artemisinin-based combination therapy to reduce transmission in this group is unknown.

Methods: This was a four-arm, open label, randomized controlled trial comparing the effect of dihydroartemisinin-piperaquine (DHAP) alone or combined with single dose of primaquine (PQ) at 0.20mg/kg, 0.40mg/kg, or 0.75mg/kg on Plasmodium falciparum gametocytaemia, infectiousness to mosquitoes and hemoglobin change in asymptomatic, malaria-infected, glucose-6-phosphate dehydrogenase (G6PD) normal individuals. Randomization was done using a computer-generated sequence of uneven block sizes with codes concealed in sequentially numbered opaque envelopes. The primary endpoint was the prevalence of P. falciparum gametocytemia at day 7 of follow-up determined by quantitative nucleic acid sequence based assay and analysis was by intention to treat. The trial has been concluded (registration number: NCT01838902; https://clinicaltrials.gov/ct2/show/NCT01838902).

Results: A total of 694 asymptomatic, malaria-infected individuals were enrolled. Gametocyte prevalence at day 7 was 37.0% (54/146; 95% CI 29.2-45.4), 19.0% (27/142; 95% CI 12.9-26.4), 17.2% (25/145; 95% CI 11.0-23.5) and 10.6% (15/141; 95% CI 6.1-16.9) in the DHAP alone, 0.20mg/kg, 0.40mg/kg, and 0.75mg/kg PQ arms, respectively. The main adverse events reported include headache (130/471, 27.6%), cough (73/471, 15.5%), history of fever (61/471, 13.0%) and abdominal pain (57/471, 12.1%). There were five serious adverse events however, none was related to the interventions.

Interpretation: A single course of PQ significantly reduces gametocyte carriage in malaria-infected asymptomatic, G6PD-normal individuals without increasing the risk of clinical anemia. The limited number of successful mosquito infections suggests that post-treatment transmission potential in this asymptomatic population is low.
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http://dx.doi.org/10.1016/j.ebiom.2016.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264436PMC
November 2016

Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

PLoS Pathog 2015 Sep 25;11(9):e1005119. Epub 2015 Sep 25.

Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.

Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis.
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http://dx.doi.org/10.1371/journal.ppat.1005119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583463PMC
September 2015

Phosphorylation at the N-terminal finger subdomain of a viral RNA-dependent RNA polymerase.

Biochem Biophys Res Commun 2015 Oct 21;466(1):21-7. Epub 2015 Aug 21.

Laboratorio de Virus Hepatitis, Departamento de Cs. Biológicas, Universidad Andrés Bello, Santiago, Chile. Electronic address:

The RNA-dependent RNA polymerase (RdRP) of the Hepatitis C virus (HCV), named NS5B, is phosphorylated by the cellular protein kinase C-related kinase 2 (PRK2) at two serine residues (Ser29 and Ser42) of the finger subdomain (genotype 1b). Herein, using bioinformatics, we selected four potential phosphorylation residues (Ser46, Ser76, Ser96 and Ser112) of NS5B (genotype 2a) for study. Whereas the NS5B Ser46D and Ser76D substitutions seemed to improve polymerase activity, the Ser96D mutation decreased colony formation efficiency. Active WT NS5B was utilized in in vitro kinase assays, and phosphopeptides were analyzed by mass spectrometry. Interestingly, the data indicated that both the NS5B Ser29 and Ser76 residues resulted phosphorylated. Thus, as Ser76 is absolutely conserved across HCV genotypes, our results confirmed the relevance of these sites for both genotypes and suggested that Ser76 becomes phosphorylated by a cellular kinase different from PRK2. By molecular dynamic simulations, we show that new interactions between space-adjacent amino acid chains could be established by the presence of a di-anionic phosphate group on the analyzed serines to possibly modify RNA polymerase activity. Together, our data present novel evidence on the complex regulation at the finger subdomain of HCV NS5B via phosphorylation.
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http://dx.doi.org/10.1016/j.bbrc.2015.08.082DOI Listing
October 2015

Efficacy of indoor residual spraying with dichlorodiphenyltrichloroethane against malaria in Gambian communities with high usage of long-lasting insecticidal mosquito nets: a cluster-randomised controlled trial.

Lancet 2015 Apr 9;385(9976):1436-46. Epub 2014 Dec 9.

London School of Hygiene and Tropical Medicine, London, UK; Durham University, Durham, UK. Electronic address:

Background: Although many malaria control programmes in sub-Saharan Africa use indoor residual spraying with long-lasting insecticidal nets (LLINs), the two studies assessing the benefit of the combination of these two interventions gave conflicting results. We aimed to assess whether the addition of indoor residual spraying to LLINs provided a significantly different level of protection against clinical malaria in children or against house entry by vector mosquitoes.

Methods: In this two-arm cluster, randomised, controlled efficacy trial we randomly allocated clusters of Gambian villages using a computerised algorithm to LLINs alone (n=35) or indoor residual spraying with dichlorodiphenyltrichloroethane plus LLINs (n=35). In each cluster, 65-213 children, aged 6 months to 14 years, were surveyed at the start of the 2010 transmission season and followed in 2010 and 2011 by passive case detection for clinical malaria. Exposure to parasite transmission was assessed by collection of vector mosquitoes with both light and exit traps indoors. Primary endpoints were the incidence of clinical malaria assessed by passive case detection and number of Anopheles gambiae sensu lato mosquitoes collected per light trap per night. Intervention teams had no role in data collection and the data collection teams were not informed of the spray status of villages. The trial is registered at the ISRCTN registry, number ISRCTN01738840.

Findings: LLIN coverage in 2011 was 3510 (93%) of 3777 children in the indoor residual spraying plus LLIN group and 3622 (95.5%) of 3791 in the LLIN group. In 2010, 7845 children were enrolled, 7829 completed passive case detection, and 7697 (98%) had complete clinical and covariate data. In 2011, 7009 children remained in the study, 648 more were enrolled, 7657 completed passive case detection, and 7545 (98.5%) had complete data. Indoor residual spraying coverage per cluster was more than 80% for both years in the indoor residual spraying plus LLIN group. Incidence of clinical malaria was 0.047 per child-month at risk in the LLIN group and 0.044 per child-month at risk in the indoor residual spraying plus LLIN group in 2010, and 0.032 per child-month at risk in the LLIN group and 0.034 per child-month at risk in the indoor residual spraying plus LLIN group in 2011. The incident rate ratio was 1.08 (95% CI 0.80-1.46) controlling for confounders and cluster by mixed-effect negative binomial regression on all malaria attacks for both years. No significant difference was recorded in the density of vector mosquitoes caught in light traps in houses over the two transmission seasons; the mean number of A gambiae sensu lato mosquitoes per trap per night was 6.7 (4.0-10.1) in the LLIN group and 4.5 (2.4-7.4) in the indoor residual spraying plus LLIN group (p=0.281 in the random-effects linear regression model).

Interpretation: We identified no significant difference in clinical malaria or vector density between study groups. In this area with high LLIN coverage, moderate seasonal transmission, and susceptible vectors, indoor residual spraying did not provide additional benefit.

Funding: UK Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(14)61007-2DOI Listing
April 2015

School-based countrywide seroprevalence survey reveals spatial heterogeneity in malaria transmission in the Gambia.

PLoS One 2014 22;9(10):e110926. Epub 2014 Oct 22.

Disease Control & Elimination Theme, Medical Research Council Unit, Fajara, The Gambia; Department of Disease Control, Faculty of infectious and Tropical Diseases, London school of Hygiene and Tropical Medicine, London, United Kingdom; Department of Public health, Institute of Tropical Medicine, Antwerp, Belgium.

Background: As the geographical distribution of malaria transmission becomes progressively clustered, identifying residual pockets of transmission is important for research and for targeting interventions. Malarial antibody-based surveillance is increasingly recognised as a valuable complement to classic methods for the detection of infection foci especially at low transmission levels. The study presents serological evidence for transmission heterogeneity among school children in The Gambia measured during the dry, non-transmission season.

Methods: Healthy primary school children were randomly selected from 30 schools across the country and screened for malaria infection (microscopy) and antimalarial antibodies (MSP119). Antibody distribution was modelled using 2-component finite mixture model with cut-off for positivity from pooled sera set at 2-standard deviation from the mean of the first component. Factors associated with a positive serological status were identified in a univariate model and then combined in a multilevel mixed-effects logistic regression model, simultaneously adjusting for variations between individuals and school.

Results: A total of 4140 children, 1897 (46%) boys, were enrolled with mean age of 10.2 years (SD 2.6, range 4-20 years). Microscopy results available for 3640 (87.9%) children showed that 1.9% (69) were positive for Plasmodium falciparum infections, most of them (97.1%, 67/69) asymptomatic. The overall seroprevalence was 12.7% (527/4140) with values for the schools ranging from 0.6% to 43.8%. Age (OR 1.12, 95% CI 1.07-1.16,) and parasite carriage (OR 3.36, 95% CI 1.95-5.79) were strongly associated with seropositivity.

Conclusion: Serological responses to malaria parasites could identify individuals who were or had been infected, and clusters of residual transmission. Field-adapted antibody tests able to guide mass screening and treatment campaigns would be extremely useful.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206471PMC
July 2015

A comparative case control study of the determinants of clinical malaria in The Gambia.

Malar J 2014 Aug 8;13:306. Epub 2014 Aug 8.

Medical Research Council Unit, Fajara, The Gambia.

Background: The massive deployment of life saving malaria interventions has not only resulted in a decline in disease burden but a change in the risk of infection and disease. The study reassesses the importance of known risk factors and reviews demographic and socio-economic determinants of malaria risk in the population.

Methods: This was a case-control study involving 150 children with test-confirmed malaria infection recruited from the outpatient clinics of three health facilities (cases) in the Greater Banjul area, The Gambia. One hundred and fifty controls, negative for malaria were matched on age, residence. Information was collected from respondents on the use of long lasting insecticidal nets, occupation, housing structure, knowledge of malaria and socio-demographic factors.

Results: The mean age of study participants was 6.8 (SD 3.3) years with 147 (49%) being males. Significant determinants of malaria risk were parent's occupation: mother as trader (OR 0.18, 95% CI 0.04 - 0.73, p = 0.017), father as trader (OR 0.02, 95% CI 0.002- 0.193, p = 0.001), civil servants (OR 0.04, 95% CI 0.008- 0.257, p =0.001) or handyman (OR 0.03, 95% CI 0.005- 0.182, p < 0.001). Children sleeping in rooms with windowpanes had a 76% reduction in their odds of malaria (OR 0.24, 95%CI 0.07- 0.82, p = 0.022.

Conclusion: Household socio-economic status plays an important role in management of illnesses. The ability of mothers to engage in an occupation increases household resources to access healthcare and on time. The balance between the type of mother's occupation and her time available to supervise the child is an interesting emerging issue that needs further investigation.
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http://dx.doi.org/10.1186/1475-2875-13-306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248480PMC
August 2014

Prolonged neutrophil dysfunction after Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-1 induction.

J Immunol 2012 Dec 24;189(11):5336-46. Epub 2012 Oct 24.

Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.

It is not known why people are more susceptible to bacterial infections such as nontyphoid Salmonella during and after a malaria infection, but in mice, malarial hemolysis impairs resistance to nontyphoid Salmonella by impairing the neutrophil oxidative burst. This acquired neutrophil dysfunction is a consequence of induction of the cytoprotective, heme-degrading enzyme heme oxygenase-1 (HO-1) in neutrophil progenitors in bone marrow. In this study, we assessed whether neutrophil dysfunction occurs in humans with malaria and how this relates to hemolysis. We evaluated neutrophil function in 58 Gambian children with Plasmodium falciparum malaria [55 (95%) with uncomplicated disease] and examined associations with erythrocyte count, haptoglobin, hemopexin, plasma heme, expression of receptors for heme uptake, and HO-1 induction. Malaria caused the appearance of a dominant population of neutrophils with reduced oxidative burst activity, which gradually normalized over 8 wk of follow-up. The degree of neutrophil impairment correlated significantly with markers of hemolysis and HO-1 induction. HO-1 expression was increased in blood during acute malaria, but at a cellular level HO-1 expression was modulated by changes in surface expression of the haptoglobin receptor (CD163). These findings demonstrate that neutrophil dysfunction occurs in P. falciparum malaria and support the relevance of the mechanistic studies in mice. Furthermore, they suggest the presence of a regulatory pathway to limit HO-1 induction by hemolysis in the context of infection and indicate new targets for therapeutic intervention to abrogate the susceptibility to bacterial infection in the context of hemolysis in humans.
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http://dx.doi.org/10.4049/jimmunol.1201028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504608PMC
December 2012

A human Phase I/IIa malaria challenge trial of a polyprotein malaria vaccine.

Vaccine 2011 Oct 16;29(43):7514-22. Epub 2011 Apr 16.

Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Old Road, Oxford, OX3 7LJ, UK.

We examined the safety, immunogenicity and efficacy of a prime-boost vaccination regime involving two poxvirus malaria subunit vaccines, FP9-PP and MVA-PP, expressing the same polyprotein consisting of six pre-erythrocytic antigens from Plasmodium falciparum. Following safety assessment of single doses, 15 volunteers received a heterologous prime-boost vaccination regime and underwent malaria sporozoite challenge. The vaccines were safe but interferon-γ ELISPOT responses were low compared to other poxvirus vectors, despite targeting multiple antigens. There was no vaccine efficacy as measured by delay in time to parasitaemia. A number of possible explanations are discussed, including the very large insert size of the polyprotein transgene.
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http://dx.doi.org/10.1016/j.vaccine.2011.03.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195259PMC
October 2011

Comparison of surveillance methods applied to a situation of low malaria prevalence at rural sites in The Gambia and Guinea Bissau.

Malar J 2009 Dec 2;8:274. Epub 2009 Dec 2.

Medical Research Council Laboratories, Fajara, PO Box 273 Banjul, The Gambia.

Background: Health record-based observations from several parts of Africa indicate a major decline in malaria, but up-to-date information on parasite prevalence in West-Africa is sparse. This study aims to provide parasite prevalence data from three sites in the Gambia and Guinea Bissau, respectively, and compares the usefulness of PCR, rapid diagnostic tests (RDT), serology and slide-microscopy for surveillance.

Methods: Cross-sectional surveys in 12 villages at three rural sites were carried out in the Gambia and Guinea Bissau in January/February 2008, shortly following the annual transmission season.

Results: A surprisingly low microscopically detectable parasite prevalence was detected in the Gambia (Farafenni: 10.9%, CI95%: 8.7-13.1%; Basse: 9.0%, CI95%: 7.2-10.8%), and Guinea Bissau (Caio: 4%, CI95%: 2.6-5.4%), with low parasite densities (geometric mean: 104 parasites/microl, CI95%: 76-143/microl). In comparison, PCR detected a more than three times higher proportion of parasite carriers, indicating its usefulness to sensitively identify foci where malaria declines, whereas the RDT had very low sensitivity. Estimates of force of infection using age sero-conversion rates were equivalent to an EIR of approximately 1 infectious bite/person/year, significantly less than previous estimates. The sero-prevalence profiles suggest a gradual decline of malaria transmission, confirming their usefulness in providing information on longer term trends of transmission. A greater variability in parasite prevalence among villages within a site than between sites was observed with all methods. The fact that serology equally captured the inter-village variability, indicates that the observed heterogeneity represents a stable pattern.

Conclusion: PCR and serology may be used as complementary tools to survey malaria in areas of declining malaria prevalence such as the Gambia and Guinea Bissau.
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http://dx.doi.org/10.1186/1475-2875-8-274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791766PMC
December 2009

Evidence of blood stage efficacy with a virosomal malaria vaccine in a phase IIa clinical trial.

PLoS One 2008 Jan 30;3(1):e1493. Epub 2008 Jan 30.

Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, United Kingdom.

Background: Previous research indicates that a combination vaccine targeting different stages of the malaria life cycle is likely to provide the most effective malaria vaccine. This trial was the first to combine two existing vaccination strategies to produce a vaccine that induces immune responses to both the pre-erythrocytic and blood stages of the P. falciparum life cycle.

Methods: This was a Phase I/IIa study of a new combination malaria vaccine FFM ME-TRAP+PEV3A. PEV3A includes peptides from both the pre-erythrocytic circumsporozoite protein and the blood-stage antigen AMA-1. This study was conducted at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK. The participants were healthy, malaria naïve volunteers, from Oxford. The interventions were vaccination with PEV3A alone, or PEV3A+FFM ME-TRAP. The main outcome measure was protection from malaria in a sporozoite challenge model. Other outcomes included measures of parasite specific immune responses induced by either vaccine; and safety, assessed by collection of adverse event data.

Results: We observed evidence of blood stage immunity in PEV3A vaccinated volunteers, but no volunteers were completely protected from malaria. PEV3A induced high antibody titres, and antibodies bound parasites in immunofluorescence assays. Moreover, we observed boosting of the vaccine-induced immune response by sporozoite challenge. Immune responses induced by FFM ME-TRAP were unexpectedly low. The vaccines were safe, with comparable side effect profiles to previous trials. Although there was no sterile protection two major observations support an effect of the vaccine-induced response on blood stage parasites: (i) Lower rates of parasite growth were observed in volunteers vaccinated with PEV3A compared to unvaccinated controls (p = 0.012), and this was reflected in the PCR results from PEV3A vaccinated volunteers. These showed early control of parasitaemia by some volunteers in this group. One volunteer, who received PEV3A alone, was diagnosed very late, on day 20 compared to an average of 11.8 days in unvaccinated controls. (ii). Morphologically abnormal parasites were present in the blood of all (n = 24) PEV3A vaccinated volunteers, and in only 2/6 controls (p = 0.001). We describe evidence of vaccine-induced blood stage efficacy for the first time in a sporozoite challenge study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2204057PMC
January 2008

Safety, immunogenicity, and efficacy of prime-boost immunization with recombinant poxvirus FP9 and modified vaccinia virus Ankara encoding the full-length Plasmodium falciparum circumsporozoite protein.

Infect Immun 2006 May;74(5):2706-16

Centre for Clinical Vaccinology & Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, United Kingdom.

Heterologous prime-boost immunization with DNA and various recombinant poxviruses encoding malaria antigens is capable of inducing strong cell-mediated immune responses and partial protection in human sporozoite challenges. Here we report a series of trials assessing recombinant fowlpox virus and modified vaccinia virus Ankara encoding the Plasmodium falciparum circumsporozoite protein in various prime-boost combinations, doses, and application routes. For the first time, these vaccines were administered intramuscularly and at doses of up to 5 x 10(8) PFU. Vaccines containing this antigen proved safe and induced modest immune responses but showed no evidence of efficacy in a sporozoite challenge.
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http://dx.doi.org/10.1128/IAI.74.5.2706-2716.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459746PMC
May 2006

Safety, immunogenicity and efficacy of a pre-erythrocytic malaria candidate vaccine, ICC-1132 formulated in Seppic ISA 720.

Vaccine 2005 Jan;23(7):857-64

Nuffield Department of Clinical Medicine, Centre for Clinical Vaccinology and Tropical Medicine, Oxford University, Old Road, Headington, Oxford OX3 7LJ, UK.

ICC-1132, a recombinant virus-like particle comprising of a modified hepatitis B core protein with a B cell (NANP) and two T cell epitopes of Plasmodium falciparum circumsporozoite protein (CSP), was administered i.m. as a single 50 microg dose in Seppic ISA 720 to 11 volunteers. Local reactogenicity and systemic side effects were acceptable with the predominant finding being mild pain at the injection site. This regimen induced anti-NANP antibodies in 10/11 and modest T cell responses. There was no evidence of protection from experimental challenge with P. falciparum sporozoites. Other formulations and/or multi-dose regimens will be required to enhance the immunogenicity and efficacy of ICC-1132.
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http://dx.doi.org/10.1016/j.vaccine.2004.08.020DOI Listing
January 2005
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