Publications by authors named "Louise Marquart"

71 Publications

Analytical validation of a real-time hydrolysis probe PCR assay for quantifying Plasmodium falciparum parasites in experimentally infected human adults.

Malar J 2021 Apr 10;20(1):181. Epub 2021 Apr 10.

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: Volunteer infection studies have become a standard model for evaluating drug efficacy against Plasmodium infections. Molecular techniques such as qPCR are used in these studies due to their ability to provide robust and accurate estimates of parasitaemia at increased sensitivity compared to microscopy. The validity and reliability of assays need to be ensured when used to evaluate the efficacy of candidate drugs in clinical trials.

Methods: A previously described 18S rRNA gene qPCR assay for quantifying Plasmodium falciparum in blood samples was evaluated. Assay performance characteristics including analytical sensitivity, reportable range, precision, accuracy and specificity were assessed using experimental data and data compiled from phase 1 volunteer infection studies conducted between 2013 and 2019. Guidelines for validation of laboratory-developed molecular assays were followed.

Results: The reportable range was 1.50 to 6.50 log parasites/mL with a limit of detection of 2.045 log parasites/mL of whole blood based on a parasite diluted standard series over this range. The assay was highly reproducible with minimal intra-assay (SD = 0.456 quantification cycle (C) units [0.137 log parasites/mL] over 21 replicates) and inter-assay (SD = 0.604 C units [0.182 log parasites/mL] over 786 qPCR runs) variability. Through an external quality assurance program, the QIMR assay was shown to generate accurate results (quantitative bias + 0.019 log parasites/mL against nominal values). Specificity was 100% after assessing 164 parasite-free human blood samples.

Conclusions: The 18S rRNA gene qPCR assay is specific and highly reproducible and can provide reliable and accurate parasite quantification. The assay is considered fit for use in evaluating drug efficacy in malaria clinical trials.
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http://dx.doi.org/10.1186/s12936-021-03717-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035755PMC
April 2021

Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies.

Malar J 2021 Feb 16;20(1):93. Epub 2021 Feb 16.

QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Background: New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated.

Methods: The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated.

Results: The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR) using non-linear mixed effects modelling was 34.6 (95% CI 18.5-64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR of 11.5 [95% CI 8.5-15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61-4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16-4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study.

Conclusion: The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies.

Trial Registration: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN12619001079134.
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http://dx.doi.org/10.1186/s12936-021-03627-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885253PMC
February 2021

Parasite-Host Dynamics throughout Antimalarial Drug Development Stages Complicate the Translation of Parasite Clearance.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Swiss Tropical and Public Health Institute, Basel, Switzerland

Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage informing the design of the next stage of development. The validity of this approach depends on confidence that results from murine malarial studies predict the outcome of clinical trials in humans. Parasite clearance rates following treatment are key parameters of drug efficacy. To investigate the validity of forward predictions, we developed a suite of mathematical models to capture parasite growth and drug clearance along the drug development pathway and estimated parasite clearance rates. When comparing the three infection experiments, we identified different relationships of parasite clearance with dose and different maximum parasite clearance rates. In -NMRI mouse infections, we estimated a maximum parasite clearance rate of 0.2 (1/h); in -SCID mouse infections, 0.05 (1/h); and in human volunteer infection studies with , we found a maximum parasite clearance rate of 0.12 (1/h) and 0.18 (1/h) after treatment with OZ439 and MMV048, respectively. Sensitivity analysis revealed that host-parasite driven processes account for up to 25% of variance in parasite clearance for medium-high doses of antimalarials. Although there are limitations in translating parasite clearance rates across these experiments, they provide insight into characterizing key parameters of drug action and dose response and assist in decision-making regarding dosage for further drug development.
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http://dx.doi.org/10.1128/AAC.01539-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097426PMC
March 2021

Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease.

Clin Transl Gastroenterol 2020 12;11(12):e00274

Center for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.

Introduction: Celiac disease is an autoimmune disorder where intestinal immunopathology arises after gluten consumption. Previous studies suggested that hookworm infection restores gluten tolerance; however, these studies were small (n = 12) and not placebo controlled.

Methods: We undertook a randomized, placebo-controlled trial of hookworm infection in 54 people with celiac disease. The 94-week study involved treatment with either 20 or 40 Necator americanus third-stage larvae (L3-20 or L3-40) or placebo, followed by escalating gluten consumption (50 mg/d for 12 weeks, 1 g intermittent twice weekly for 12 weeks, 2 g/d sustained for 6 weeks, liberal diet for 1 year).

Results: Successful study completion rates at week 42 (primary outcome) were similar in each group (placebo: 57%, L3-20: 37%, and L3-40: 44%; P = 0.61), however gluten-related adverse events were significantly reduced in hookworm-treated participants: Median (range) adverse events/participant were as follows: placebo, 4 (1-9); L3-20, 1 (0-9); and L3-40, 0 (0-3) (P = 0.019). Duodenal villous height:crypt depth deteriorated similarly compared with their enrolment values in each group (mean change [95% confidence interval]: placebo, -0.6 [-1.3 to 0.2]; L3-20, -0.5 [-0.8 to 0.2]; and L3-40, -1.1 [-1.8 to 0.4]; P = 0.12). A retrospective analysis revealed that 9 of the 40 L3-treated participants failed to establish hookworm infections. Although week 42 completion rates were similar in hookworm-positive vs hookworm-negative participants (48% vs 44%, P = 0.43), quality of life symptom scores were lower in hookworm-positive participants after intermittent gluten challenge (mean [95% confidence interval]: 38.9 [33.9-44] vs 45.9 [39.2-52.6]).

Discussion: Hookworm infection does not restore tolerance to sustained moderate consumption of gluten (2 g/d) but was associated with improved symptom scores after intermittent consumption of lower, intermittent gluten doses.
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http://dx.doi.org/10.14309/ctg.0000000000000274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678792PMC
December 2020

Defining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage Plasmodium falciparum.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

Novartis Pharma AG, Basel, Switzerland.

The spiroindolone cipargamin, a new antimalarial compound that inhibits ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia and plasma cipargamin concentrations. Parasite regrowth was treated with piperaquine monotherapy to clear asexual parasites, while allowing gametocyte transmissibility to mosquitoes to be investigated. An initial rapid decrease in parasitemia occurred in all participants following cipargamin dosing, with a parasite clearance half-life of 3.99 h. As anticipated from the dose selected, parasite regrowth occurred in all 8 subjects 3 to 8 days after dosing and allowed the pharmacokinetic/pharmacodynamic relationship to be determined. Based on the limited data from the single subtherapeutic dose cohort, a MIC of 11.6 ng/ml and minimum parasiticidal concentration that achieves 90% of maximum effect of 23.5 ng/ml were estimated, and a single 95-mg dose (95% confidence interval [CI], 50 to 270) was predicted to clear 10 parasites/ml. Low gametocyte densities were detected in all subjects following piperaquine treatment, which did not transmit to mosquitoes. Serious adverse liver function changes were observed in three subjects, which led to premature study termination. The antimalarial activity characterized in this study supports the further clinical development of cipargamin as a new treatment for malaria, although the hepatic safety profile of the compound warrants further evaluation. (This study has been registered at ClinicalTrials.gov under identifier NCT02543086.).
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http://dx.doi.org/10.1128/AAC.01423-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849011PMC
January 2021

Omega-3 fatty acid intake and decreased risk of skin cancer in organ transplant recipients.

Eur J Nutr 2020 Sep 9. Epub 2020 Sep 9.

Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, Australia.

Purpose: Organ transplant recipients have over 100-fold higher risk of developing skin cancer than the general population and are in need of further preventive strategies. We assessed the possible preventive effects of omega-3 polyunsaturated fatty acid (PUFA) intake from food on the two main skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in kidney and liver transplant recipients.

Methods: Adult kidney or liver transplant recipients transplanted for at least 1 year and at high risk of skin cancer were recruited from the main transplant hospital in Queensland, 2012-2014 and followed until mid-2016. We estimated their dietary total long-chain omega-3 PUFAs and α-linolenic acid intakes at baseline using a food frequency questionnaire and ranked PUFA intakes as low, medium, or high. Relative risks (RRs) of skin cancer adjusted for confounding factors with 95% confidence intervals (CIs) were calculated.

Results: There were 449 transplant recipients (mean age, 55 years; 286 (64%) male). During follow-up, 149 (33%) patients developed SCC (median 2/person; range 1-40) and 134 (30%), BCC. Transplant recipients with high total long-chain omega-3 PUFA compared with low intakes showed substantially reduced SCC tumour risk (RR 0.33, 95% CI 0.18-0.60), and those with high α-linolenic acid intakes experienced significantly fewer BCCs (RR 0.40, 95% CI 0.22-0.74). No other significant associations were seen.

Conclusion: Among organ transplant recipients, relatively high intakes of long-chain omega-3 PUFAs and of α-linolenic acid may reduce risks of SCC and BCC, respectively.
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http://dx.doi.org/10.1007/s00394-020-02378-yDOI Listing
September 2020

Destructive and topical treatments of skin lesions in organ transplant recipients and relation to skin cancer.

Arch Dermatol Res 2020 Sep 5. Epub 2020 Sep 5.

Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Various treatments of keratotic skin lesions and early skin cancers are performed in organ transplant recipients (OTRs) at high risk of skin malignancies but the frequency of their use is unknown. We prospectively assessed the frequency of use of cryotherapy, diathermy, and topical therapies and also investigated their associations with background incidence of histologically-confirmed squamous-cell carcinoma (SCC) and basal cell carcinoma (BCC) in a cohort of OTRs in Queensland, Australia. Median follow-up ranged from 1.7 to 3.2 years across organ transplant groups. Among 285 kidney, 125 lung and 203 liver transplant recipients [382 (62%) male, 380 (62%) immunosuppressed > 5 years, 394 (64%) previously diagnosed with skin cancer], 306 (50%) reported treatment of skin lesions with major types of non-excision therapies during follow-up: 278 (45%) cryotherapy or diathermy; 121 (20%) topical treatments. Of these 306, 150 (49%) developed SCC at double the incidence of those who did not receive these treatments, as assessed by incidence rate ratio (IRR) adjusted for age, sex, type of organ transplant, skin color and history of skin cancer at baseline, calculated by multivariable Poisson regression (IRR = 2.1, 95% confidence interval (CI) 1.4-3.1). BCC incidence was not associated with these therapies. Skin lesions in OTRs that are treated with cryotherapy, diathermy, or topical treatment warrant judicious selection and careful follow-up.
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http://dx.doi.org/10.1007/s00403-020-02136-4DOI Listing
September 2020

Effect of Serotype and Strain Diversity on Dengue Virus Replication in Australian Mosquito Vectors.

Pathogens 2020 Aug 18;9(8). Epub 2020 Aug 18.

Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane 4000, Australia.

Dengue virus (DENV) is the most important mosquito-borne viral pathogen of humans, comprising four serotypes (DENV-1 to -4) with a myriad of genotypes and strains. The kinetics of DENV replication within the mosquito following ingestion of a blood meal influence the pathogen's ability to reach the salivary glands and thus the transmission potential. The influence of DENV serotype and strain diversity on virus kinetics in the two main vector species, and , has been poorly characterized. We tested whether DENV replication kinetics vary systematically among serotypes and strains, using Australian strains of the two vectors. Mosquitoes were blood fed with two strains per serotype, and sampled at 3, 6, 10 and 14-days post-exposure. Virus infection in mosquito bodies, and dissemination of virus to legs and wings, was detected using qRT-PCR. For both vectors, we found significant differences among serotypes in proportions of mosquitoes infected, with higher numbers for DENV-1 and -2 versus other serotypes. Consistent with this, we observed that DENV-1 and -2 generally replicated to higher RNA levels than other serotypes, particularly at earlier time points. There were no significant differences in either speed of infection or dissemination between the mosquito species. Our results suggest that DENV diversity may have important epidemiological consequences by influencing virus kinetics in mosquito vectors.
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http://dx.doi.org/10.3390/pathogens9080668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460537PMC
August 2020

Safety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: A pilot and a randomised volunteer infection study in Australia.

PLoS Med 2020 08 21;17(8):e1003203. Epub 2020 Aug 21.

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: Artemisinin resistance is threatening malaria control. We aimed to develop and test a human model of artemisinin-resistant (ART-R) Plasmodium falciparum to evaluate the efficacy of drugs against ART-R malaria.

Methods And Findings: We conducted 2 sequential phase 1, single-centre, open-label clinical trials at Q-Pharm, Brisbane, Australia, using the induced blood-stage malaria (IBSM) model, whereby healthy participants are intravenously inoculated with blood-stage parasites. In a pilot study, participants were inoculated (Day 0) with approximately 2,800 viable P. falciparum ART-R parasites. In a comparative study, participants were randomised to receive approximately 2,800 viable P. falciparum ART-R (Day 0) or artemisinin-sensitive (ART-S) parasites (Day 1). In both studies, participants were administered a single approximately 2 mg/kg oral dose of artesunate (AS; Day 9). Primary outcomes were safety, ART-R parasite infectivity, and parasite clearance. In the pilot study, 2 participants were enrolled between April 27, 2017, and September 12, 2017, and included in final analyses (males n = 2 [100%], mean age = 26 years [range, 23-28 years]). In the comparative study, 25 participants were enrolled between October 26, 2017, and October 18, 2018, of whom 22 were inoculated and included in final analyses (ART-R infected participants: males n = 7 [53.8%], median age = 22 years [range, 18-40 years]; ART-S infected participants: males n = 5 [55.6%], median age = 28 years [range, 22-35 years]). In both studies, all participants inoculated with ART-R parasites became parasitaemic. A total of 36 adverse events were reported in the pilot study and 277 in the comparative study. Common adverse events in both studies included headache, pyrexia, myalgia, nausea, and chills; none were serious. Seven participants experienced transient severe falls in white cell counts and/or elevations in liver transaminase levels which were considered related to malaria. Additionally, 2 participants developed ventricular extrasystoles that were attributed to unmasking of a predisposition to benign fever-induced tachyarrhythmia. In the comparative study, parasite clearance half-life after AS was significantly longer for ART-R infected participants (n = 13, 6.5 hours; 95% confidence interval [CI] 6.3-6.7 hours) compared with ART-S infected participants (n = 9, 3.2 hours; 95% CI 3.0-3.3 hours; p < 0.001). The main limitation of this study was that the ART-R and ART-S parasite strains did not share the same genetic background.

Conclusions: We developed the first (to our knowledge) human model of ART-R malaria. The delayed clearance profile of ART-R parasites after AS aligns with field study observations. Although based on a relatively small sample size, results indicate that this model can be safely used to assess new drugs against ART-R P. falciparum.

Trial Registration: The studies were registered with the Australian New Zealand Clinical Trials Registry: ACTRN12617000244303 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372357) and ACTRN12617001394336 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373637).
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http://dx.doi.org/10.1371/journal.pmed.1003203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444516PMC
August 2020

Liver Function Test Abnormalities in Experimental and Clinical Infection.

Am J Trop Med Hyg 2020 11;103(5):1910-1917

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human VISs where subjects were treated with chloroquine ( = 24) or artefenomel ( = 8) and compared them with studies in Thailand ( = 41) and Malaysia ( = 76). In the VISs, alanine transaminase (ALT) increased to ≥ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5-8 days post-treatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ≥ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26-14.59; = 0.02) for every log increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ≥ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91-27.47; = 0.06), this risk disappeared when corrected for PCB. Peak ALT also correlated with peak C-reactive protein ( = 0.44; = 0.012). Elevations in ALT (≥ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory.
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http://dx.doi.org/10.4269/ajtmh.20-0491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646782PMC
November 2020

Assays for quantification of male and female gametocytes in human blood by qRT-PCR in the absence of pure sex-specific gametocyte standards.

Malar J 2020 Jun 23;19(1):218. Epub 2020 Jun 23.

QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Background: Malaria transmission from humans to Anopheles mosquitoes requires the presence of gametocytes in human peripheral circulation, and the dynamics of transmission are determined largely by the density and sex ratio of the gametocytes. Molecular methods are thus employed to measure gametocyte densities, particularly when assessing transmission epidemiology and the efficacy of transmission-blocking interventions. However, accurate quantification of male and female gametocytes with molecular methods requires pure male and female gametocytes as reference standards, which are not widely available.

Methods: qRT-PCR assays were used to quantify levels of sex-specific mRNA transcripts in Plasmodium falciparum female and male gametocytes (pfs25 and pfMGET, respectively) using synthetic complimentary RNA standards and in vitro cultured gametocytes. Assays were validated and assay performance was investigated in blood samples of clinical trial participants using these standards and compared to absolute quantification by droplet digital PCR (ddPCR).

Results: The number of transcript copies per gametocyte were determined to be 279.3 (95% CI 253.5-307.6) for the female-specific transcript pfs25, and 12.5 (95% CI 10.6-14.9) for the male-specific transcript pfMGET. These numbers can be used to convert from transcript copies/mL to gametocyte/mL. The reportable range was determined to be 5.71 × 10 to 5.71 female gametocytes/mL for pfs25, and 1.73 × 10 to 1.73 × 10 male gametocytes/mL for pfMGET. The limit of detection was 3.9 (95% CI 2.5-8.2) female gametocytes/mL for pfs25, and 26.9 (95% CI 19.3-51.7) male gametocytes/mL for PfMGET. Both assays showed minimal intra-assay and inter-assay variability with coefficient of variation < 3%. No cross-reactivity was observed in both assays in uninfected human blood samples. Comparison of results from ddPCR to qRT-PCR assays on clinical blood samples indicated a high-level agreement (ICC = 0.998 for pfs25 and 0.995 for pfMGET).

Conclusions: This study reports the validation of qRT-PCR assays that are able to accurately quantify female and male P. falciparum gametocytes at sub-microscopic densities. The assays showed excellent reproducibility, sensitivity, precision, specificity, and accuracy. The methodology will enable the estimation of gametocyte density in the absence of pure female and male gametocyte standards, and will facilitate clinical trials and epidemiological studies.
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http://dx.doi.org/10.1186/s12936-020-03291-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310411PMC
June 2020

Antimalarial activity of artefenomel against asexual parasites and transmissible gametocytes during experimental blood-stage Plasmodium vivax infection.

J Infect Dis 2020 Jun 1. Epub 2020 Jun 1.

QIMR Berghofer Medical Research Institute, Herston QLD, Australia.

Background: Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterise the antimalarial activity of artefenomel, a new drug candidate.

Methods: Eight healthy, malaria-naïve participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200 mg dose of artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma artefenomel concentration. Mosquito feeding assays were conducted prior to artefenomel dosing to investigate parasite transmissibility.

Results: Initial parasite clearance occurred in all participants following artefenomel administration (log10 parasite reduction ratio over 48 hours 1.67; parasite clearance half-life 8.67 h). Recrudescence occurred in 7 participants 11-14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL was estimated, and a single 300 mg dose was predicted to clear 109 parasites/mL with 95% certainty. Gametocytemia developed in all participants and was cleared 4-8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes.

Conclusions: The in vivo antimalarial activity of artefenomel supports its further clinical development as a treatment for P. vivax malaria.
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http://dx.doi.org/10.1093/infdis/jiaa287DOI Listing
June 2020

Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study.

Clin Pharmacol Ther 2020 11 2;108(5):1055-1066. Epub 2020 Jul 2.

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with blood-stage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two-compartment model with first-order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half-lives were 32.7 hours (95% confidence interval (CI) 27.4-40.5) for plasma data and 24.1 hours (95% CI 19.0-32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14-20) and maximum parasite killing rate by chloroquine was 0.213 hour (95% CI 0.196-0.230), translating to a parasite clearance half-life of 4.5 hours (95% CI 4.1-5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI 320-500). This is the first study that characterized the PK/PD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semimechanistic population PK/PD modeling. This PK/PD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing.
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http://dx.doi.org/10.1002/cpt.1893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276750PMC
November 2020

A Phase 1, Placebo-controlled, Randomized, Single Ascending Dose Study and a Volunteer Infection Study to Characterize the Safety, Pharmacokinetics, and Antimalarial Activity of the Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048.

Clin Infect Dis 2020 12;71(10):e657-e664

Medicines for Malaria Venture, Geneva, Switzerland.

Background: MMV390048 is the first Plasmodium phosphatidylinositol 4-kinase inhibitor to reach clinical development as a new antimalarial. We aimed to characterize the safety, pharmacokinetics, and antimalarial activity of a tablet formulation of MMV390048.

Methods: A 2-part, phase 1 trial was conducted in healthy adults. Part 1 was a double-blind, randomized, placebo-controlled, single ascending dose study consisting of 3 cohorts (40, 80, 120 mg MMV390048). Part 2 was an open-label volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model consisting of 2 cohorts (40 mg and 80 mg MMV390048).

Results: Twenty four subjects were enrolled in part 1 (n = 8 per cohort, randomized 3:1 MMV390048:placebo) and 15 subjects were enrolled in part 2 (40 mg [n = 7] and 80 mg [n = 8] cohorts). One subject was withdrawn from part 2 (80 mg cohort) before dosing and was not included in analyses. No serious or severe adverse events were attributed to MMV390048. The rate of parasite clearance was greater in subjects administered 80 mg compared to those administered 40 mg (clearance half-life 5.5 hours [95% confidence interval {CI}, 5.2-6.0 hours] vs 6.4 hours [95% CI, 6.0-6.9 hours]; P = .005). Pharmacokinetic/pharmacodynamic modeling estimated a minimum inhibitory concentration of 83 ng/mL and a minimal parasiticidal concentration that would achieve 90% of the maximum effect of 238 ng/mL, and predicted that a single 120-mg dose would achieve an adequate clinical and parasitological response with 92% certainty.

Conclusions: The safety, pharmacokinetics, and pharmacodynamics of MMV390048 support its further development as a partner drug of a single-dose combination therapy for malaria.

Clinical Trials Registration: NCT02783820 (part 1); NCT02783833 (part 2).
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http://dx.doi.org/10.1093/cid/ciaa368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744986PMC
December 2020

A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers.

Antimicrob Agents Chemother 2019 12 20;64(1). Epub 2019 Dec 20.

Medicines for Malaria Venture, Meyrin, Switzerland

Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the -induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 ( = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 ( = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log parasite reduction ratios over 48 h [PRR] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.).
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http://dx.doi.org/10.1128/AAC.01371-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187626PMC
December 2019

Growth Rate of Plasmodium falciparum: Analysis of Parasite Growth Data From Malaria Volunteer Infection Studies.

J Infect Dis 2020 03;221(6):963-972

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Background: Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines.

Methods: We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hours (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration. We compared these parameters to those from studies conducted elsewhere with infections induced by IBSM (n = 66), sporozoites via mosquito bite (n = 336), or injection (n = 51).

Results: The parasite growth rate of 3D7 in QIMR Berghofer studies was 0.75/day (95% confidence interval [CI], .73-.77/day), PMR48 was 31.9 (95% CI, 28.7-35.4), PMRLC was 16.4 (95% CI, 15.1-17.8), and parasite life-cycle was 38.8 hours (95% CI, 38.3-39.2 hours). These parameters were similar to estimates from IBSM studies elsewhere (0.71/day, 95% CI, .67-.75/day; PMR48 26.6, 95% CI, 22.2-31.8) but significantly higher (P < .001) than in sporozoite studies (0.47/day, 95% CI, .43-.50/day; PMR48 8.6, 95% CI, 7.3-10.1).

Conclusions: Parasite growth rates were similar across different IBSM studies and higher than infections induced by sporozoite.
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http://dx.doi.org/10.1093/infdis/jiz557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198127PMC
March 2020

DNA extraction from placental, fetal and neonatal tissue at autopsy: what organ to sample for DNA in the genomic era?

Pathology 2019 Dec 18;51(7):705-710. Epub 2019 Oct 18.

Anatomical Pathology, Mater Health, South Brisbane, Qld, Australia.

Incorporation of genome and exome sequencing into fetal and neonatal autopsy investigations has been shown to improve diagnostic yield. This requires deoxyribonucleic acid (DNA) to be extracted from either the placenta or autopsy tissue for molecular testing. However, the sources and quality of DNA obtained are highly variable and there are no adequate published data on what tissue is most ideal to sample for DNA extraction in this setting. Here we compare the quality of DNA extracted from sampling the placenta and various solid organs at fetal and neonatal autopsy, thereby determining the optimal tissue from which to source DNA for ancillary testing as part of the modern perinatal autopsy. A total of 898 tissue samples were obtained at autopsy from 176 fetuses (gestational ages 17-40 weeks) and 44 neonates (age range 0-28 days) at our tertiary institution. Fetal tissue was processed using the QIAsymphony DSP DNA Mini kit and placental tissue was extracted using the New iGENatal Kit. DNA concentration was quantified using the Qubit dsDNA BR Assay Kit. DNA integrity, as stratified by gel electrophoresis was classified as high (≥5 kb) or low quality (<5 kb). Genome sequencing was performed on the extracted DNA, together with respective parental DNA from blood samples, and confirmed absence of maternal contamination in all cases. Analyses used logistic mixed models to test for associations between tissue types, intrauterine retention times, delivery to autopsy and death to autopsy intervals with DNA quality. In the fetal cohort, the placenta had the highest proportion of high quality DNA samples (93.1%), and liver had the lowest proportion (35.3%). Among the neonates, all tissue samples with the exception of liver had over 88% high DNA quality with the placenta also yielding the highest quality (100%). There was statistically significant deterioration in DNA quality with prolonged time interval between demise and autopsy (≥5 days). In the 726 fetal samples, the odds of obtaining higher quality DNA from the placenta, thymus, and spleen were 70.4 [95% confidence interval (CI) 29.2-169.6], 3.6 (95% CI 2.0-6.6) and 3.3 (95% CI 1.8-6.1) times, respectively, more likely than samples from the liver (p values <0.001). DNA yield from other fetal solid organs investigated was not significantly superior to that from the liver. This study shows that, when available, refrigerated unfixed placenta is the most suitable source of high quality DNA during perinatal investigations. Of the solid fetal organs sampled at autopsy, lymphocyte-rich, lytic enzymes-poor organs such as thymus and spleen were significantly more likely to yield good quality DNA than the liver.
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http://dx.doi.org/10.1016/j.pathol.2019.09.001DOI Listing
December 2019

A validation study of microscopy versus quantitative PCR for measuring parasitemia.

Trop Med Health 2019 27;47:49. Epub 2019 Aug 27.

1QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Microscopy and 18S qPCR are the most common and field-friendly methods for quantifying malaria parasite density, and it is important that these methods can be interpreted as giving equivalent results. We compared results of quantitative measurement of parasitemia by microscopy and by 18S qPCR in a phase 2a study. Microscopy positive samples ( = 355; median 810 parasites/μL [IQR 40-10,471]) showed close agreement with 18S qPCR in mean log/mL transformed parasitemia values by paired test (difference 0.04, 95%CI - 0.01-0.10,  = 0.088). Excellent intraclass correlation (0.97) and no evidence of systematic or proportional differences by Passing-Bablok regression were observed. 18S qPCR appears to give equivalent parasitemia values to microscopy, which indicates 18S qPCR is an appropriate alternative method to quantify parasitemia in clinical trials.
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http://dx.doi.org/10.1186/s41182-019-0176-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712708PMC
August 2019

DSM265 at 400 Milligrams Clears Asexual Stage Parasites but Not Mature Gametocytes from the Blood of Healthy Subjects Experimentally Infected with .

Antimicrob Agents Chemother 2019 04 27;63(4). Epub 2019 Mar 27.

QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

DSM265 is a novel antimalarial drug in clinical development that acts as a selective inhibitor of dihydroorotate dehydrogenase. In a previous phase 1b study, a single 150-mg dose of DSM265 showed partial efficacy against experimentally induced blood-stage malaria (IBSM). Pharmacokinetic/pharmacodynamic modeling predicted a human efficacious dose of 340 mg. The primary objectives of the current study were to determine the safety and efficacy of a single oral 400-mg dose of DSM265 against in the IBSM model. Eight healthy participants were inoculated intravenously with 2,800 parasites and treated with DSM265 7 days later. Unexpectedly, one participant did not develop parasitemia during the study. All other participants developed parasitemia, with the complete clearance of asexual parasites occurring following DSM265 treatment. All seven subjects also became gametocytemic. The secondary objectives were to investigate the gametocytocidal and transmission-blocking activity of a second 400-mg dose of DSM265, which was administered 23 days after inoculation. Gametocytes were not cleared by the second dose of DSM265, and transmission-blocking activity could not be determined due to low gametocyte densities. Three DSM265-related adverse events occurred, including a cutaneous rash in one subject on the day of the second DSM265 dose. The results obtained in this study support the prediction of the efficacious dose of DSM265 and provide further evidence that DSM265 is generally safe and well tolerated. In addition, this study confirms preclinical data indicating that DSM265 permits the development and maturation of gametocytes and does not clear mature circulating gametocytes. (This study has been registered at ClinicalTrials.gov under identifier NCT02573857.).
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http://dx.doi.org/10.1128/AAC.01837-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437518PMC
April 2019

A Randomized Trial of Baby Triple P for Preterm Infants: Child Outcomes at 2 Years of Corrected Age.

J Pediatr 2019 07 8;210:48-54.e2. Epub 2019 Mar 8.

The Parenting and Family Support Center, School of Psychology, Faculty of Health and Behavioral Sciences, The University of Queensland, Brisbane, Australia.

Objective: To determine the efficacy of a hospital-based intervention that transitions into existing community support, in enhancing developmental outcomes at 2 years of corrected age in infants born at less than 32 weeks.

Study Design: In total, 323 families of 384 infants born <32 weeks were randomized to receive intervention or care-as-usual. The intervention teaches parents coping skills, partner support, and effective parenting strategies over 4 hospital-based and 4 home-phone sessions. At 2 years of corrected age maternally reported child behavior was assessed by the Infant and Toddler Social Emotional Adjustment Scale. Observed child behavior was coded with the Revised Family Observation Schedule. Cognitive, language, and motor skills were assessed with the Bayley Scales of Infant and Toddler Development III.

Results: Mean gestational age of infants was 28.5 weeks (SD = 2.1), and mothers' mean age was 30.6 years (SD = 5.8). A total of 162 families (n = 196 infants) were allocated to intervention and 161 families (n = 188 infants) received care-as-usual. There was no significant adjusted difference between treatment groups on dysregulation (0.2; 95% CI -2.5 to 3.0, P = .9) externalizing (0.3; 95% CI -1.6 to 2.2, P = .8), internalizing (-1.5; 95% CI -4.3 to 1.3, P = .3), observed aversive (0.00; -0.04 to 0.04, P = .9), or nonaversive behavior (-0.01; 95% CI -0.05 to 0.03, P = .7). Intervention children scored significantly higher on cognition (3.5; 95% CI 0.2-6.8, P = .04) and motor skill (5.5; 95% CI 2.5-8.4, P < .001), and approached significance on language (3.8; 95% CI -0.3 to 7.9, P = .07).

Conclusions: Baby Triple P for Preterm Infants increases cognitive and motor skills but does not impact behavior. The results are evidence that hospital-based interventions can improve some developmental outcomes for infants <32 weeks.

Trial Registration: ACTRN 12612000194864.
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http://dx.doi.org/10.1016/j.jpeds.2019.01.024DOI Listing
July 2019

An Experimental Human Blood-Stage Model for Studying Plasmodium malariae Infection.

J Infect Dis 2020 03;221(6):948-955

QIMR Berghofer Medical Research Institute.

Background: Plasmodium malariae is considered a minor malaria parasite, although its global disease burden is underappreciated. The aim of this study was to develop an induced blood-stage malaria (IBSM) model of P. malariae to study parasite biology, diagnostic assays, and treatment.

Methods: This clinical trial involved 2 healthy subjects who were intravenously inoculated with cryopreserved P. malariae-infected erythrocytes. Subjects were treated with artemether-lumefantrine after development of clinical symptoms. Prior to antimalarial therapy, mosquito-feeding assays were performed to investigate transmission, and blood samples were collected for rapid diagnostic testing and parasite transcription profiling. Serial blood samples were collected for biomarker analysis.

Results: Both subjects experienced symptoms and signs typical of early malaria. Parasitemia was detected 7 days after inoculation, and parasite concentrations increased until antimalarial treatment was initiated 25 and 21 days after inoculation for subjects 1 and 2 respectively (peak parasitemia levels, 174 182 and 50 291 parasites/mL, respectively). The parasite clearance half-life following artemether-lumefantrine treatment was 6.7 hours. Mosquito transmission was observed for 1 subject, while in vivo parasite transcription and biomarkers were successfully profiled.

Conclusions: An IBSM model of P. malariae has been successfully developed and may be used to study the biology of, diagnostic testing for, and treatment of this neglected malaria species.

Clinical Trials Registration: ACTRN12617000048381.
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http://dx.doi.org/10.1093/infdis/jiz102DOI Listing
March 2020

Serum MicroRNAs as Biomarkers in Hepatitis C: Preliminary Evidence of a MicroRNA Panel for the Diagnosis of Hepatocellular Carcinoma.

Int J Mol Sci 2019 Feb 17;20(4). Epub 2019 Feb 17.

Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.

Early diagnosis of cirrhosis and hepatocellular carcinoma (HCC) due to chronic Hepatitis C (CHC) remain clinical priorities. In this pilot study, we assessed serum microRNA (miRNA) expression to distinguish cirrhosis and HCC, alone and in combination with the aminotransferase-to-platelet ratio (APRI), Fibrosis 4 (FIB-4), and alpha-fetoprotein (AFP). Sixty CHC patients were subdivided into 3 cohorts: Mild disease (fibrosis stage F0-2; = 20); cirrhosis ( = 20); and cirrhosis with HCC ( = 20). Circulating miRNA signatures were determined using a liver-specific real-time quantitative reverse transcription PCR (qRT-PCR) microarray assessing 372 miRNAs simultaneously. Differentially-expressed miRNA candidates were independently validated using qRT-PCR. Serum miRNA-409-3p was increased in cirrhosis versus mild disease. In HCC versus cirrhosis, miRNA-486-5p was increased, whereas miRNA-122-5p and miRNA-151a-5p were decreased. A logistic regression model-generated panel, consisting of miRNA-122-5p + miRNA-409-3p, distinguished cirrhosis from mild disease (area under the curve, AUC = 0.80; sensitivity = 85%, specificity = 70%; < 0.001). When combined with FIB-4 or APRI, performance was improved with AUC = 0.89 ( < 0.001) and 0.87 ( < 0.001), respectively. A panel consisting of miRNA-122-5p + miRNA-486-5p + miRNA-142-3p distinguished HCC from cirrhosis (AUC = 0.94; sensitivity = 80%, specificity = 95%; < 0.001), outperforming AFP (AUC = 0.64, = 0.065). Serum miRNAs are differentially expressed across the spectrum of disease severity in CHC. MicroRNAs have great potential as diagnostic biomarkers in CHC, particularly in HCC where they outperform the only currently-used biomarker, AFP.
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http://dx.doi.org/10.3390/ijms20040864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412219PMC
February 2019

Blood Schizonticidal Activity and Safety of Tafenoquine When Administered as Chemoprophylaxis to Healthy, Nonimmune Participants Followed by Blood Stage Plasmodium falciparum Challenge: A Randomized, Double-blind, Placebo-controlled Phase 1b Study.

Clin Infect Dis 2019 07;69(3):480-486

60P Australia Pty Ltd, Sydney, New South Wales.

Background: Tafenoquine was recently approved for chemoprophylaxis of malaria. Its specific activity against liver and blood stages of Plasmodium species has been separately characterized in animals but not in humans.

Methods: In this randomized, double-blind, placebo-controlled study, 16 malaria-naive, glucose-6-phosphate dehydrogenase-normal participants aged 20-42 years received tafenoquine chemoprophylaxis prior to challenge with blood stage Plasmodium falciparum. Participants were randomly assigned to either tafenoquine (n = 12) or placebo (n = 4) and took blinded study medication (single 200-mg dose) on days 1, 2, 3, and 10, followed by intravenous inoculation with approximately 2800 P. falciparum parasitized erythrocytes on day 13. The primary endpoint was the number of participants requiring rescue treatment with artemether/lumefantrine due to the onset of parasitemia as determined by quantitative polymerase chain reaction.

Results: None of the 12 participants who received tafenoquine developed parasitemia, whereas all placebo participants developed parasitemia (P = .0005). Two cases of mild hemoglobin decrease and a single case of mild hyperbilirubinemia occurred in the tafenoquine group.

Conclusions: Tafenoquine chemoprophylaxis is safe and effective in preventing malaria in healthy nonimmune participants challenged with blood stage P. falciparum.

Clinical Trials Registration: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12617000102370.
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http://dx.doi.org/10.1093/cid/ciy939DOI Listing
July 2019

PREDICTING ATTENDANCE OF A PREVENTIVE PARENTING INTERVENTION FOR VERY PRETERM INFANTS.

Infant Ment Health J 2018 11 19;39(6):699-706. Epub 2018 Oct 19.

University of Queensland and Royal Brisbane and Women's Hospital.

Preventive parenting interventions can experience challenges in maximizing dosage, or the amount of intervention received by parents. This study examined the associations of baseline mother, father, and very preterm infant (VPT; <32 weeks) characteristics with satisfactory intervention attendance of the family within a randomized controlled trial of Baby Triple P for Preterm Infants (Colditz et al., 2015). Mothers (n = 160) and fathers (n = 115) completed questionnaires prior to the randomization of family units (n = 160) to receive the intervention. Satisfactory session attendance (seven or eight sessions of eight in total) was achieved by 114 families (71.25%). In the logistic model for mothers, satisfactory attendance of the family was more likely when infants were extremely low birth weight (ELBW), odds ratio (OR) = 2.81, 95% confidence interval (CI) [1.16, 6.80], when the mother had a university, OR = 11.38, 95% CI [4.03, 32.19], or trade-certificate-level education, OR = 4.97, 95% CI [1.93, 12.84], or when she was not under financial stress, OR = 3.53, 95% CI [1.34, 9.28]. A similar pattern of results was found in the model for fathers. Session attendance of preventive parenting interventions for VPT infants may be improved by increasing the engagement of parents with infants not born ELBW, who have lower education, or are experiencing financial stress.
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http://dx.doi.org/10.1002/imhj.21749DOI Listing
November 2018

Increased maternal abdominal subcutaneous fat thickness and body mass index are associated with increased cesarean delivery: A prospective cohort study.

Acta Obstet Gynecol Scand 2019 02 15;98(2):196-204. Epub 2018 Nov 15.

Statistics Unit, Queensland Institute of Medical Research Berghofer, Herston, Queensland, Australia.

Introduction: Early pregnancy body mass index (BMI) is known to predict adverse pregnancy outcomes but does not account for body fat distribution. This study aimed to determine prospectively whether maternal abdominal subcutaneous fat thickness (SCFT) measured by ultrasound at the fetal morphology scan is a better predictor than BMI of mode of delivery and other pregnancy outcomes.

Material And Methods: This was a prospective cohort study of women delivering singleton neonates at a tertiary public hospital. Women were included if they had appropriate images at the routine fetal anomaly ultrasound scan and delivered in the facility. The primary outcome was mode of delivery categorized as cesarean section or vaginal delivery. The relation between maternal SCFT and BMI was described using the Pearson correlation coefficient. The association of maternal abdominal SCFT BMI at booking-in was compared with pregnancy outcomes using univariate linear and logistic regression.

Results: SCFT and BMI were obtained for 997 women. The median (interquartile range) SCFT was 15.3 mm (12.8-19.6) and median (interquartile range) BMI 24.3 kg/m (21.7-28.3). Maternal abdominal SCFT and BMI were highly correlated (R = 0.55). Both were significantly associated with cesarean delivery: SCFT per 5 mm (odds ratio [OR] 1.32, 95% confidence interval (CI) 1.18-1.48; BMI per 5 kg/m OR 1.29, 95% CI 1.15-1.44.

Conclusions: Maternal abdominal SCFT and BMI were both significantly associated with cesarean delivery and other outcomes. More research is needed to define the strengths of maternal SCFT in predicting pregnancy outcomes.
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http://dx.doi.org/10.1111/aogs.13486DOI Listing
February 2019

Correction: Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.

Eur J Hum Genet 2019 01;27(1):167-168

Department of Medicine, Cancer Biology and Genetics, Clinical Genetics Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

This Article was originally published under a CC BY-NC-SA 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
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http://dx.doi.org/10.1038/s41431-018-0216-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303246PMC
January 2019

Evaluation of safety and immunogenicity of a group A streptococcus vaccine candidate (MJ8VAX) in a randomized clinical trial.

PLoS One 2018 2;13(7):e0198658. Epub 2018 Jul 2.

The Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia.

Background: Group A streptococcus (GAS) is a serious human pathogen that affects people of different ages and socio-economic levels. Although vaccination is potentially one of the most effective methods to control GAS infection and its sequelae, few prototype vaccines have been investigated in humans. In this study, we report the safety and immunogenicity of a novel acetylated peptide-protein conjugate vaccine candidate MJ8VAX (J8-DT), when delivered intramuscularly to healthy adults.

Methods: A randomized, double-blinded, controlled Phase I clinical trial was conducted in 10 healthy adult participants. Participants were randomized 4:1 to receive the vaccine candidate (N = 8) or placebo (N = 2). A single dose of the vaccine candidate (MJ8VAX), contained 50 μg of peptide conjugate (J8-DT) adsorbed onto aluminium hydroxide and re-suspended in PBS in a total volume of 0.5 mL. Safety of the vaccine candidate was assessed by monitoring local and systemic adverse reactions following intramuscular administration. The immunogenicity of the vaccine was assessed by measuring the levels of peptide (anti-J8) and toxoid carrier (anti-DT)-specific antibodies in serum samples.

Results: No serious adverse events were reported over 12 months of study. A total of 13 adverse events (AEs) were recorded, two of which were assessed to be associated with the vaccine. Both were mild in severity. No local reactogenicity was recorded in any of the participants. MJ8VAX was shown to be immunogenic, with increase in vaccine-specific antibodies in the participants who received the vaccine. The maximum level of vaccine-specific antibodies was detected at 28 days post immunization. The level of these antibodies decreased with time during follow-up. Participants who received the vaccine also had a corresponding increase in anti-DT serum antibodies.

Conclusions: Intramuscular administration of MJ8VAX was demonstrated to be safe and immunogenic. The presence of DT in the vaccine formulation resulted in a boost in the level of anti-DT antibodies.

Trial Registration: ACTRN12613000030774.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198658PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028081PMC
December 2018

Depression, posttraumatic stress and relationship distress in parents of very preterm infants.

Arch Womens Ment Health 2018 08 3;21(4):445-451. Epub 2018 Mar 3.

Mater Mothers' Hospital, Brisbane, Australia.

To determine the prevalence, associated factors, and relationships between symptoms of depression, symptoms of posttraumatic stress (PTS), and relationship distress in mothers and fathers of very preterm (VPT) infants (< 32 weeks). Mothers (n = 323) and fathers (n = 237) completed self-report measures on demographic and outcome variables at 38 days (SD = 23.1, range 9-116) postpartum while their infants were still hospitalised. Of mothers, 46.7% had a moderate to high likelihood of depression, 38.1% had moderate to severe symptoms of PTS, and 25.1% were in higher than average relationship distress. The corresponding percentages in fathers were 16.9, 23.7, and 27%. Depression was positively associated with having previous children (p = 0.01), speaking little or no English at home (p = 0.01), financial stress (p = 0.03), and recently accessing mental health services (p = 0.003) for mothers, and financial stress (p = 0.005) and not being the primary income earner (p = 0.04) for fathers. Similar associations were found for symptoms of PTS and relationship distress. Being in higher relationship distress increased the risk of depression in both mothers (p < .001) and fathers (p = 0.03), and PTS symptoms in mothers (p = 0.001). For both mothers and fathers, depression was associated with more severe PTS symptoms (p < .001). Fathers of VPT infants should be screened for mental health problems alongside mothers, and postpartum parent support programs for VPT infants should include strategies to improve the couple relationship.
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http://dx.doi.org/10.1007/s00737-018-0821-6DOI Listing
August 2018

Incidence and Regression of Actinic Keratoses in Organ Transplant Recipients.

Acta Derm Venereol 2018 Jan;98(1):77-81

Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Locked Bag 2000 Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia. E-mail:

Actinic keratoses (AKs) are highly dynamic lesions and AK activity has been shown to be associated with squamous cell carcinoma (SCC). We sought to explore risk factors which may affect the 12-month turnover of AKs in organ transplant recipients (OTRs). The number of incident AKs, regressed AKs and net change in AK counts were calculated. Negative binomial regression and Poisson regression models were used to estimate rate ratios (RR) for these 3 outcomes. Among 150 renal and 89 liver OTRs, those who spent > 50% of a typical weekday in the sun had a lower rate of AK regression than those who spent minimal time in the sun during a typical weekday. Age, parents' country of origin, hair colour, skin cancer history and recent AK treatment were all significantly associated with AK turnover. Clinically, these risk factors may be used to monitor OTRs at increased risk of SCC.
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http://dx.doi.org/10.2340/00015555-2783DOI Listing
January 2018