Publications by authors named "James McCarthy"

614 Publications

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

N Engl J Med 2021 09;385(11):971-981

From the Mobile Stroke Unit, Memorial Hermann Hospital-Texas Medical Center (J.C.G., J. McCarthy, T.F.), the Departments of Biostatistics and Data Science (J.-M.Y., A.P.J., M.W., N.S., M.G.) and Management, Policy, and Community Heath (S.S.R.), University of Texas School of Public Health, the Departments of Neurology (S.A.P., N.R.G., P.L.B., N.R.-G., E.L., J.S., K.P., Y.S., E.A.N., R.B.) and Emergency Medicine (D.P.), University of Texas McGovern Medical School, the Departments of Emergency Medicine (D.P.) and Neurology (C.P.V.R.), Baylor College of Medicine, the Department of Neurology, Houston Methodist Hospital (D.C., J.V., V.M.), the Department of Neurology, Harris Health-Ben Taub General Hospital (J.S.K.), and HCA Houston Healthcare (L.G.) - all in Houston; the Department of Neurology, University of Colorado, UCHealth Anschutz Medical Campus, Aurora (W.J.J., B.D.S., K.A., M.E., D.O.), and the Department of Neurology, UCHealth Memorial Hospital, Colorado Springs (J. Miller) - both in Colorado; the Department of Neurology, University of Tennessee Health Science Center, Memphis (A.W.A., A.V.A., J.P.R.); the Department of Neurology, Weill Cornell Medicine (B.B.N., M.E.F., C.S., M.L., S.M.), and the Department of Neurology, Columbia University Irving Medical Center (J.Z.W.) - both in New York; the Department of Neurology, Ronald Reagan UCLA Medical Center, Los Angeles (M.N., J.L.S., K.M.B., B.M.V.), the Department of Neurology, Mills Peninsula Medical Center, Burlingame (I.S., J.E., N. Barazangi, J.I.), Los Angeles County Emergency Medical Services, Santa Fe Springs (M.G.-H., N. Bosson), and San Mateo County Emergency Medical Services, South San Francisco (G.G.) - all in California; and the Department of Neurology, Indiana University School of Medicine, Indianapolis (J. Mackey, S.Q.C., K.S.).

Background: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied.

Methods: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients.

Results: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group.

Conclusions: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).
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http://dx.doi.org/10.1056/NEJMoa2103879DOI Listing
September 2021

Post-severe Acute Respiratory Syndrome Coronavirus 2 Monoclonal Antibody Treatment Hospitalizations as a Sentinel for Emergence of Viral Variants in New York City.

Open Forum Infect Dis 2021 Aug 12;8(8):ofab313. Epub 2021 Jun 12.

Department of Emergency Medicine Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.

We partnered with the US Department of Health and Human Services to treat high-risk, nonadmitted coronavirus disease 2019 (COVID-19) patients with bamlanivimab in the Bronx, New York per Emergency Use Authorization criteria. Increasing posttreatment hospitalizations were observed monthly between December 2020 and March 2021 in parallel to the emergence of severe acute respiratory syndrome coronavirus 2 variants in New York City.
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http://dx.doi.org/10.1093/ofid/ofab313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391090PMC
August 2021

Prevalence of Neutralising Antibodies to HCoV-NL63 in Healthy Adults in Australia.

Viruses 2021 08 16;13(8). Epub 2021 Aug 16.

Centre for Immunology and Infection Control, School of Biomedical Science, Faculty of Health, Queensland University of Technology, South Brisbane, QLD 4007, Australia.

The COVID-19 pandemic has highlighted the importance of understanding the immune response to seasonal human coronavirus (HCoV) infections such as HCoV-NL63, how existing neutralising antibodies to HCoV may modulate responses to SARS-CoV-2 infection, and the utility of seasonal HCoV as human challenge models. Therefore, in this study we quantified HCoV-NL63 neutralising antibody titres in a healthy adult population using plasma from 100 blood donors in Australia. A microneutralisation assay was performed with plasma diluted from 1:10 to 1:160 and tested with the HCoV-NL63 Amsterdam-1 strain. Neutralising antibodies were detected in 71% of the plasma samples, with a median geometric mean titre of 14. This titre was similar to those reported in convalescent sera taken from individuals 3-7 months following asymptomatic SARS-CoV-2 infection, and 2-3 years post-infection from symptomatic SARS-CoV-1 patients. HCoV-NL63 neutralising antibody titres decreased with increasing age (R = 0.042, = 0.038), but did not differ by sex. Overall, this study demonstrates that neutralising antibody to HCoV-NL63 is detectable in approximately 71% of the healthy adult population of Australia. Similar titres did not impede the use of another seasonal human coronavirus (HCoV-229E) in a human challenge model, thus, HCoV-NL63 may be useful as a human challenge model for more pathogenic coronaviruses.
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http://dx.doi.org/10.3390/v13081618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402802PMC
August 2021

Areas of global importance for conserving terrestrial biodiversity, carbon and water.

Nat Ecol Evol 2021 Aug 23. Epub 2021 Aug 23.

Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA.

To meet the ambitious objectives of biodiversity and climate conventions, the international community requires clarity on how these objectives can be operationalized spatially and how multiple targets can be pursued concurrently. To support goal setting and the implementation of international strategies and action plans, spatial guidance is needed to identify which land areas have the potential to generate the greatest synergies between conserving biodiversity and nature's contributions to people. Here we present results from a joint optimization that minimizes the number of threatened species, maximizes carbon retention and water quality regulation, and ranks terrestrial conservation priorities globally. We found that selecting the top-ranked 30% and 50% of terrestrial land area would conserve respectively 60.7% and 85.3% of the estimated total carbon stock and 66% and 89.8% of all clean water, in addition to meeting conservation targets for 57.9% and 79% of all species considered. Our data and prioritization further suggest that adequately conserving all species considered (vertebrates and plants) would require giving conservation attention to ~70% of the terrestrial land surface. If priority was given to biodiversity only, managing 30% of optimally located land area for conservation may be sufficient to meet conservation targets for 81.3% of the terrestrial plant and vertebrate species considered. Our results provide a global assessment of where land could be optimally managed for conservation. We discuss how such a spatial prioritization framework can support the implementation of the biodiversity and climate conventions.
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http://dx.doi.org/10.1038/s41559-021-01528-7DOI Listing
August 2021

Vaccination of human participants with attenuated Necator americanus hookworm larvae and human challenge in Australia: a dose-finding study and randomised, placebo-controlled, phase 1 trial.

Lancet Infect Dis 2021 Aug 19. Epub 2021 Aug 19.

Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Infectious Diseases Unit, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.

Background: Control of human hookworm infection would be greatly aided by the development of an effective vaccine. We aimed to develop a live attenuated human hookworm vaccine.

Methods: This was a two-part clinical trial done at Q-Pharm in Brisbane (QLD, Australia) using a live ultraviolet C (UVC)-attenuated Necator americanus larvae vaccine. Part one was an open-label, dose-finding study using 50 L3 larvae suspended in water to a volume of 200 μL, attenuated with UVC exposure of 700 μJ (L3-700) or 1000 μJ (L3-1000). Part two was a randomised, double-blind, placebo-controlled, challenge study, in which participants were randomly assigned 2:1 to the vaccine group or placebo group. Healthy hookworm-naive adults aged 18-65 years with body-mass index 18-35 kg/m received two doses of either placebo (Tabasco sauce) or vaccine (50 L3-700) on day 1 and day 42, followed by challenge with 30 unattenuated L3 larvae to both groups. All participants received a single oral dose of 400 mg albendazole 4 weeks after each inoculation and a 3-day course (400 mg orally daily) initiated on day 161 after the challenge phase, to eliminate any remaining infection. The primary outcome of part 1 was the level of larval attenuation the resulted in a grade 2 or 3 dermal adverse event. The primary outcome of part 2 was safety and tolerability, assessed by frequency and severity of adverse events in all randomly assigned participants. Prespecified exploratory outcomes in the challenge study were faecal N americanus DNA concentration, the number of N americanus larvae recovered per g of faeces cultured, hookworm antigen-specific serum IgG antibody responses, and hookworm antigen-specific peripheral blood cytokine responses. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617001007325).

Findings: Between Sept 19, 2017, and Oct 24, 2018, seven participants were enrolled into three cohorts in part one (two participants in cohort 1, who received L3-700; two participants in cohort 2, who received L3-700; and three participants in cohort 3, who received L3-1000) and a further 15 were enrolled into part two. There were no serious adverse events in part one or part two. In part one, a greater number of skin penetration sites were observed after administration of L3-700 than L3-1000 (mean 15·75 [95% CI 11·18 to 20·32] with L3-700 vs 4·33 [-1·40 to 10·07] with L3-1000). Similarly, greater erythema (median 225 mm [IQR 150 to 325] vs 25 mm [12·5 to 80]) and a longer duration of the dermal reaction (median 8·0 days [IQR 3·5 to 11·5] vs 2·0 days [2·0 to 4·5]) were observed after L3-700 than L3-1000. The mean number of adverse events per participant did not differ between the groups (3·25 [95% CI 1·48 to 5·02] vs 3·00 [1·04 to 4·96]). Thus, L3-700 was used for vaccination in part two. In part two, ten participants were randomly assigned to receive L3-700 and five to placebo. Significantly more adverse events occurred after vaccination with attenuated larvae than with placebo (incident rate ratio [IRR] 2·13 [95% CI 2·09 to 5·51]; p=0·0030). There was no difference between groups in the frequency of adverse events after challenge (IRR 1·25 [0·78 to 2·01]; p=0·36). Most adverse events were mild in severity, with only one severe adverse event reported (erythematous and indurated pruritic rash >100 mm in a vaccine group participant after challenge). The eosinophil count increased in all participants after challenge, with a significantly greater increase among vaccinated participants than placebo participants (1·55 × 10 cells per L [IQR 0·92 to 1·81] in the vaccine group vs 0·49 × 10 cells per L [0·43 to 0·63] in the placebo group; p=0·014). Vaccinated participants had an IgG response to larval extract after challenge that was higher than that in placebo participants (increase in IgG titre 0·22 [IQR 0·10 to 0·41] vs 0·03 [-0·40 to 0·06]; p=0·020). Significantly fewer larvae per g of faeces were recovered in the vaccine group than in the placebo group after challenge (median larvae per g 0·8 [IQR 0·00 to 3·91] vs 10·2 [5·1 to 18·1]; p=0·014). The concentration of N americanus DNA in faeces was not significantly different between the vaccinated group and the placebo group (log DNA intensity 4·28 [95% CI 3·92 to 4·63] vs 4·88 [4·31 to 5·46]; p=0·14). Peripheral blood mononuclear cells from vaccinated participants exhibited significantly greater cytokine production at day 112 than placebo participants for IFNγ, TNFα, IL-2, IL-4, and IL-5 (p<0·05), but not IL-10.

Interpretation: Vaccination with UVC-attenuated N americanus larvae is well tolerated, induces humoral and cellular responses to hookworm antigens, and reduces larval output after challenge with unattenuated larvae. Larger studies are required to confirm protective efficacy.

Funding: National Health and Medical Research Council of Australia.
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http://dx.doi.org/10.1016/S1473-3099(21)00153-5DOI Listing
August 2021

Reply to White and Watson.

J Infect Dis 2021 Aug;224(4):739-740

Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1093/infdis/jiaa791DOI Listing
August 2021

Pragmatic comparative effectiveness study of multimodal fascia iliaca nerve block and continuous lumbar epidural-based protocols for periacetabular osteotomy.

J Hip Preserv Surg 2020 Dec 26;7(4):728-739. Epub 2021 Feb 26.

Department of Anesthesiology, Cincinnati Children's Hospital, Cincinnati, OH, USA.

Perioperative pain management protocols have a significant impact on early surgical outcomes and recovery. We hypothesized that multimodal protocol including fascia iliaca compartment nerve block (MM-FICNB) would decrease the length of hospital stay (LOS) by facilitating earlier mobilization, without compromising analgesia, compared to a traditional lumbar epidural-based protocol (EP). Demographics/comorbidities, surgical/block characteristics and perioperative pain/mobilization data were collected from a prospectively recruited MM-FICNB group ( = 16) and a retrospective EP cohort ( = 16) who underwent PAO using similar surgical techniques, physical therapy/discharge criteria. Association of MM-FICNB group with LOS (primary outcome), postoperative pain, postoperative opioid requirements in morphine equivalent rates (MER) (mcg/kg/h) and time to complete physical therapy were tested using multivariable and survival regression. Patient and surgical characteristics were similar between groups. Median time for FICNB performance was significantly less than epidural (6 versus 15 min;  < 0.001). LOS was significantly decreased in the MM-FICNB group (2.88 ± 0.72 days) compared to the EP group (4.38 ± 1.02 days);  < 0.001. MM-FICNB group had significantly lower MER on POD1 ( = 0.006) and POD2 ( < 0.001), with similar pain scores on all POD. MM-FICNB group was associated with decreased LOS and earlier mobilization ( < 0.001) by covariate-adjusted multivariate regression. Cox proportional hazard regression model showed MM-FICNB subjects had 63 (95% CI 7-571,  < 0.001) times the chance of completing physical therapy goals, compared to EP. Compared to EP, MM-FICNB protocol allowed earlier mobilization and decreased post-surgical hospitalization by 1.5 days, without compromising analgesia, with important implications for value-based healthcare and cost-effectiveness.
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http://dx.doi.org/10.1093/jhps/hnab010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349585PMC
December 2020

Local anaesthesia as a standard of care for penetrating keratoplasty?

Eye (Lond) 2021 Jul 9. Epub 2021 Jul 9.

Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada.

Background/objectives: To determine preferences in the use of local anaesthesia (LA) versus general anaesthesia (GA) for penetrating keratoplasty (PK), and to examine the safety of LA for PK.

Subjects/methods: A retrospective analysis of PKs performed at an ophthalmology department in Canada from 01/01/2008 to 01/01/2020 was conducted to investigate rate of major complications. A questionnaire was also sent out to cornea specialists in the United Kingdom (UK) and Canada to determine trends in anaesthesia use for PK. Data on anaesthesia use in keratoplasty data was also obtained from the National Health Service Blood and Tissue (NHSBT) register.

Results: The retrospective study found that 2143 PKs were performed under LA by 4 surgeons. The following complications were revealed: 1 acute anxiety attack with tachycardia, 3 extraocular myotoxicity cases requiring squint surgery, 1 expulsive suprachoroidal haemorrhage and 1 retrobulbar haemorrhage. The survey revealed 92% of cornea specialists in Canada preferred LA to GA. In the UK, 4.5% of specialists preferred LA, with most preferring GA due to suprachoroidal haemorrhage risk. NHSBT data revealed that 86.6% of 6181 PKs performed in UK between 01/04/2015 and 31/03/2020 were done under GA.

Conclusions: LA is preferred for PK in Canada, in contrast to the UK where GA is preferred. Our retrospective study suggests a low incidence of LA-related complications. We suggest that LA should be considered for most cornea transplant techniques, including optical penetrating keratoplasty. Rising worldwide keratoplasty numbers, ageing populations and risks of pandemics (e.g. COVID-19) give more reason for reduced reliance on GA.
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http://dx.doi.org/10.1038/s41433-021-01618-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267224PMC
July 2021

Distal rectus femoris surgery in children with cerebral palsy: results of a Delphi consensus project.

J Child Orthop 2021 Jun;15(3):270-278

Universitäts-Kinderspital, Zürich, Switzerland.

Purpose: The purpose of this study was for an international panel of experts to establish consensus indications for distal rectus femoris surgery in children with cerebral palsy (CP) using a modified Delphi method.

Methods: The panel used a five-level Likert scale to record agreement or disagreement with 33 statements regarding distal rectus femoris surgery. The panel responded to statements regarding general characteristics, clinical indications, computerized gait data, intraoperative techniques and outcome measures. Consensus was defined as at least 80% of responses being in the highest or lowest two of the five Likert ratings, and general agreement as 60% to 79% falling into the highest or lowest two ratings. There was no agreement if neither threshold was reached.

Results: Consensus or general agreement was reached for 17 of 33 statements (52%). There was general consensus that distal rectus femoris surgery is better for stiff knee gait than is proximal rectus femoris release. There was no consensus about whether the results of distal rectus femoris release were comparable to those following distal rectus femoris transfer. Gross Motor Function Classification System (GMFCS) level was an important factor for the panel, with the best outcomes expected in children functioning at GMFCS levels I and II. The panel also reached consensus that they do distal rectus femoris surgery less frequently than earlier in their careers, in large part reflecting the narrowing of indications for this surgery over the last decade.

Conclusion: This study can help paediatric orthopaedic surgeons optimize decision-making for, and outcomes of, distal rectus femoris surgery in children with CP.

Level Of Evidence: V.
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http://dx.doi.org/10.1302/1863-2548.15.210044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223080PMC
June 2021

Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria.

J Antimicrob Chemother 2021 Aug;76(9):2325-2334

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.

Background: The efficacy of artemisinin-based combination therapies (ACTs), the first-line treatments for uncomplicated falciparum malaria, has been declining in malaria-endemic countries due to the emergence of malaria parasites resistant to these compounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs.

Objectives: This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model.

Methods: A within-host model was developed, which accounts for the differential killing of these compounds against different stages of the parasite's life cycle and accommodates the pharmacodynamic interaction between the drugs. Data of healthy volunteers infected with falciparum malaria collected from four trials (three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439 and DSM265) were analysed. Model parameters were estimated in a hierarchical Bayesian framework.

Results: The posterior predictive simulations of our model predicted that 800 mg of OZ439 combined with 450 mg of DSM265, which are within the safe and tolerable dose range, can provide above 90% cure rates 42 days after drug administration.

Conclusions: Our results show that the combination of OZ439 and DSM265 can be a promising alternative to replace ACTs. Our model can be used to inform future Phase 2 and 3 clinical trials of OZ439/DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing. The dosing regimens that are shown to be efficacious and within safe and tolerable limits are suggested for future investigations.
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http://dx.doi.org/10.1093/jac/dkab181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361368PMC
August 2021

Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study.

PLoS Med 2021 05 26;18(5):e1003567. Epub 2021 May 26.

Clinical Tropical Medicine Laboratory, QIMR-Berghofer Medical Research Institute, Brisbane, Australia.

Background: Plasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum, which is known to undergo microvascular tissue sequestration, little is known about the behavior of P. vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life.

Methods And Findings: To identify organ-specific changes during the early stages of P. vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P. vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P. falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species (n = 3 P. vivax; n = 4 P. falciparum). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume (P. vivax: +28.8% [confidence interval (CI) +10.3% to +57.3%], P. falciparum: +22.9 [CI -15.3% to +61.1%]) and radiotracer uptake (P. vivax: +15.5% [CI -0.7% to +31.7%], P. falciparum: +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P. vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow (P. vivax: +4.6% [CI -15.9% to +25.0%], P. falciparum: +3.2% [CI -3.2% to +9.6%]) or liver (P. vivax: +6.2% [CI -8.7% to +21.1%], P. falciparum: -1.4% [CI -4.6% to +1.8%]) following infection with either species. In participants with P. vivax, hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P. vivax infection compared to P. falciparum. The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity.

Conclusions: PET/MRI indicated greater splenic tropism and metabolic activity in early P. vivax infection compared to P. falciparum, supporting the hypothesis of splenic accumulation of P. vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism.
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http://dx.doi.org/10.1371/journal.pmed.1003567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154100PMC
May 2021

Development of P301S tau seeded organotypic hippocampal slice cultures to study potential therapeutics.

Sci Rep 2021 05 13;11(1):10309. Epub 2021 May 13.

Neuroscience, Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.

Intracellular tau inclusions are a pathological hallmark of Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates may spread to neighbouring cells and functionally connected brain regions, where they can seed further tau aggregation. This process is referred to as tau propagation. Here we describe an ex vivo system using organotypic hippocampal slice cultures (OHCs) which recapitulates aspects of this phenomenon. OHCs are explants of hippocampal tissue which may be maintained in culture for months. They maintain their synaptic connections and multicellular 3D architecture whilst also permitting direct control of the environment and direct access for various analysis types. We inoculated OHCs prepared from P301S mouse pups with brain homogenate from terminally ill P301S mice and then examined the slices for viability and the production and localization of insoluble phosphorylated tau. We show that following seeding, phosphorylated insoluble tau accumulate in a time and concentration dependent manner within OHCs. Furthermore, we show the ability of the conformation dependent anti-tau antibody, MC1, to compromise tau accrual in OHCs, thus showcasing the potential of this therapeutic approach and the utility of OHCs as an ex vivo model system for assessing such therapeutics.
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http://dx.doi.org/10.1038/s41598-021-89230-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119691PMC
May 2021

The catabolic triad: case report of fasting, major cardiac surgery and sodium-glucose co-transporter 2 inhibitors leading to perioperative euglycaemic ketoacidosis.

Interact Cardiovasc Thorac Surg 2021 Aug;33(3):494-495

Blackrock Clinic, Dublin, Ireland.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are novel oral hypoglycaemic agents. For patients with diabetes mellitus, without a prior history of myocardial infarction or atherosclerotic disease, SGLT2i have been shown to reduce incident heart failure and worsening renal function. SGLT2i therapy is increasing among patients presenting for cardiac surgery. However, the perioperative use of SGLT2i carries a significant risk of euglycaemic diabetic ketoacidosis, due to their catabolic mechanism of action. This case report demonstrates euglycaemic ketoacidosis post-coronary artery bypass grafting secondary to SGLT2i, highlighting the multiple risk factors and consequences of this iatrogenic complication.
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http://dx.doi.org/10.1093/icvts/ivab104DOI Listing
August 2021

The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons.

Stem Cell Reports 2021 May 22;16(5):1276-1289. Epub 2021 Apr 22.

Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK. Electronic address:

Sequestosome-1 (SQSTM1/p62) is involved in cellular processes such as autophagy and metabolic reprogramming. Mutations resulting in the loss of function of SQSTM1 lead to neurodegenerative diseases including frontotemporal dementia. The pathogenic mechanism that contributes to SQSTM1-related neurodegeneration has been linked to its role as an autophagy adaptor, but this is poorly understood, and its precise role in mitochondrial function and clearance remains to be clarified. Here, we assessed the importance of SQSTM1 in human induced pluripotent stem cell (iPSC)-derived cortical neurons through the knockout of SQSTM1. We show that SQSTM1 depletion causes altered mitochondrial gene expression and functionality, as well as autophagy flux, in iPSC-derived neurons. However, SQSTM1 is not essential for mitophagy despite having a significant impact on early PINK1-dependent mitophagy processes including PINK1 recruitment and phosphorylation of ubiquitin on depolarized mitochondria. These findings suggest that SQSTM1 is important for mitochondrial function rather than clearance.
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http://dx.doi.org/10.1016/j.stemcr.2021.03.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185463PMC
May 2021

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

Molecular diagnosis of scabies using a novel probe-based polymerase chain reaction assay targeting high-copy number repetitive sequences in the Sarcoptes scabiei genome.

PLoS Negl Trop Dis 2021 02 24;15(2):e0009149. Epub 2021 Feb 24.

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Background: The suboptimal sensitivity and specificity of available diagnostic methods for scabies hampers clinical management, trials of new therapies and epidemiologic studies. Additionally, parasitologic diagnosis by microscopic examination of skin scrapings requires sample collection with a sharp scalpel blade, causing discomfort to patients and difficulty in children. Polymerase chain reaction (PCR)-based diagnostic assays, combined with non-invasive sampling methods, represent an attractive approach. In this study, we aimed to develop a real-time probe-based PCR test for scabies, test a non-invasive sampling method and evaluate its diagnostic performance in two clinical settings.

Methodology/principal Findings: High copy-number repetitive DNA elements were identified in draft Sarcoptes scabiei genome sequences and used as assay targets for diagnostic PCR. Two suitable repetitive DNA sequences, a 375 base pair microsatellite (SSR5) and a 606 base pair long tandem repeat (SSR6), were identified. Diagnostic sensitivity and specificity were tested using relevant positive and negative control materials and compared to a published assay targeting the mitochondrial cox1 gene. Both assays were positive at a 1:100 dilution of DNA from a single mite; no amplification was observed in DNA from samples from 19 patients with other skin conditions nor from house dust, sheep or dog mites, head and body lice or from six common skin bacterial and fungal species. Moderate sensitivity of the assays was achieved in a pilot study, detecting 5/7 (71.4% [95% CI: 29.0% - 96.3%]) of clinically diagnosed untreated scabies patients). Greater sensitivity was observed in samples collected by FLOQ swabs compared to skin scrapings.

Conclusions/significance: This newly developed qPCR assay, combined with the use of an alternative non-invasive swab sampling technique offers the possibility of enhanced diagnosis of scabies. Further studies will be required to better define the diagnostic performance of these tests.
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http://dx.doi.org/10.1371/journal.pntd.0009149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939366PMC
February 2021

Reduced circulating dendritic cells in acute Plasmodium knowlesi and Plasmodium falciparum malaria despite elevated plasma Flt3 ligand levels.

Malar J 2021 Feb 16;20(1):97. Epub 2021 Feb 16.

Menzies School of Health Research and Charles Darwin University, Darwin, Australia.

Background: Plasmodium falciparum malaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasite Plasmodium knowlesi impacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection.

Methods: Plasma Flt3L concentration and blood CD141 DC, CD1c DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected with P. falciparum and in Malaysian patients with uncomplicated (ii) P. falciparum or (iii) P. knowlesi malaria.

Results: Plasmodium knowlesi caused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acute P. falciparum and P. knowlesi malaria with no increase in a subclinical experimental infection. Circulating CD141 DCs, CD1c DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasite P. knowlesi.

Conclusions: In adults, submicroscopic Plasmodium infection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141 DCs, CD1c DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonotic P. knowlesi is similar to other Plasmodium spp in compromising DC in adult malaria.
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http://dx.doi.org/10.1186/s12936-021-03642-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888183PMC
February 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

Rheumatic pericarditis: a rare cause of constrictive pericarditis.

BMJ Case Rep 2021 Jan 25;14(1). Epub 2021 Jan 25.

Cardiology Department, Limerick Regional Hospital, Dooradoyle, Limerick, Ireland.

Constrictive pericarditis is a relatively uncommon form of cardiac failure and presents due to scarring and consequent loss of the normal elasticity of the pericardial sac. This results in abnormal/limited ventricular filling and symptoms of heart failure. The aetiology is varied, from infective causes to idiopathic causes, or can manifest after cardiothoracic surgery. This case involves a 46-year-old man presenting with acute group A beta haemolytic streptococcus infection, and over the subsequent 6 months develops constrictive pericarditis due to what is believed to be a rheumatic aetiology. The patient subsequently underwent pericardiectomy and had restoration of normal filling dynamics confirmed on follow-up echocardiography. This case provides a subject matter for the review of the features of constrictive pericarditis and its investigation and management. This case is that it highlights the fact that pericarditis is not a benign condition. Emerging evidence suggests that pericarditis is due to a failure in inflammatory regulatory mechanisms, and patients suffering this condition have a preponderance to 'autoinflammation'. Pericarditis should be recognised early and treated fully with anti-inflammatory agents.
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http://dx.doi.org/10.1136/bcr-2020-236639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839920PMC
January 2021

Semimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage Malaria.

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

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that might be useful when optimizing the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated with 1,800 blood-stage parasites. All volunteers received a single oral dose of piperaquine (960 mg, 640 mg, or 480 mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Parasite densities were measured by quantitative PCR (qPCR), and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modeling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. The pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semimechanistic parasite dynamics model was developed to explain the maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with malaria. Piperaquine-associated parasite killing was estimated using a maximum effect ( ) function. Treatment simulations (i.e., 3-day oral dosing of dihydroartemisinin-piperaquine) indicated that to be able to combat multidrug-resistant infections, an ideal additional drug in a new antimalarial triple-combination therapy should have a parasite reduction ratio of ≥10 per life cycle (38.8 h) with a duration of action of ≥2 weeks. The semimechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool for assessing and optimizing current and new antimalarial drug combination therapies containing piperaquine and the impact of these therapies on killing multidrug-resistant infections. (This study has been registered in the Australian and New Zealand Clinical Trials Registry under no. ANZCTRN12613000565741.).
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http://dx.doi.org/10.1128/AAC.01583-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097471PMC
March 2021

Safety and feasibility of apheresis to harvest and concentrate parasites from subjects with induced blood stage Plasmodium vivax infection.

Malar J 2021 Jan 14;20(1):43. Epub 2021 Jan 14.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD, 4006, Australia.

Background: In the absence of a method to culture Plasmodium vivax, the only way to source parasites is ex vivo. This hampers many aspects of P. vivax research. This study aimed to assess the safety of apheresis, a method for selective removal of specific components of blood as a means of extracting and concentrating P. vivax parasites.

Methods: An iterative approach was employed across four non-immune healthy human subjects in single subject cohorts. All four subjects were inoculated with ~ 564 blood stage P. vivax (HMP013-Pv) and subjected to apheresis 10 to 11 days later. Blood samples collected during apheresis (haematocrit layers 0.5% to 11%) were tested for the presence and concentration of P. vivax by microscopy, flow cytometry, 18S rDNA qPCR for total parasites, and pvs25 qRT-PCR for female gametocyte transcripts. Safety was determined by monitoring adverse events. Malaria transmission to mosquitoes was assessed by membrane feeding assays.

Results: There were no serious adverse events and no significant safety concerns. Apheresis concentrated asexual parasites by up to 4.9-fold (range: 0.9-4.9-fold) and gametocytes by up to 1.45-fold (range: 0.38-1.45-fold) compared to pre-apheresis densities. No single haematocrit layer contained > 40% of all the recovered P. vivax asexual parasites. Ex vivo concentration of parasites by Percoll gradient centrifugation of whole blood achieved greater concentration of gametocytes than apheresis. Mosquito transmission was enhanced by up to fivefold in a single apheresis sample compared to pre-apheresis.

Conclusion: The modest level of parasite concentration suggests that the use of apheresis may not be an ideal method for harvesting P. vivax. Trial Registration Australia New Zealand Clinical Trials Registry (ANZCTR) Trial ID: ACTRN12617001502325 registered on 19th October 2017. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373812.
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http://dx.doi.org/10.1186/s12936-021-03581-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807416PMC
January 2021

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Infection.

Cell Rep Med 2020 Dec 22;1(9):100157. Epub 2020 Dec 22.

Life Sciences, Burnet Institute, Melbourne, VIC 3004, Australia.

CD4 T follicular helper cells (Tfh) are key drivers of antibody development. During malaria in children, the activation of Tfh is restricted to the Th1 subset and not associated with antibody levels. To identify Tfh subsets that are associated with antibody development in malaria, we assess Tfh and antibodies longitudinally in human volunteers with experimental infection. Tfh cells activate during infection, with distinct dynamics in different Tfh subsets. Th2-Tfh cells activate early, during peak infection, while Th1-Tfh cells activate 1 week after peak infection and treatment. Th2-Tfh cell activation is associated with the functional breadth and magnitude of parasite antibodies. In contrast, Th1-Tfh activation is not associated with antibody development but instead with plasma cells, which have previously been shown to play a detrimental role in the development of long-lived immunity. Thus, our study identifies the contrasting roles of Th2 and Th1-Tfh cells during experimental malaria.
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http://dx.doi.org/10.1016/j.xcrm.2020.100157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762767PMC
December 2020

Epidemiology of soil-transmitted helminth infections in Semarang, Central Java, Indonesia.

PLoS Negl Trop Dis 2020 12 28;14(12):e0008907. Epub 2020 Dec 28.

Department of Global Health, Research School of Population Health, Australian National University, Acton, Australia.

Soil-transmitted helminth (STH) infections are endemic in Indonesia. However, prevalence data for many parts of the country are incomplete. The aim of this study was to determine human STH prevalence and knowledge and practices relating to STH risk behaviour, to provide a current view of the status of STH infection in rural communities in Central Java. A cross-sectional survey of 16 villages was conducted in Semarang, Central Java in 2015. Demographic and household data together with information about knowledge and practices relating to STH and hygiene were elicited through face-to-face interviews. Stool samples were collected and examined using the flotation method. Children (aged 2-12 years) also had their haemoglobin (Hb) levels, height and weight data collected, and BMI estimated. Data were analysed using univariate logistic regression analysis. A total of 6,466 individuals with a mean age of 33.5 years (range: 2-93) from 2,195 households were interviewed. The overall prevalence of STH was 33.8% with Ascaris lumbricoides (roundworm) the predominant nematode identified (prevalence = 26.0%). Hookworm and Trichuris trichiura (whipworm) were found in 7.9% and 1.8% of participants, respectively. Females were at increased odds of infection with A. lumbricoides (adjusted OR 1.14, 95% CI [1.02-1.29], p = 0.02). Adults in age groups 51-60 and over 60 years had the highest odds of being infected with hookworm (adjusted OR 3.01, 95% CI [1.84-4.91], p<0.001 and adjusted OR 3.79, 95% CI [2.30-6.26], p<0.001, respectively) compared to 6-12 year olds. Farmers also had higher odds of being infected with hookworm (adjusted OR 2.36, 95% CI [1.17-4.76], p = 0.02) compared to other occupation categories. Poverty (OR 2.14, 95% CI [1.77-2.58], p<0.001), overcrowding (OR 1.35, 95% CI [1.27-1.44], p<0.001), goat ownership (OR 1.61, 95% CI [1.10-2.41], p = 0.02) and the presence of dry floor space in the home (OR 0.73, 95% CI [0.58-0.91], p = 0.01) were all household factors significantly associated with an increased odds of infection. Infection with STH was not significantly associated with the gastrointestinal illness (p>0.05), BMI or Hb levels; however, one third of all 2-12 year olds surveyed were found to be anaemic (i.e. Hb concentrations below 110g/l or 115g/l for children under 5 and 5 years or older, respectively), with a greater proportion of school-age children at risk. Knowledge and behaviour related to hygiene and gastrointestinal diseases varied widely and were generally not associated with STH infection. The study revealed that STH infection remains endemic in Central Java despite ongoing deworming programs. Current control efforts would benefit from being re-evaluated to determine a more effective way forward.
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http://dx.doi.org/10.1371/journal.pntd.0008907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793285PMC
December 2020

Response to White and Watson.

J Infect Dis 2020 Dec 26. Epub 2020 Dec 26.

Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.

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http://dx.doi.org/10.1093/infdis/jiaa791DOI Listing
December 2020

Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development.

Clin Transl Sci 2021 03 16;14(2):712-719. Epub 2020 Dec 16.

Medicines for Malaria Venture, Geneva, Switzerland.

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been shown to facilitate antimalarial drug development. Such studies have traditionally been undertaken in single-dose cohorts, as many as necessary to obtain the dose-response relationship. To enhance ethical and logistic aspects of such studies, and to reduce the number of cohorts needed to establish the dose-response relationship, we undertook a retrospective in silico analysis of previously accrued data to improve study design. A pharmacokinetic (PK)/pharmacodynamic (PD) model was developed from initial fictive-cohort data for OZ439 (mixing the data of the three single-dose cohorts as: n = 2 on 100 mg, 2 on 200 mg, and 4 on 500 mg). A three-compartment model described OZ439 PKs. Net growth of parasites was modeled using a Gompertz function and drug-induced parasite death using a Hill function. Parameter estimates for the PK and PD models were comparable for the multidose single-cohort vs. the pooled analysis of all cohorts. Simulations based on the multidose single-cohort design described the complete data from the original IBSM study. The novel design allows for the ascertainment of the PK/PD relationship early in the study, providing a basis for rational dose selection for subsequent cohorts and studies.
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http://dx.doi.org/10.1111/cts.12934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993277PMC
March 2021

The transcriptome of circulating sexually committed Plasmodium falciparum ring stage parasites forecasts malaria transmission potential.

Nat Commun 2020 12 2;11(1):6159. Epub 2020 Dec 2.

Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Malaria is spread by the transmission of sexual stage parasites, called gametocytes. However, with Plasmodium falciparum, gametocytes can only be detected in peripheral blood when they are mature and transmissible to a mosquito, which complicates control efforts. Here, we identify the set of genes overexpressed in patient blood samples with high levels of gametocyte-committed ring stage parasites. Expression of all 18 genes is regulated by transcription factor AP2-G, which is required for gametocytogenesis. We select three genes, not expressed in mature gametocytes, to develop as biomarkers. All three biomarkers we validate in vitro using 6 different parasite lines and develop an algorithm that predicts gametocyte production in ex vivo samples and volunteer infection studies. The biomarkers are also sensitive enough to monitor gametocyte production in asymptomatic P. falciparum carriers allowing early detection and treatment of infectious reservoirs, as well as the in vivo analysis of factors that modulate sexual conversion.
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http://dx.doi.org/10.1038/s41467-020-19988-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710746PMC
December 2020
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