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Objectives: Acquisition of antibodies to Plasmodium falciparum variant surface antigens (VSA) expressed on infected red blood cells (iRBCs) is associated with naturally acquired immunity to malaria. We have previously shown that antibodies to VSA on iRBCs are associated with protection against parasite growth in the context of controlled human malaria infection (CHMI). This study explored whether antibodies to recombinant antigens derived from PfEMP1 domains were independently associated with protection during CHMI in semi-immune Kenyan adults., Methods: We used a multiplex bead assay to measure levels of IgG antibody against a panel of 27 recombinant PfEMP1 antigens derived from the PfEMP1 repertoire of the 3D7 parasite clone. We measured IgG levels in plasma samples collected from the CHMI participants before inoculation with Sanaria® PfSPZ Challenge, on the day of diagnosis, and 35 days post-inoculation. Univariable and multivariable Cox regression analysis was used to evaluate the relationship between the levels of antibodies to the antigens and CHMI outcome. We also adjusted for previous data including antibodies to VSA on iRBCs, and we assessed the kinetics of antibody acquisition to the different PfEMP1 recombinant antigens over time., Results: All study participants had detectable antibodies to multiple PfEMP1 proteins before inoculation. All PfEMP1 antigens were associated with protection against parasite growth to the threshold criteria for treatment in CHMI, albeit with substantial collinearity. However, individual PfEMP1 antigens were not independently associated with protection following adjustment for breadth of reactivity to VSA on iRBCs and schizont extract. In addition, antibodies to PfEMP1 antigens derived from group B PfEMP1 were induced and sustained in the participants who could not control parasite growth., Conclusion: This study shows that the breadth of antibody response to VSA on iRBCs, and not to specific PfEMP1 antigens, is predictive of protection against malaria in CHMI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: B Kim Lee Sim and members of the CHMI-SIKA Study Team (Yonas Abebe, Stephen L. Hoffman, Eric R. James, Thomas L. Richie, and Peter F. Billingsley are salaried, full-time employees of Sanaria, the manufacturer of Sanaria PfSPZ Challenge (NF54)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Malaria remains a major global health priority, and monoclonal antibodies (mAbs) are emerging as potential new tools to support efforts to control the disease. Recent data suggest that Fc-dependent mechanisms of immunity are important mediators of protection against the blood stages of the infection, but few studies have investigated this in the context of mAbs. We aimed to isolate mAbs agnostic to cognate antigens that target whole merozoites and simultaneously induce potent neutrophil activity measured by the level of reactive oxygen species (ROS) production using an antibody-dependent respiratory burst (ADRB) assay., Methods: We used samples from semi-immune adults living in coastal Kenya to isolate mAbs that induce merozoite-specific ADRB activity. We then tested whether modifying the expressed IgG1 isotype to an IgG-IgA Fc region chimera would enhance the level of ADRB activity., Results: We isolated a panel of nine mAbs with specificity to whole merozoites. mAb J31 induced ADRB activity in a dose-dependent fashion. Compared to IgG1, our modified antibody IgG-IgA bi-isotype induced higher ADRB activity across all concentrations tested. Further, we observed a negative hook effect at high IgG1 mAb concentrations (i.e., >200 µg/mL), but this was reversed by Fc modification. We identified MSP3.5 as the potential cognate target of mAb J31., Conclusions: We demonstrate an approach to engineer mAbs with enhanced ADRB potency against blood-stage parasites., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ogwang, Murugu, Nkumama, Nyamako, Kai, Mwai, Murungi, Idro, Bejon, Tuju, Kinyanjui and Osier.)

Malaria transmission intensity affects the development of naturally acquired immunity to malaria. An absolute correlate measure of protection against malaria is lacking. However, antibody-mediated functions against Plasmodium falciparum correlate with protection against malaria. In children, antibody-mediated functions against P. falciparum decline with reduced exposure. It is unclear whether adults maintain antibody-mediated functions as malaria transmission declines. This study assessed antibody-dependent respiratory burst (ADRB) in individuals from an area with declining malaria transmission. In an age-matched analysis, we compare ADRB activity during high versus low malaria transmission periods. Age significantly predicted higher ADRB activity in the high ( p < 0.001) and low ( p < 0.001) malaria transmission periods. ADRB activity was higher during the high compared to the low malaria transmission period in older children and adults. Only older adults during the high malaria transmission period had their median ADRB activity above the ADRB cut-off. Ongoing P. falciparum infection influenced ADRB activity during the low ( p = 0.01) but not the high ( p = 0.29) malaria transmission period. These findings propose that naturally acquired immunity to P. falciparum is affected in children and adults as malaria transmission declines, implying that vaccines will be necessary to induce and maintain protection against malaria.

Purpose: Positron emission tomography/magnetic resonance imaging (PET/MRI) is a powerful tool for brain imaging, but the spatial resolution of the PET scanners currently used for brain imaging can be further improved to enhance the quantitative accuracy of brain PET imaging. The purpose of this study is to develop an MR-compatible brain PET scanner that can simultaneously achieve a uniform high spatial resolution and high sensitivity by using dual-ended readout depth encoding detectors., Methods: The MR-compatible brain PET scanner, named SIAT bPET, consists of 224 dual-ended readout detectors. Each detector contains a 26 × 26 lutetium yttrium oxyorthosilicate (LYSO) crystal array of 1.4 × 1.4 × 20 mm 3 crystal size read out by two 10 × 10 silicon photomultiplier (SiPM) arrays from both ends. The scanner has a detector ring diameter of 376.8 mm and an axial field of view (FOV) of 329 mm. The performance of the scanner including spatial resolution, sensitivity, count rate, scatter fraction, and image quality was measured. Imaging studies of phantoms and the brain of a volunteer were performed. The mutual interferences of the PET insert and the uMR790 3 T MRI scanner were measured, and simultaneous PET/MRI imaging of the brain of a volunteer was performed., Results: A spatial resolution of better than 1.5 mm with an average of 1.2 mm within the whole FOV was obtained. A sensitivity of 11.0% was achieved at the center FOV for an energy window of 350-750 keV. Except for the dedicated RF coil, which caused a ~ 30% reduction of the sensitivity of the PET scanner, the MRI sequences running had a negligible effect on the performance of the PET scanner. The reduction of the SNR and homogeneity of the MRI images was less than 2% as the PET scanner was inserted to the MRI scanner and powered-on. High quality PET and MRI images of a human brain were obtained from simultaneous PET/MRI scans., Conclusion: The SIAT bPET scanner achieved a spatial resolution and sensitivity better than all MR-compatible brain PET scanners developed up to date. It can be used either as a standalone brain PET scanner or a PET insert placed inside a commercial whole-body MRI scanner to perform simultaneous PET/MRI imaging., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective. Spatial resolution is a crucial parameter for a positron emission tomography (PET) scanner. The spatial resolution of a high-resolution small animal PET scanner is significantly influenced by the effect of depth of interaction (DOI) uncertainty. The aim of this work is to investigate the impact of DOI resolution on the spatial resolution of a small animal PET scanner called SIAT aPET and determine the required DOI resolution to achieve nearly uniform spatial resolution within the field of view (FOV). Approach . The SIAT aPET detectors utilize 1.0 × 1.0 × 20 mm 3 crystals, with an average DOI resolution of ∼2 mm. A default number of 16 DOI bins are used during data acquisition. First, a Na-22 point source was scanned in the center of the axial FOV with different radial offsets. Then, a Derenzo phantom was scanned at radial offsets of 0 and 15 mm in the center axial FOV. The measured DOI information was rebinned to 1, 2, 4 and 8 DOI bins to mimic different DOI resolutions of the detectors during image reconstruction. Main results . Significant artifacts were observed in images obtained from both the point source and Derenzo phantom when using only one DOI bin. When accurate measurement of DOI is not achieved, degradation in spatial resolution is more pronounced in the radial direction compared to tangential and axial directions for large radial offsets. The radial spatial resolutions at a 30 mm radial offset are 5.05, 2.62, 1.24, 0.86 and 0.78 mm when using 1, 2, 4, 8, or 16 DOI bins, respectively. The axial spatial resolution improved from ∼1.3 to 0.7 mm as the number of DOI bins increased from 1 to 16 at radial offsets from 0 to 25 mm. Two DOI bins are required to obtain images without significant artifacts. The required DOI resolution is about three times the crystal width of SIAT aPET to achieve a uniform submillimeter spatial resolution within the central 60 mm FOV and resolve the 1 mm rods of the Derenzo phantom at both positions., (© 2023 Institute of Physics and Engineering in Medicine.)

Background: Plasmodium falciparum variant surface antigens (VSAs) contribute to malaria pathogenesis by mediating cytoadhesion of infected red blood cells to the microvasculature endothelium. In this study, we investigated the association between anti-VSA antibodies and clinical outcome in a controlled human malaria infection (CHMI) study., Method: We used flow cytometry and ELISA to measure levels of IgG antibodies to VSAs of five heterologous and one homologous P. falciparum parasite isolates, and to two PfEMP1 DBLβ domains in blood samples collected a day before the challenge and 14 days after infection. We also measured the ability of an individual's plasma to inhibit the interaction between PfEMP1 and ICAM1 using competition ELISA. We then assessed the association between the antibody levels, function, and CHMI defined clinical outcome during a 21-day follow-up period post infection using Cox proportional hazards regression., Results: Antibody levels to the individual isolate VSAs, or to two ICAM1-binding DBLβ domains of PfEMP1, were not associated with a significantly reduced risk of developing parasitemia or of meeting treatment criteria after the challenge after adjusting for exposure. However, anti-VSA antibody breadth (i.e., cumulative response to all the isolates) was a significant predictor of reduced risk of requiring treatment [HR 0.23 (0.10-0.50) p= 0.0002]., Conclusion: The breadth of IgG antibodies to VSAs, but not to individual isolate VSAs, is associated with protection in CHMI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kimingi, Kinyua, Achieng, Wambui, Mwangi, Nguti, Kivisi, Jensen, Bejon, Kapulu, Abdi, Kinyanjui and CHMI-SIKA Study Team.)

Aim: To investigate geographical change over time in the burden of neurological impairments in school-aged children in a demographic surveillance area., Method: We investigated changes in neurological impairment prevalence in five domains (epilepsy and cognitive, hearing, vision, and motor impairments) using similar two-phase surveys conducted in 2001 (n=10 218) and 2015 (n=11 223) and determined changes in location-level prevalence, geographical clustering, and significant risk factors for children aged 6 to 9 years (mean 7y 6mo, SD 1y) of whom 50.4% were males. Admission trends for preterm birth, low birthweight (LBW), and encephalopathy were determined using admission data to a local hospital., Results: Overall prevalence for any neurological impairment decreased from 61 per 1000 (95% confidence interval [CI] 48.0-74.0) in 2001 to 44.7 per 1000 (95% CI 40.9-48.6) in 2015 (p<0.001). There was little evidence of geographical variation in the prevalence of neurological impairments in either survey. The association between neurological impairments and some risk factors changed significantly with year of survey; for example, the increased association of adverse perinatal events with hearing impairments (exponentiated coefficient for the interaction=5.94, p=0.03). Annual admission rates with preterm birth (rate ratio 1.08, range 1.07-1.09), LBW (rate ratio 1.08, range 1.06-1.10), and encephalopathy (rate ratio 1.08, range 1.06-1.09) significantly increased between 2005 and 2016 (p<0.001)., Interpretation: There was a significant decline in the prevalence of neurological impairments and differential changes in the associations of some risk factors with neurological impairments over the study period. Limited geographical variation suggests that similar interventions are appropriate across the defined area., (© 2021 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Neurological impairment (NI) and disability are common in sub-Saharan Africa (SSA), but the overall burden in terms of morbidity and mortality in older children remains unknown. We estimated the burden of NI in disability-adjusted life years (DALYs), years of life lost to premature mortality (YLLs), and years lived with disability (YLDs) for older children in a defined rural setting in Kenya. We used empirical and literature estimates to model the overall burden for children aged 5-14 years in five domains: epilepsy (lifetime and active) and moderate/severe cognitive, hearing, motor, and visual impairments. We obtained internally consistent estimates of prevalence, mortality, and transitional hazards using DisMod II software. Disability weights and life expectancy estimates were based on the global burden of disease (GBD) studies. We used the most plausible parameters to calculate YLLs, YLDs, and DALYs and their bootstrapped 95% uncertainty intervals (95%UI) for the defined area. NI in the five domains resulted in a total of 4587 (95%UI 4459-4715) absolute DALYs or 53 (95%UI 39-67) DALYs per 1000 children aged 5-14 years, of which 83% were YLLs and 17% YLDs. Girls had significantly more YLLs and DALYs than boys (p-values <0.001, respectively). Besides being the leading cause of fatal and non-fatal outcomes, epilepsy accounted for the greatest proportion of the total burden for a single domain (20 DALYs per 1000, 95%UI 11-26, or 38.5% of the total DALYs). Visual impairment accounted for the least proportion of the total burden (6 per 1000, 95%UI 1-17, or 12.1%). Children with NI and disability bear a significantly high burden of fatal and non-fatal outcomes. The burden is highest among girls and those with childhood-onset epilepsy. We recommend active identification, treatment, and rehabilitative support for the affected children to prevent premature mortality and improve their quality of life., Competing Interests: Competing interests: The authors have declared that no competing interests exist.

Background: Neurological impairments (NI) and disability are common among older children in low-and middle-income countries (LMICs). We conducted a systematic review to examine the barriers limiting access and utilization of biomedical and rehabilitative care by children and adolescents with NI in LMICs. Methods: We searched PubMed, Latin America and Caribbean Health Sciences Literature, Global Index Medicus, and Google Scholar for studies published between 01/01/1990 and 14/11/2019 to identify relevant studies. We included all studies reporting on barriers limiting access and utilization of preventive, curative, and rehabilitative care for children aged 0-19 years with NI in five domains: epilepsy, and cognitive, auditory, visual, and motor function impairment. Data from primary studies were synthesized using both qualitative and quantitative approaches. Results: Our literature searches identified 3,258 reports of which 20 were included in the final analysis. Fifteen studies (75.0%) originated from diverse settings in sub-Saharan Africa (SSA). Factors limiting access and utilization of healthcare services in >50% of the studies were: financial constraints (N=17, 85.0%), geographical and physical inaccessibility (N=14, 70.0%), inadequate healthcare resources (N=14, 70.0%), prohibitive culture and beliefs (N=12, 60.0%), and inadequate education/awareness (N=11, 55.0%). Factors reported in <50% of the studies included competing domestic roles (N=4, 20%) and a lack of confidentiality for personal information (N=2, 10.0%). Very few reports were identified from outside Africa preventing a statistical analysis by continent and economic level. Conclusions: Financial constraints, geographic and physical inaccessibility, and inadequate healthcare resources were the most common barriers limiting access and utilization of healthcare services by children with NI in LMICs. PROSPERO registration: CRD42020165296 (28/04/2020)., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Mwangi LW et al.)

Background: The rising digitisation and proliferation of data sources and repositories cannot be ignored. This trend expands opportunities to integrate and share population health data. Such platforms have many benefits, including the potential to efficiently translate information arising from such data to evidence needed to address complex global health challenges. There are pockets of quality data on the continent that may benefit from greater integration. Integration of data sources is however under-explored in Africa. The aim of this article is to identify the requirements and provide practical recommendations for developing a multi-consortia public and population health data-sharing framework for Africa. Methods: We conducted a narrative review of global best practices and policies on data sharing and its optimisation. We searched eight databases for publications and undertook an iterative snowballing search of articles cited in the identified publications. The Leximancer software © enabled content analysis and selection of a sample of the most relevant articles for detailed review. Themes were developed through immersion in the extracts of selected articles using inductive thematic analysis. We also performed interviews with public and population health stakeholders in Africa to gather their experiences, perceptions, and expectations of data sharing. Results: Our findings described global stakeholder experiences on research data sharing. We identified some challenges and measures to harness available resources and incentivise data sharing.  We further highlight progress made by the different groups in Africa and identified the infrastructural requirements and considerations when implementing data sharing platforms. Furthermore, the review suggests key reforms required, particularly in the areas of consenting, privacy protection, data ownership, governance, and data access. Conclusions: The findings underscore the critical role of inclusion, social justice, public good, data security, accountability, legislation, reciprocity, and mutual respect in developing a responsive, ethical, durable, and integrated research data sharing ecosystem., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Igumbor JO et al.)

Genomic surveillance of SARS-CoV-2 is important for understanding both the evolution and the patterns of local and global transmission. Here, we generated 311 SARS-CoV-2 genomes from samples collected in coastal Kenya between 17 th March and 31 st July 2020. We estimated multiple independent SARS-CoV-2 introductions into the region were primarily of European origin, although introductions could have come through neighbouring countries. Lineage B.1 accounted for 74% of sequenced cases. Lineages A, B and B.4 were detected in screened individuals at the Kenya-Tanzania border or returning travellers. Though multiple lineages were introduced into coastal Kenya following the initial confirmed case, none showed extensive local expansion other than lineage B.1. International points of entry were important conduits of SARS-CoV-2 importations into coastal Kenya and early public health responses prevented established transmission of some lineages. Undetected introductions through points of entry including imports from elsewhere in the country gave rise to the local epidemic at the Kenyan coast., (© 2021. The Author(s).)

Background: Neurological impairment (NI) and disability are associated with reduced life expectancy, but the risk and magnitude of premature mortality in children vary considerably across study settings. We conducted a systematic review to estimate the magnitude of premature mortality following childhood-onset NI worldwide and to summarize known risk factors and causes of death. Methods: We searched various databases for published studies from their inception up to 31st October 2020. We included all cohort studies that assessed the overall risk of mortality in individuals with childhood-onset epilepsy, intellectual disability (ID), and deficits in hearing, vision and motor functions. Comparative measures of mortality such as the standardized mortality ratio (SMR), risk factors and causes were synthesized quantitatively under each domain of impairment. This review is registered on the PROSPERO database (registration number CRD42019119239). Results: The search identified 2,159 studies, of which 24 studies were included in the final synthesis. Twenty-two (91.7%) studies originated from high-income countries (HICs). The median SMR was higher for epilepsy compared with ID (7.1 [range 3.1-22.4] vs. 2.9 [range 2.0-11.6]). In epilepsy, mortality was highest among younger age groups, comorbid neurological disorders, generalized seizures (at univariable levels), untreatable epilepsy, soon after diagnosis and among cases with structural/metabolic types, but there were no differences by sex. Most deaths (87.5%) were caused by non-epilepsy-related causes. For ID, mortality was highest in younger age groups and girls had a higher risk compared to the general population. Important risk factors for premature mortality were severe-to-profound severity, congenital disorders e.g., Down Syndrome, comorbid neurological disorders and adverse pregnancy and perinatal events. Respiratory infections and comorbid neurological disorders were the leading causes of death in ID. Mortality is infrequently examined in impairments of vision, hearing and motor functions. Summary: The risk of premature mortality is elevated in individuals with childhood-onset NI, particularly in epilepsy and lower in ID, with a need for more studies for vision, hearing, and motor impairments. Survival in NI could be improved through interventions targeting modifiable risk factors and underlying causes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Abuga, Kariuki, Kinyanjui, Boele van Hensbroek and Newton.)

Background: Neurological impairments (NI) and disability are common among survivors of childhood mortality in low-and middle-income countries (LMICs). We conducted a systematic review to examine the barriers limiting access and utilization of biomedical care by children and adolescents with NI in LMICs. Methods: We searched PubMed, Latin America and Caribbean Health Sciences Literature, Global Index Medicus, and Google Scholar for studies published between 01/01/1990 and 14/11/2019 to identify relevant studies. We included all reports on barriers limiting access and utilization of preventive, curative, and rehabilitative care for children aged 0-19 years with NI in five domains: epilepsy, and cognitive, auditory, visual, and motor function impairment. Data from primary studies were synthesized using both qualitative and quantitative approaches, and we report a synthesized analysis of the barriers identified in the primary studies. Results: Our literature searches identified 3,074 reports of which 16 were included in the final analysis. Fourteen studies (87.5%) originated from rural settings in sub-Saharan Africa (SSA). Factors limiting access and utilization of healthcare services in >50% of the studies were: financial constraints (N=15, 93.8%), geographical inaccessibility (N=11, 68.8%), inadequate healthcare resources (N=11, 68.8%), inadequate education/awareness (N=9, 56.3%), and prohibitive culture/beliefs (N=9, 56.3%). Factors reported in <50% of the studies related to the attitude of the patient, health worker, or society (N=7, 43.8%), poor doctor-patient communication (N=5, 31.3%), physical inaccessibility (N=3, 18.8%), and a lack of confidentiality for personal information (N=2, 12.5%). Very few reports were identified from outside Africa preventing a statistical analysis by continent and economic level. Conclusions: Financial constraints, geographic inaccessibility, and inadequate healthcare resources were the most common barriers limiting access and utilization of healthcare services by children with NI in LMICs. PROSPERO registration: CRD42020165296 (28/04/2020)., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Mwangi LW et al.)

Introduction: Fieldworkers are part of the system that promotes scientific and ethical standards in research, through data collection, consenting and supporting research, due to their insider cultural knowledge and fluency in local languages. The credibility and integrity of health research, therefore, rely on how fieldworkers adhere to institutional and research procedures and guidelines., Objectives: This study mapped out existing practices in training, support and performance management of fieldworkers in Africa, described fieldworkers' and their managers' experiences, and lessons learnt. A consultative process, involving field managers from 15 international health research institutions, was used to identify appropriate ways of addressing the challenges fieldworkers face., Methods: In phase 1, we conducted 32 telephone interviews with 20 field managers and 12 senior fieldworkers from 18 major research centres in Africa, Medical Research Council-UK and the INDEPTH Network Secretariat. In phase 2, we held a 2.5-day workshop involving 25 delegates, including 18 field managers from the institutions that were involved in phase 1 and 7 additional stakeholders from the KEMRI Wellcome Trust Research Programme (KWTRP). An earlier report from phase 1 was published in BMC Med ical Ethics in 2015. Data transcribed from the interviews and workshop proceedings were analysed thematically using NVivo V.10 software., Results: Most institutions employed fieldworkers, usually with 12 years of formal education and residing within the geographical areas of research, to support studies. Although their roles were common, there were marked differences in the type of training, professional development schemes and fieldworkers support. Fieldworkers faced various challenges, with the potential to affect their ethical and scientific practices., Discussion: Fieldworkers undertake vital tasks that promote data quality and ethical practice in research. There is a need for research institutions to develop a structured support system, provide fieldworkers with interpersonal skills training, and provide space for discussion, reflection and experience sharing to help fieldworkers tackle the practical and ethical challenges they face., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Neurological impairments might significantly contribute to reduced life expectancy in low-income and middle-income countries (LMICs). There are no empirical studies of premature mortality in children with neurological impairments in Africa. This study estimated the risk of premature mortality in children with neurological impairments and identified risk factors and causes of death., Methods: We did a cohort study based on a two-stage epidemiological survey in the Kilifi Health and Demographic Surveillance System (Kilifi, Kenya). Study participants were children aged 6-9 years. In the first stage, five trained field workers administered a low-cost screening tool to a random sample of households. In the second stage, we assessed for neurological impairments in five domains (epilepsy, cognitive impairments, vision impairments, hearing impairments, and motor impairments) using comprehensive clinical evaluation and extensive neuropsychological assessments. From the two-stage survey we identified a cohort of children with neurological impairment and a cohort of matched controls. We also enrolled an age-matched sample from the general population. The primary outcome was all-cause mortality. Mortality rates, standardised mortality ratio (SMR), and hazard ratios (HR) for risk factors were estimated and causes of death identified., Findings: We enrolled 306 children with neurological impairment, 9912 survey controls, and 22 873 age-matched participants from the general population, and followed up the cohorts between June 1, 2001, and Aug 31, 2018. Median follow-up was 14·5 years (IQR 8·6-17·2). 11 (3·9%) of 284 children with neurological impairment, 92 (1·0%) of 9009 controls, and 272 (1·2%) of 22 873 participants in the general population sample died during the follow-up. Overall mortality rates were 309·8 per 100 000 person-years of observation (95% CI 126·7-492·9) in children with neurological impairment, 80·8 per 100 000 person-years of observation (64·3-97·3) in controls, and 98·8 per 100 000 person-years of observation (87·1-110·6) in the general population sample (mortality rate ratio 3·83, 95% CI 2·05-7·16, p<0·001, compared with controls; 3·13, 1·71-5·72, p<0·001, compared with the general population). Mortality risk in children with neurological impairment was not dependent on the severity of impairment (p=0·291) nor on a specific neurological impairment domain (p=0·205). The overall risk of death adjusted for age and sex was higher in children with neurological impairment compared with controls (HR 4·24, 95% CI 2·26-7·94, p=0·002). An SMR of 3·15 (95% CI 1·66-5·49) was obtained after using the general population sample as the reference for indirect standardisation. In multivariable risk factor analysis, developmental delay (adjusted HR 18·92, 95% CI 2·23-160·44, p=0·007) and severe malnutrition (20·92, 3·14-139·11, p=0·002) increased the risk of mortality in children with neurological impairment. Infections such as HIV/AIDS and accidents were common among all decedents., Interpretation: The risk of premature mortality was higher in children diagnosed with neurological impairments compared with the general population and was increased by developmental delay and severe malnutrition. Child development and nutritional status should be assessed in all children in LMICs and tailored interventions started to improve outcomes., Funding: Wellcome Trust, DELTAS Africa Initiative., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Passive transfer studies in humans clearly demonstrated the protective role of IgG antibodies against malaria. Identifying the precise parasite antigens that mediate immunity is essential for vaccine design, but has proved difficult. Completion of the Plasmodium falciparum genome revealed thousands of potential vaccine candidates, but a significant bottleneck remains in their validation and prioritization for further evaluation in clinical trials. Focusing initially on the Plasmodium falciparum merozoite proteome, we used peer-reviewed publications, multiple proteomic and bioinformatic approaches, to select and prioritize potential immune targets. We expressed 109 P. falciparum recombinant proteins, the majority of which were obtained using a mammalian expression system that has been shown to produce biologically functional extracellular proteins, and used them to create KILchip v1.0: a novel protein microarray to facilitate high-throughput multiplexed antibody detection from individual samples. The microarray assay was highly specific; antibodies against P. falciparum proteins were detected exclusively in sera from malaria-exposed but not malaria-naïve individuals. The intensity of antibody reactivity varied as expected from strong to weak across well-studied antigens such as AMA1 and RH5 (Kruskal-Wallis H test for trend: p < 0.0001). The inter-assay and intra-assay variability was minimal, with reproducible results obtained in re-assays using the same chip over a duration of 3 months. Antibodies quantified using the multiplexed format in KILchip v1.0 were highly correlated with those measured in the gold-standard monoplex ELISA [median (range) Spearman's R of 0.84 (0.65-0.95)]. KILchip v1.0 is a robust, scalable and adaptable protein microarray that has broad applicability to studies of naturally acquired immunity against malaria by providing a standardized tool for the detection of antibody correlates of protection. It will facilitate rapid high-throughput validation and prioritization of potential Plasmodium falciparum merozoite-stage antigens paving the way for urgently needed clinical trials for the next generation of malaria vaccines.

Antibodies to selected Plasmodium falciparum merozoite antigens are often reported to be associated with protection from malaria in one epidemiological cohort, but not in another. Here, we sought to understand this paradox by exploring the hypothesis that a threshold concentration of antibodies is necessary for protection. We analyzed data from two independent cohorts along the Kenyan coast, one in which antibodies to AMA1, MSP-2 and MSP-3 were associated with protection from malaria (Chonyi) and another in which this association was not observed (Junju). We used a malaria reference reagent to standardize antibody measurements across both cohorts, and applied statistical methods to derive the threshold concentration of antibodies against each antigen that best correlated with a reduced risk of malaria (the protective threshold), in the Chonyi cohort. We then tested whether antibodies in Junju reached the protective threshold concentrations observed in the Chonyi cohort. Except for children under 3 years, the age-matched proportions of children achieving protective threshold concentrations of antibodies against AMA1 and MSP-2 were significantly lower in Junju compared to Chonyi (Fishers exact test, P<0.01). For MSP-3, this difference was significant only among 4-5 year olds. We conclude that although antibodies are commonly detected in malaria endemic populations, they may be present in concentrations that are insufficient for protection. Our results have implications for the analysis and interpretation of similar data from immuno-epidemiological studies., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In sub-Saharan Africa, the distributions of malaria and HIV widely overlap. Among pregnant and non-pregnant adults, HIV affects susceptibility to malaria, its clinical course and impairs antibody responses to malaria antigens. However, the relationship between the two diseases in childhood, when most deaths from malaria occur, is less clear. It was previously reported that HIV is associated with admission to hospital in rural Kenya with severe malaria among children, except in infancy. HIV-infected children with severe malaria were older, had higher parasite density and increased mortality, raising a hypothesis that HIV interferes with naturally acquired immunity to malaria, hence with little effect at younger ages (a shorter history of exposure). To test this hypothesis, levels of anti-merozoite and schizont extract antibodies were compared between HIV-infected and uninfected children who participated in the original study., Methods: IgG responses to malaria antigens that are potential targets for immunity to malaria (AMA1, MSP2, MSP3 and schizont extract) were compared between 115 HIV-infected and 115 age-matched, HIV-uninfected children who presented with severe malaria. The children were classified as high and low responders for each antigen and assigned antibody-response breadth scores according to the number of antigens to which they were responsive. A predictive logistic regression model was used to test if HIV was an effect modifier on the age-related acquisition of antibody responses, with age as a continuous variable., Results: Point estimates of the responses to all antigens were lower amongst HIV-infected children, but this was only statistically significant for AMA1 (P = 0.028). HIV-infected children were less likely to be high responders to AMA1 [OR 0.44 (95%CI, 0.2-0.90) P = 0.024]. HIV was associated with a reduced breadth of responses to individual merozoite antigens (P = 0.02). HIV strongly modified the acquisition of antibodies against schizont extract with increasing age (P < 0.0001), but did not modify the rate of age-related acquisition of responses to individual merozoite antigens., Conclusions: In children with severe malaria, HIV infection is associated with a lower magnitude and narrower breadth of IgG responses to merozoite antigens and stunting of age-related acquisition of the IgG antibody response to schizont extract.

Background: A major handicap in developing a malaria vaccine is the difficulty in pinpointing the immune responses that protect against malaria. The protective efficacy of natural or vaccine-induced immune responses against malaria is normally assessed by relating the level of the responses in an individual at the beginning of a follow-up period and the individual's experience of malaria infection or disease during the follow-up. This approach has identified a number of important responses against malaria, but their protective efficacies vary considerably between studies., Hypothesis: It is likely that apart from differences in study methodologies, differences in exposure among study subjects within each study and brevity of antibody responses to malaria antigen are important sources of the variation in protective efficacy of anti-malaria immune responses mentioned above. Since malaria immunity is not complete, anyone in an area of stable malaria transmission who does not become asymptomatically or symptomatically infected during follow-up subsequent to treatment is most likely unexposed rather than immune., Testing the Hypothesis: It is proposed that individuals involved in a longitudinal study of malaria immunity should be treated for malaria prior to the start of the study and only those who present with at least an asymptomatic infection during the follow-up should be included in the analysis. In addition, it is proposed that more closely repeated serological survey should be carried out during follow-up in order to get a better picture of an individual's serological status., Implications of the Hypothesis: Failure to distinguish between individuals who do not get a clinical episode during follow-up because they were unexposed and those who are genuinely immune undermines our ability to assign a protective role to immune responses against malaria. The brevity of antibodies responses makes it difficult to assign the true serological status of an individual at any given time, i.e. those positive at a survey may be negative by the time they encounter the next infection.

In studies of immunity to malaria, the absence of febrile malaria is commonly considered evidence of "protection." However, apparent "protection" may be due to a lack of exposure to infective mosquito bites or due to immunity. We studied a cohort that was given curative antimalarials before monitoring began and documented newly acquired asymptomatic parasitemia and febrile malaria episodes during 3 months of surveillance. With increasing age, there was a shift away from febrile malaria to acquiring asymptomatic parasitemia, with no change in the overall incidence of infection. Antibodies to the infected red cell surface were associated with acquiring asymptomatic infection rather than febrile malaria or remaining uninfected. Bed net use was associated with remaining uninfected rather than acquiring asymptomatic infection or febrile malaria. These observations suggest that most uninfected children were unexposed rather than "immune." Had they been immune, we would have expected the proportion of uninfected children to rise with age and that the uninfected children would have been distinguished from children with febrile malaria by the protective antibody response. We show that removing the less exposed children from conventional analyses clarifies the effects of immunity, transmission intensity, bed nets, and age. Observational studies and vaccine trials will have increased power if they differentiate between unexposed and immune children.

Following infection with Plasmodium falciparum malaria, children in endemic areas develop antibodies specific to antigens on the parasite-infected red cell surface of the infecting isolate, antibodies associated with protection against subsequent infection with that isolate. In some circumstances induction of antibodies to heterologous parasite isolates also occurs and this has been suggested as evidence for cross-reactivity of responses against the erythrocyte surface. The role of these relatively cross-reactive antibodies in protection from clinical malaria is currently unknown. We studied the incidence of clinical malaria amongst children living on the coast of Kenya through one high transmission season. By categorising individuals according to their pre-season parasite status and antibody response to the surface of erythrocytes infected with four parasite isolates we were able to identify a group of children, those who failed to make a concomitant antibody response in the presence of an asymptomatic parasitaemia, at increased susceptibility to clinical malaria in the subsequent 6 months. The fact that this susceptible group was identified regardless of the parasite isolate tested infers a cross-reactive or conserved target is present on the surface of infected erythrocytes. Identification of this target will significantly aid understanding of naturally acquired immunity to clinical malaria amongst children in endemic areas.

Background: It may be assumed that patterns of clinical malaria in children of similar age under the same level of exposure would follow a Poisson distribution with no over-dispersion. Longitudinal studies that have been conducted over many years suggest that some children may experience more episodes of clinical malaria than would be expected. The aim of this study was to identify this group of children and investigate possible causes for this increased susceptibility., Methodology and Principal Findings: Using Poisson regression, we chose a group of children whom we designated as 'more susceptible' to malaria from 373 children under 10 years of age who were followed up for between 3 to 5 years from 1998-2003. About 21% of the children were categorized as 'more susceptible' and although they contributed only 23% of the person-time of follow-up, they experienced 55% of total clinical malaria episodes. Children that were parasite negative at all cross-sectional survey were less likely to belong to this group [AOR = 0.09, (95% CI: 0.14-0.61), p = 0.001]., Conclusions and Significance: The pattern of clinical malaria episodes follows a negative binomial distribution. Use of lack of a clinical malaria episode in a certain time period as endpoints for intervention or immunological studies may not adequately distinguish groups who are more or less immune. It may be useful in such studies, in addition to the usual endpoint of the time to first episode, to include end points which take into account the total number of clinical episodes experienced per child.

Background: Data suggest that antibody responses to malaria parasites merozoite antigens are generally short-lived and this has implications for serological studies and malaria vaccine designs. However, precise data on the kinetics of these responses is lacking., Methods: IgG1 and IgG3 responses to five recombinant Plasmodium falciparum merozoite antigens (MSP-119, MSP-2 type A and B, AMA-1 ectodomain and EBA-175 region II) among Kenyan children were monitored using ELISA for 12 weeks after an acute episode of malaria and their half-lives estimated using an exponential decay model., Results: The responses peaked mainly at week 1 and then decayed rapidly to very low levels within 6 weeks. Estimation of the half-lives of 40 IgG1 responses yielded a mean half-life of 9.8 days (95% CI: 7.6-12.0) while for 16 IgG3 responses it was 6.1 days (95% CI: 3.7-8.4), periods that are shorter than those normally described for the catabolic half-life of these antibody subclasses., Conclusion: This study indicates antibodies against merozoite antigens have very short half-lives and this has to be taken into account when designing serological studies and vaccines based on the antigens.

Background: Variant surface antigens (VSA) on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria. We previously identified a VSA phenotype--VSA with a high frequency of antibody recognition (VSA(FoRH))--that is associated with young host age and severe malaria. We hypothesized that VSA(FoRH) are positively selected by host molecules such as intercellular adhesion molecule 1 (ICAM1) and CD36 and dominate in the absence of an effective immune response. Here, we assessed, in 115 Kenyan children, the potential role played by in vivo selection pressures in either favoring or selecting against VSA(FoRH) among parasites that cause malaria., Methods: We tested for associations between VSA(FoRH) and (1) the repertoire of VSA antibodies carried by children at the time of acute malaria and (2) polymorphisms in ICAM1 (K29M) and CD36 (T188G) that could potentially reduce the positive selection of VSA(FoRH)., Results: An expected negative association between VSA antibody repertoire and VSA(FoRH) was observed in children with nonsevere malaria. However, this association did not extend to children with severe malaria, many of whom apparently had well-developed VSA antibody responses despite being infected by parasites expressing VSA(FoRH). There was no evidence for involvement of CD36 or ICAM1 in positive selection of VSA(FoRH). On the contrary, a weak positive association between carriage of the CD36 (T188G) allele and VSA(FoRH) was observed in children with severe malaria., Conclusion: The association between the VSA(FoRH) parasite phenotype and severe malaria cannot be explained simply in terms of the total repertoire of VSA antibodies carried at the time of acute disease.

Objective: To develop a simulation model for dental arch shapes., Design: Analysis of measurements of dental casts to determine a general second degree equation for the dental arches., Setting: Department of Human Anatomy and School of Computing and Informatics, University of Nairobi., Subjects: The measurement of dental casts, 30 (15M and 15F) each from three Kenyan ethnic groups (Maasai, Kalenjin, Kikuyu), aged 12 years., Results: The arches change their shapes from a parabola to an ellipse, governed by the boundary conditions at the position of the canine tooth, based on the general second degree equation for the conic sections., Conclusion: The simulation model graphically confirms the change from parabolic to elliptic shapes of dental arches with boundary conditions at the canine. This could be used to show the changes in dental arches for other ethnic groups.

Erythrocytes infected with mature stages of Plasmodium falciparum express variant surface antigens (VSAs) of parasite origin, including P. falciparum erythrocyte membrane protein 1. Anti-VSA antibodies protect against clinical malaria caused by parasites bearing VSAs to which they are specific (homologous), but their role in protecting against heterologous infection is unclear. Here, we report that, among 256 Kenyan children involved in a 1-year active case surveillance study, asymptomatic parasitemia was associated with an enlarged repertoire of anti-VSA immunoglobulin G (IgG) antibodies specific to apparently heterologous parasite isolates, as measured by flow cytometry. Together, asymptomatic infection and anti-VSA IgG were associated with reduced odds of experiencing an episode of clinical malaria during follow-up, whereas, independently, they were associated with increased susceptibility. These results support previous findings and underline the importance of considering the parasitological status of study participants when examining the role that immune responses to VSAs and other malaria antigens play.

Mature stages of Plasmodium falciparum insert variant antigens (VSA) into the surface of infected erythrocytes, and antibodies against such antigen provide variant-specific protection against malaria. Because mature P. falciparum trophozoites normally sequester away from the peripheral circulation, parasites for anti-VSA antibody studies are obtained from patients as ring trophozoites, cryopreserved, and cultured to maturity when required. However, this process is associated with problems of poor recovery from cryopreservation, growth failure and variations in time different isolates take to mature after recovery. We therefore assessed the use of cryopreserved mature trophozoites in anti-VSA assays. Cryopreservation of parasites did not alter their anti-VSA antibody reactivity phenotype as determined by agglutination assays or flow cytometry. We have therefore demonstrated that cryopreserved mature trophozoites are suitable for use in anti-VSA antibody assays. The use of cryopreserved mature trophozoites could help to circumvent the problems associated with recovery of cryopreserved ring trophozoites., (Copyright 2004 Elsevier B.V.)

The kinetics of antibody responses to the Plasmodium falciparum malaria parasite-induced erythrocyte surface antigens (PIESAs) in 26 Kenyan children were examined by use of flow cytometry and agglutination assays. Although 19 of the 26 children mounted a primary antibody response to PIESAs within 2 weeks of experiencing an acute episode and maintained high antibody levels for at least 12 weeks, the remaining 7 children had responses that were weak and brief. Resistance to reparasitization was decreased in the children with short-lived responses. Isotype profiles of responses in 11 of the children studied suggest that they may have failed to switch to IgG after the initial IgM response. These data suggest that children vary widely in their ability to respond to PIESAs and that, in some individuals or with certain PIESA variants, short-lived antibody responses are induced that may be associated with poor antibody class switching.

We have studied the reversal of activity against Plasmodium falciparum of WR99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic acid (FA) and folinic acid (FNA). Folic acid and FNA inhibit the growth of P. falciparum in vitro at concentrations > 10(-4.5) and 10(-3.5) mol/L, respectively. The activity of pyrimethamine against Kenyan strains M24 and K39 is reduced 10-12-fold by 10(-5) mol/L of FA, and virtually eliminated by 10(-5) mol/L of FNA. Folates do not antagonise the action of WR99210 against Kenyan strains, and only partially antagonize the action of WR99210 action against the Southeast Asian strains V1/S and W282. Similarly, FA and FNA exerted weak or no antagonism of the action of PS-15. The inability of folates to antagonize the action of WR99210 can be explained in terms of high drug-enzyme affinity, but this does not account for the inability of FA and FNA to antagonize PS-15. These results suggest that action of PS-15 against P. falciparum is primarily due to a non-folate mechanism.

Aqueous and organic fractions from Cassia abbreviata, Senna petersiana (both Caesalpiniaceae) and Azanza garckeana (Malvaceae) were tested for in-vitro antimalarial activity against the multi-drug-resistant, Vietnam-Smith strain of Plasmodium falciparum; VI/S. Both roots and leaves from these Malawian medicinal plants were investigated. High activity, with a median inhibitory concentration < 3 micrograms/ml, was seen in the organic fractions of C. abbreviata and S. petersiana, the two species most commonly cited by traditional healers in an ethnobotanical investigation of Malawian antimalarials. Extracts of A. garckeana showed weaker activity. Biologically active compounds have thus been detected within species of the family Caesalpiniaceae. Ethnobotanical investigation appears to be useful in identifying plants with antimalarial activity.