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| Open AccessThe potential of polygenic scores to improve cost and efficiency of clinical trials
Polygenic scores can identify individuals with high disease risk based on inborn DNA variation. We explore their potential to enrich clinical trials by identifying individuals based on higher risk of disease (‘prognostic enrichment’), or increased probability of benefit (‘predictive enrichment’).
- Akl C. Fahed
- , Anthony A. Philippakis
- & Amit V. Khera
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Article
| Open AccessProspective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients
Clinical studies have suggested that the therapeutic potential of polyclonal convalescent plasma is highest in the first days of symptoms. Here, the authors present results from a pooled analysis of two clinical trials in COVID-19 outpatients that did not provide conclusive evidence in favor of convalescent plasma.
- Pere Millat-Martinez
- , Arvind Gharbharan
- & Michael Marks
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Article
| Open AccessSafety and serum distribution of anti-SARS-CoV-2 monoclonal antibody MAD0004J08 after intramuscular injection
Monoclonal antibodies (mAbs) are a potential therapeutic option for treatment of COVID-19. Here, the authors report safety and pharmacokinetics of an intramuscularly injected mAb (MAD0004J08) during the first 30 days of a phase 1 clinical study.
- Simone Lanini
- , Stefano Milleri
- & Rino Rappuoli
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Article
| Open AccessPhase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia
Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat.
- Rebecca Anderson
- , Lance D. Miller
- & Timothy S. Pardee
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Article
| Open AccessRandomized clinical trial to assess the protective efficacy of a Plasmodium vivax CS synthetic vaccine
In this phase 2 clinical trial, the authors assess protective efficacy of a Plasmodium vivax circumsporozoite vaccine in naïve and semi-immune individuals from controlled human malaria infection as well as antibody and IFN-γ response to vaccination.
- Myriam Arévalo-Herrera
- , Xiomara Gaitán
- & Sócrates Herrera
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Article
| Open AccessCancer patient survival can be parametrized to improve trial precision and reveal time-dependent therapeutic effects
Analysis of more than 150 Phase 3 oncology clinical trials supports parametric statistical analysis, significantly increasing the precision of small early-phase trials and relating deviations from the Cox proportional hazards model to trial duration.
- Deborah Plana
- , Geoffrey Fell
- & Peter K. Sorger
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Article
| Open AccessTolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia
Anti-drug antibodies (ADA) induced by biologic drugs may hamper the efficacy of treatment, so inhibiting ADA induction is desirable. Here, in two clinical trials, the authors show that ImmTOR, previously reported to reduce drug immunogenicity in animal studies, helps mitigate ADA induced by pegylated uricase for treating patients with hyperuricemia.
- Earl Sands
- , Alan Kivitz
- & Takashi Kei Kishimoto
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Article
| Open AccessNeoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma
Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. .
- Joris L. Vos
- , Joris B. W. Elbers
- & Charlotte L. Zuur
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Article
| Open AccessA randomized study to evaluate safety and immunogenicity of the BNT162b2 COVID-19 vaccine in healthy Japanese adults
Here the authors provide the interim analysis of an ongoing phase 1/2 study of the BNT162b2 vaccine in healthy Japanese adults. They report mainly mild to moderate local reactions and no serious adverse events as well as good antibody induction one month after the second dose.
- Miwa Haranaka
- , James Baber
- & Stephen Lockhart
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Article
| Open AccessA Phase I/II randomized trial of H56:IC31 vaccination and adjunctive cyclooxygenase-2-inhibitor treatment in tuberculosis patients
Modulating the host immune response during tuberculosis is an emerging and critical advance in the therapeutic approach. Here the authors present data from a first-in-human phase I/II randomised trial on the safety and immunogenicity of adjuvant therapy of the H56:IC31 vaccine and cyclooxygenase-2 inhibitors in patients with tuberculosis.
- Synne Jenum
- , Kristian Tonby
- & Anne Ma Dyrhol-Riise
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Article
| Open AccessThree-year outcomes of the randomized phase III SEIPLUS trial of extensive intraoperative peritoneal lavage for locally advanced gastric cancer
Extensive intraoperative peritoneal lavage (EIPL) has been proposed as an approach to reduce peritoneal metastasis in patients with locally advanced gastric cancer undergoing gastrectomy. Here the authors report the results of the multicentric phase III SEIPLUS trial, showing that EIPL does not improve 3-year survival rate in patients with advanced gastric cancer.
- Jing Guo
- , Aman Xu
- & Dazhi Xu
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Article
| Open AccessNoninvasive spinal stimulation safely enables upright posture in children with spinal cord injury
Scoliosis due to trunk muscle paralysis frequently requires surgical treatment in children with spinal cord injury. The authors demonstrate the safety and efficacy of transcutaneous spinal stimulation to enable upright sitting posture in 7/8 children with trunk control impairment in a within-subjects, repeated measures pilot clinical trial.
- Anastasia Keller
- , Goutam Singh
- & Andrea L. Behrman
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Article
| Open AccessCholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.
- Amand F. Schmidt
- , Nicholas B. Hunt
- & Chris Finan
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Article
| Open AccessThe PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma
The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma. Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival.
- Lars Ny
- , Henrik Jespersen
- & Jonas A. Nilsson
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Article
| Open AccessLack of consideration of sex and gender in COVID-19 clinical studies
Sex and gender have been associated with differences in SARS-CoV-2 incidence and clinical outcomes and therefore warrant consideration in study designs. Here, the authors assess registered and published clinical COVID-19 studies and find that sex-disaggregated analyses are infrequently presented or planned.
- Emer Brady
- , Mathias Wullum Nielsen
- & Sabine Oertelt-Prigione
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Article
| Open AccessIn-silico trial of intracranial flow diverters replicates and expands insights from conventional clinical trials
In-silico trials rely on virtual populations and interventions simulated using patient-specific models and may offer a solution to lower costs. Here, the authors present the flow diverter performance assessment in-silico trial, which models the treatment of intracranial aneurysms with a flow-diverting stent.
- Ali Sarrami-Foroushani
- , Toni Lassila
- & Alejandro F. Frangi
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Article
| Open AccessGut microbiota diversity after autologous fecal microbiota transfer in acute myeloid leukemia patients
The combination of chemotherapy and broad-spectrum antibiotics induces gut microbiota (GM) dysbiosis in acute myeloid leukaemia (AML) leading to additional complications. Here, the authors report the efficacy in GM restoration and safety of autologous faecal microbiota transfer in treated AML patients in a phase II clinical trial.
- Florent Malard
- , Anne Vekhoff
- & Mohamad Mohty
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Article
| Open AccessHeterologous protection against malaria by a simple chemoattenuated PfSPZ vaccine regimen in a randomized trial
In this placebo-controlled trial, 10/13 malaria naïve subjects immunized with a simplified regimen of chemoattenuated P. falciparum sporozoites, PfSPZ-CVac, show sterile protection from heterologous malaria challenge. Immunization was well tolerated and induced high levels of anti-PfCSP antibodies.
- Zita Sulyok
- , Rolf Fendel
- & Peter G. Kremsner
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Article
| Open AccessPeginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial
Here the authors report the results of randomized, single-blind, placebocontrolled trial on the effects of a asingle subcutaneous dose of Peginterferon Lambda-1a (Lambda) in 120 outpatients with mild to moderate COVID-19, showing that while treatment is well tolerated it does not shorten the duration of SARS-CoV-2 viral shedding nor improves symptoms.
- Prasanna Jagannathan
- , Jason R. Andrews
- & Upinder Singh
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Matters Arising
| Open AccessHypothermic machine perfusion before viability testing of previously discarded human livers
- Otto B. van Leeuwen
- , Yvonne de Vries
- & Robert J. Porte
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Article
| Open AccessThe effects of releasing early results from ongoing clinical trials
Sharing early evidence, as a trial is ongoing, is fundamental for both physicians and patients to make enrollment decisions. Here, the authors report the results of a simulation study evaluating the potential effects of early release of interim efficacy and safety data on the duration and validity of an ongoing clinical trial and demonstrate that positive interim results may shorten trial duration through increased enrollment.
- Steffen Ventz
- , Sergio Bacallado
- & Lorenzo Trippa
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Article
| Open AccessNeoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer
Neoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial.
- Birendra Kumar Sah
- , Benyan Zhang
- & Zhenggang Zhu
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Article
| Open AccessCo-administered antibody improves penetration of antibody–dye conjugate into human cancers with implications for antibody–drug conjugates
Antibody-drug conjugates targeting high expression receptors can suffer from poor tumour penetration. Here, the authors use unconjugated antibody to improve the penetration of an antibody-dye conjugate in a clinical study, supporting further clinical investigation of the co-administration strategy.
- Guolan Lu
- , Naoki Nishio
- & Eben L. Rosenthal
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Article
| Open AccessA pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics
The use of hydroxychloroquine therapy for the treatment of Covid-19 is controversial. In this study, Lyngbakken and colleagues present a randomized controlled trial and show that the drug has no antiviral effects in humans infected with SARS-CoV-2.
- Magnus Nakrem Lyngbakken
- , Jan-Erik Berdal
- & Olav Dalgard
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Article
| Open AccessPhase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer
All-trans retinoic acid - ATRA- is known to remodulate the stroma of pancreatic cancer in mice. Here, the authors carried out a Phase Ib trial in pancreatic patients and show that ATRA in combination with chemotherapy is a safe potential treatment for patients with advanced pancreatic cancer, and demonstrate a stromal modulatory effect.
- Hemant M. Kocher
- , Bristi Basu
- & David J. Propper
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Article
| Open AccessA nonrandomized open-label phase 2 trial of nonischemic heart preservation for human heart transplantation
Ischemia and reperfusion damage contribute to early graft dysfunction and recipient’s death. Here the authors show the feasibility and safety of a non-ischemic heart preservation method for heart transplantation in a non-randomized trial.
- Johan Nilsson
- , Victoria Jernryd
- & Stig Steen
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Article
| Open AccessClonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy
Understanding factors that impact CAR T cell expansion in the clinic is crucial to improving its therapeutic success. Here the authors document heterogeneity in the clonal dynamics of CAR-T cells by tracking individual clones using the endogenous TCR and integration sites and provide further insights into the role of transcriptional states in clonal kinetics.
- Alyssa Sheih
- , Valentin Voillet
- & Cameron J. Turtle
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Article
| Open AccessStress sensitization among severely neglected children and protection by social enrichment
Early adversity may sensitize people to the effects of later stress, amplifying psychopathology risk. Here, the authors show this stress sensitization effect for adolescents who experienced prolonged institutional deprivation in childhood, but not those assigned to foster care intervention.
- Mark Wade
- , Charles H. Zeanah
- & Charles A. Nelson
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Article
| Open AccessBridging the gap between efficacy trials and model-based impact evaluation for new tuberculosis vaccines
One measurement of tuberculosis vaccine efficacy in clinical trials is prevention of disease, but different mechanisms can underlie disease prevention. Here, the authors develop a mathematical model that allows to identify mechanisms of action of a vaccine preventing TB disease.
- Mario Tovar
- , Sergio Arregui
- & Yamir Moreno
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Perspective
| Open AccessDesigning development programs for non-traditional antibacterial agents
Non-traditional antibacterial agents are challenging to develop. In this Perspective, the authors argue that the distinction between traditional and non-traditional agents has only limited relevance for regulatory purposes, although products with non-traditional goals focused on population-level benefits might benefit from extension of current paradigms.
- John H. Rex
- , Holly Fernandez Lynch
- & Kevin Outterson
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Article
| Open AccessA zwitterionic near-infrared fluorophore for real-time ureter identification during laparoscopic abdominopelvic surgery
Iatrogenic injury of the ureters is a feared complication of laparoscopic abdominal surgery. Here the authors present the NIR fluorophore ZW800-1 as an intraoperative imaging agent for ureter mapping, showing its safety, pharmacokinetic properties, and efficacy in healthy volunteers and patients undergoing abdominopelvic surgery.
- Kim S. de Valk
- , Henricus J. Handgraaf
- & Alexander L. Vahrmeijer
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Article
| Open AccessPrototype of running clinical trials in an untrustworthy environment using blockchain
Ensuring the integrity of clinical trial data is crucial to securing trust in the process. Here, the authors present a prototype of a blockchain-based clinical trial management system that ensures immutability and traceability of trial data, and demonstrate a proof of concept web portal service.
- Daniel R. Wong
- , Sanchita Bhattacharya
- & Atul J. Butte
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Article
| Open AccessImplementation and benchmarking of a novel analytical framework to clinically evaluate tumor-specific fluorescent tracers
Fluorescent tracers are being tested in clinical trials to improve detection of tumor margins, but procedures are not standardised. Here, the authors develop an analytical framework that is compatible with the workflow in the operating theatre, and show that it leads to an 88% increase in intraoperative detection of tumor margins in patients with breast cancer.
- Marjory Koller
- , Si-Qi Qiu
- & Gooitzen M. van Dam
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Article
| Open AccessRefined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning
Clinical trials for the CYD-TDV dengue vaccine showed that vaccine efficacy varies with prior dengue exposure, but baseline serostatus is only known for 12% of subjects. Here, Dorigatti et al. use machine learning to impute baseline serostatus and determine vaccine efficacy by baseline serostatus, age and dengue serotype.
- I. Dorigatti
- , C. A. Donnelly
- & N. M. Ferguson
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Article
| Open AccessTreating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement
Allergen-specific immunotherapy is used to treat patients affected by acute immunoglobulin E (IgE) responses, but the function mechanism is unclear. Here the authors show that the administration of two cat allergen-specific IgGs reduces allergic responses in mouse models and helps ameliorate clinical symptoms in a phase 1b clinical trial.
- J. M. Orengo
- , A. R. Radin
- & G. D. Yancopoulos
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Article
| Open AccessChronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults
Declining NAD+ levels have been linked to aging-associated pathologies. Here the authors present results of a double-blind, randomized crossover trial on 30 healthy middle-aged individuals to show that nicotinamide riboside effectively elevates NAD+ levels in humans, appears to be well tolerated, and may have potential to improve cardiovascular parameters.
- Christopher R. Martens
- , Blair A. Denman
- & Douglas R. Seals
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Article
| Open AccessA randomized and open-label phase II trial reports the efficacy of neoadjuvant lobaplatin in breast cancer
Triple-negative breast cancer (TNBC) is one of the most aggressive and difficult to treat types of breast cancer. Here, a phase 2 clinical trial in TNBC patients reveals that the addition of lobaplatin to docetaxel and epirubicin regime improves pCR and ORR rates with tolerable side-effects.
- Xiujuan Wu
- , Peng Tang
- & Yi Zhang
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Article
| Open AccessVertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers
Cancer patients often respond well to primary treatment but then develop resistance. Here, Misale et al. show that dual treatment with EGFR and MEK inhibitors block resistance in mice containing patient-derived xenografts and provide a mathematical model that describes the temporal development of resistant tumour clones.
- Sandra Misale
- , Ivana Bozic
- & Alberto Bardelli
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Article
| Open AccessDefining the relationship between infection prevalence and clinical incidence of Plasmodium falciparum malaria
Mathematical models are used to predict malaria burden to inform disease control efforts. Here, Cameron et al. use Bayesian statistics to calibrate previous models against a data set of age-structured prevalence and incidence, generating stratified forecasts of the prevalence–incidence relationship.
- Ewan Cameron
- , Katherine E. Battle
- & Peter W. Gething
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Article
| Open AccessLonger-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study
Long-chain omega-3 polyunsaturated fatty acids are essential for neural development and lack of these fatty acids has been implicated in a number of mental health conditions. Here the authors report the longer-term efficacy of a randomized, double-blind, placebo-controlled clinical trial assessing the effects of fish oil capsules in individuals at ultrahigh risk for psychosis.
- G. Paul Amminger
- , Miriam R. Schäfer
- & Patrick D. McGorry
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Article |
Fat, fibre and cancer risk in African Americans and rural Africans
African Americans have much higher colon cancer rates than rural South Africans, which is associated with dietary and metabolic differences. Here, O’Keefe et al.show that switching quantities of fat and fibre leads to reciprocal changes in gut microbiota, metabolites and cancer biomarkers.
- Stephen J. D. O’Keefe
- , Jia V. Li
- & Erwin G. Zoetendal
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Article |
Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo
Inhibiting the interaction between the membrane protein P-selectin and its ligand PSGL-1 is thought to block inflammation. Here the authors report an efficient stereoselective synthesis for PSGL-1 glycopeptide mimics and show that these compounds inhibit PSGL-1/P-selectin in vitro and in vivo.
- Venkata R. Krishnamurthy
- , Mohammed Y. R. Sardar
- & Elliot L. Chaikof
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Article
| Open AccessWhole-genome sequence-based analysis of thyroid function
Levels of circulating thyrotropin and free thyroxine reflect thyroid function, however, their genetic underpinnings remain poorly understood. Taylor et al. take advantage of whole-genome sequence data from cohorts within the UK10K project to identify novel variants associated with these traits.
- Peter N. Taylor
- , Eleonora Porcu
- & Pingbo Zhang
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Article |
Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα
Endurance exercise is associated with an increased risk of atrial fibrillation. Here, the authors show the adipokine TNFα is a crucial mediator of exercise-induced atrial fibrillation and irreversible atrial remodelling characterized by fibrosis and inflammation.
- Roozbeh Aschar-Sobbi
- , Farzad Izaddoustdar
- & Peter H. Backx
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Article
| Open AccessHuman-to-mosquito transmission efficiency increases as malaria is controlled
Understanding the epidemiology of malaria transmission between humans and mosquitoes is crucial for successful disease control. Analysing data from an 18-year malaria control programme, Churcher et al. show that decreased parasite prevalence in humans can be found concurrently with an increase in transmission efficiency.
- Thomas S. Churcher
- , Jean-François Trape
- & Anna Cohuet
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Article
| Open AccessEstimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa
Reduction in malaria transmission has changed the age pattern of malaria incidence. This study brings insights into the changes in age distributions of clinical malaria across Africa, with importance for improving within-population targeting of malaria control interventions.
- Jamie T. Griffin
- , Neil M. Ferguson
- & Azra C. Ghani
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Article
| Open AccessWind direction and proximity to larval sites determines malaria risk in Kilifi District in Kenya
Spatial epidemiology studies identify malaria hotspots, which sustain transmission and so could be targeted by control programmes. This study uses spatial data on larval sites and malaria episodes to show that transmission can be disrupted by targeting vector breeding sites close to and downwind of malaria hotspots.
- Janet T. Midega
- , Dave L. Smith
- & Philip Bejon