95 research outputs found
Uncomplicated and severe malaria numbers, and incidence of severe malaria, by infecting <i>Plasmodium</i> species from a longitudinal surveillance study of 264 children followed over 17 months in neighbouring East Sepik Province.
No full text<p>Data are from Lin <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029203#pone.0029203-Lin1" target="_blank">[32]</a>.</p><p>*Single or mixed infections with <i>P. malariae</i> or <i>P. ovale</i>;</p>¶<p>(95% confidence intervals);</p>†<p><i>P</i><0.05 vs <i>P. vivax</i>.</p
A high force of Plasmodium vivax blood-stage infection drives the rapid acquisition of immunity in Papua New Guinean children
No full textWhen both parasite species are co-endemic, Plasmodium vivax incidence peaks in younger children compared to P. falciparum. To identify differences in the number of blood stage infections of these species and its potential link to acquisition of immunity, we have estimated the molecular force of blood-stage infection of P. vivax (molFOB, i.e. the number of genetically distinct blood-stage infections over time), and compared it to previously reported values for P. falciparum.; P. vivax molFOB was estimated by high resolution genotyping parasites in samples collected over 16 months in a cohort of 264 Papua New Guinean children living in an area highly endemic for P. falciparum and P. vivax. In this cohort, P. vivax episodes decreased three-fold over the age range of 1-4.5 years.; On average, children acquired 14.0 new P. vivax blood-stage clones/child/year-at-risk. While the incidence of clinical P. vivax illness was strongly associated with mol FOB (incidence rate ratio (IRR) = 1.99, 95% confidence interval (CI95) [1.80, 2.19]), molFOB did not change with age. The incidence of P. vivax showed a faster decrease with age in children with high (IRR = 0.49, CI95 [0.38, 0.64] p>0.001) compared to those with low exposure (IRR = 0.63, CI95[0.43, 0.93] p = 0.02).; P. vivax molFOB is considerably higher than P. falciparum molFOB (5.5 clones/child/year-at-risk). The high number of P. vivax clones that infect children in early childhood contribute to the rapid acquisition of immunity against clinical P. vivax malaria
The Global Kidney Patient Trials Network and the CAPTIVATE Platform Clinical Trial Design:A Trial Protocol
No full textImportance: Chronic kidney disease (CKD) is a global health priority affecting almost 1 billion people. New therapeutic options and clinical trial innovations such as adaptive platform trials provide an opportunity to efficiently test combination therapies. Objective: To describe the design and baseline results of the Global Kidney Patient Trials Network (GKPTN) and the design and structure of the global adaptive platform clinical trial Chronic Kidney Disease Adaptive Platform Trial Investigating Various Agents for Therapeutic Effect (CAPTIVATE) to find new therapeutic options and treatments for people with kidney disease. Design, Setting, and Participants: The GKPTN is a multicenter registry that started in May 2020 and is ongoing, while CAPTIVATE is a multicenter, multifactorial, phase 3, placebo-controlled adaptive platform randomized clinical trial that includes patients with CKD. The first participant was randomized in September 2024. The GKPTN recruits patients from kidney and endocrinology practices, and CAPTIVATE aims to recruit patients from GKPTN sites where possible. Both the GKPTN and CAPTIVATE recruit patients with nondialysis CKD. Intervention: CAPTIVATE will test several investigational agents or combinations of agents, beginning with a mineralocorticoid receptor antagonist. Main Outcomes and Measures: The GKPTN monitors clinical characteristics, treatment, and outcomes to identify eligible clinical trial participants and provide a contemporary global picture of patients with CKD. The primary outcome of CAPTIVATE is to identify investigational agents or combinations of agents to reduce the rate of chronic estimated glomerular filtration rate (eGFR) decline. The default maximum sample size per treatment arm in each domain, based on bayesian simulations, is 500 participants, providing approximately 90% power to detect a clinically meaningful improvement of 2.6 mL/min/1.73 m2 in eGFR at the end of the 104-week study period. Results: The GKPTN has enrolled 4334 patients across 119 sites in 8 countries (US, Australia, Argentina, China, Italy, Canada, Spain, and Japan). The mean (SD) participant age at enrollment was 64.5 (16.2) years, 2542 participants (58.7%) were female, and diabetic kidney disease was most frequently reported among patients for CKD etiology (1875 [43.3%]). Among the participants, the mean (SD) eGFR was 52.9 (29.3) mL/min/1.73 m2, and the median urinary albumin-to-creatinine ratio was 89 mg/g (coefficient of variation, 20-420 mg/g). In the GKPTN cohort, the mean eGFR decline was steeper among participants with a baseline eGFR of 60 mL/min/1.73 m2 or more (-2.29 [95% CI, -3.14 to -1.44]) compared with those with an eGFR of less than 60 mL/min/1.73 m2 (-1.16 [95% CI, -1.77 to -1.44]) and was progressively steeper in more severe albuminuria subgroups. Conclusions and Relevance: The GKPTN registry and the CAPTIVATE trial have the potential to expand and optimize therapeutic options for people with CKD using an adaptive platform clinical trial design. Trial Registration: ClinicalTrials.gov Identifiers: NCT04389827 and NCT06058585.</p
Lung, breast and bowel cancer treatment for Aboriginal people in New South Wales: a population‐based cohort study
No full textBACKGROUND:Aboriginal Australians have higher cancer mortality than non-Aboriginal Australians. Lower rates of cancer treatment among Aboriginal people can contribute to this. AIMS:To investigate demographic, clinical and access factors associated with lung, breast, and bowel cancer treatment for Aboriginal people compared with non-Aboriginal people in New South Wales, Australia. METHODS:Population-based cohort study using linked routinely-collected datasets, including all diagnoses of primary lung, breast, or bowel cancer from January 2009-June 2012. Treatment (surgery, radiotherapy, or chemotherapy) within six months from diagnosis was measured. Access was measured using minimum distance to radiotherapy or hospital with a cancer-specific multidisciplinary team, visit to a specialist, and possession of private health insurance. Logistic regression modelling was employed. RESULTS:There were 587 Aboriginal and 34 015 non-Aboriginal people diagnosed with cancer. For lung cancer, significantly fewer Aboriginal than non-Aboriginal people received surgery (odds ratio (OR) 0.46 (95% confidence interval (CI) 0.29-0.73, p < 0.001)) or any treatment (surgery, chemotherapy or radiotherapy; OR 0.64, 95% CI 0.47-0.88, p = 0.006) after adjusting for sex, age, disease extent and comorbidities. They were less likely to have an attendance with a surgeon (27.0%, 62/230 v 33.3%, 2865/8597, p = 0.04) compared with non-Aboriginal people. There were no significant differences in cancer treatment for Aboriginal people compared with non-Aboriginal people for breast or bowel cancers after adjusting for patient sex, age, disease extent and comorbidities. CONCLUSION:Aboriginal people were significantly less likely to receive surgery for lung cancer than non-Aboriginal people and had fewer attendances with a surgeon, suggesting a need to strengthen referral pathways. This article is protected by copyright. All rights reserved
Comparison of Plasmodium falciparum allelic frequency distribution in different endemic settings by high-resolution genotyping
No full textBACKGROUND: The diversity of genotyping markers of Plasmodium falciparum depends on transmission intensity. It has been reported that the diversity of the merozoite surface protein 2 (msp2) is greater in areas of high compared to low endemicity, however, results for msp1 were inconsistent. These previous reports relied on low resolution genotyping techniques. METHODS: In the present study, a high-resolution capillary electrophoresis-based technique was applied to genotype samples from areas of different endemicity in Papua New Guinea and Tanzania. For both endemic settings, the diversity of msp1 and msp2 was investigated; the mean multiplicity of infection (MOI) and the FST values were determined to investigate whether more accurate sizing generates different results. RESULTS AND CONCLUSION: The results of the present study confirmed previous reports of a higher mean MOI for both marker genes and increased genetic diversity in areas of higher endemicity as estimated by the total number of distinct alleles for msp2. For msp1 a minor increase in diversity was observed. Measures of between population variance in allele frequencies (FST) indicated little genetic differentiation for both marker genes between the two populations from different endemic settings. MOI adjusted for the probability of multiple infections sharing the same allele was estimated by using the msp2 allele frequency distribution and the distribution of observed numbers of concurrent infections. For the high-resolution typing technique applied in this study, this adjustment made little difference to the estimated mean MOI compared to the observed mean MO
Naturally acquired immune responses to P. vivax merozoite surface protein 3α and merozoite surface protein 9 are associated with reduced risk of P. vivax malaria in young Papua New Guinean children
No full textPlasmodium vivax is the most geographically widespread human malaria parasite. Cohort studies in Papua New Guinea have identified a rapid onset of immunity against vivax-malaria in children living in highly endemic areas. Although numerous P. vivax merozoite antigens are targets of naturally acquired antibodies, the role of many of these antibodies in protective immunity is yet unknown.; In a cohort of children aged 1-3 years, antibodies to different regions of Merozoite Surface Protein 3α (PvMSP3α) and Merozoite Surface Protein 9 (PvMSP9) were measured and related to prospective risk of P. vivax malaria during 16 months of active follow-up. Overall, there was a low prevalence of antibodies to PvMSP3α and PvMSP9 proteins (9-65%). Antibodies to the PvMSP3α N-terminal, Block I and Block II regions increased significantly with age while antibodies to the PvMSP3α Block I and PvMSP9 N-terminal regions were positively associated with concurrent P. vivax infection. Independent of exposure (defined as the number of genetically distinct blood-stage infection acquired over time (molFOB)) and age, antibodies specific to both PvMSP3α Block II (adjusted incidence ratio (aIRR) = 0.59, p = 0.011) and PvMSP9 N-terminus (aIRR = 0.68, p = 0.035) were associated with protection against clinical P. vivax malaria. This protection was most pronounced against high-density infections. For PvMSP3α Block II, the effect was stronger with higher levels of antibodies.; These results indicate that PvMSP3α Block II and PvMSP9 N-terminus should be further investigated for their potential as P. vivax vaccine antigens. Controlling for molFOB assures that the observed associations are not confounded by individual differences in exposure
Author response: Identification of highly-protective combinations of Plasmodium vivax recombinant proteins for vaccine development
No full textMinimal Association of Common Red Blood Cell Polymorphisms with Plasmodium falciparum Infection and Uncomplicated Malaria in Papua New Guinean School Children
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Plasmodium vivax Reticulocyte Binding Proteins Are Key Targets of Naturally Acquired Immunity in Young Papua New Guinean Children
No full textBackground: Major gaps in our understanding of Plasmodium vivax biology and the acquisition of immunity to this parasite hinder vaccine development. P. vivax merozoites exclusively invade reticulocytes, making parasite proteins that mediate reticulocyte binding and/or invasion potential key vaccine or drug targets. While protein interactions that mediate invasion are still poorly understood, the P. vivax Reticulocyte-Binding Protein family (PvRBP) is thought to be involved in P. vivax restricted host-cell selectivity. Methodology/Principal findings: We assessed the binding specificity of five members of the PvRBP family (PvRBP1a, PvRBP1b, PvRBP2a, PvRBP2b, PvRBP2-P2 and a non-binding fragment of PvRBP2c) to normocytes or reticulocytes. PvRBP2b was identified as the only reticulocyte-specific binder (P<0.001), whereas the others preferentially bound to normocytes (PvRBP1a/b P≤0.034), or showed comparable binding to both (PvRBP2a/2-P2, P = 0.38). Furthermore, we measured levels of total and IgG subclasses 1, 2, 3 and 4 to the six PvRBPs in a cohort of young Papua New Guinean children, and assessed their relationship with prospective risk of P. vivax malaria. Children had substantial, highly correlated (rho = 0.49–0.82, P<0.001) antibody levels to all six PvRBPs, with dominant IgG1 and IgG3 subclasses. Both total IgG (Incidence Rate Ratio [IRR] 0.63–0.73, P = 0.008–0.041) and IgG1 (IRR 0.56–0.69, P = 0.001–0.035) to PvRBP2b and PvRBP1a were strongly associated with reduced risk of vivax-malaria, independently of age and exposure. Conclusion/Significance: These results demonstrate a diversity of erythrocyte-binding phenotypes of PvRBPs, indicating binding to both reticulocyte-specific and normocyte-specific ligands. Our findings provide further insights into the naturally acquired immunity to P. vivax and highlight the importance of PvRBP proteins as targets of naturally acquired humoral immunity. In-depth studies of the role of PvRBPs in P. vivax invasion and functional validation of the role of anti-PvRBP antibodies in clinical immunity against P. vivax are now required to confirm the potential of the reticulocyte-binding PvRBP2b and PvRBP1a as vaccine candidate antigens.Version of Recor
Seasonality of <i>P.</i><i>vivax</i> clinical episodes (as compared to the first week of January, where incidence peaked) excluding <sub>mol</sub>FOB (blue) and adjusted for <sub>mol</sub>FOB (red).
No full text<p><sub>mol</sub>FOB accounts for approximately 50% of the seasonal variation in incidence. IRR = incidence rate ratio.</p
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