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207. Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort

Author

Ataide, Ricardo, Ashley, Elizabeth A., Powell, Rosanna, Chan, Jo-Anne, Malloy, Michael J., O’Flaherty, Katherine, Takashima, Eizo, Langer, Christine, Tsuboi, Takafumi, Dondorp, Arjen M., Day, Nicholas P., Dhorda, Mehul, Fairhurst, Rick M., Lim, Pharath, Amaratunga, Chanaki, Pukrittayakamee, Sasithon, Hien, Tran Tinh, Htut, Ye, Mayxay, Mayfong, Faiz, M. Abul, Beeson, James G., Nosten, Francois, Simpson, Julie A., White, Nicholas J., and Fowkes, Freya J. I.

Published
2017

210. Safety and efficacy of dihydroartemisinin-piperaquine in falciparum malaria: a prospective multi-centre individual patient data analysis.

Author

Zwang, Julien, Ashley, Elizabeth A, Karema, Corine, D'Alessandro, Umberto, Smithuis, Frank, Dorsey, Grant, Janssens, Bart, Mayxay, Mayfong, Newton, Paul, Singhasivanon, Pratap, Stepniewska, Kasia, White, Nicholas J, and Nosten, François

Subjects
Humans, Malaria, Falciparum, Artemisinins, Quinolines, Antimalarials, Prospective Studies, Adolescent, Adult, Aged, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Randomized Controlled Trials as Topic, Malaria, Falciparum, Preschool, General Science & Technology
Abstract

BackgroundThe fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda.Methods and findingsIn total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site).ConclusionsDP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3.

Published
2009

213. Clinical antiviral efficacy of remdesivir in COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)

Author

Jittamala, Podjanee, primary, Schilling, William H K, additional, Watson, James A, additional, Luvira, Viravarn, additional, Siripoon, Tanaya, additional, Ngamprasertchai, Thundon, additional, Almeida, Pedro J, additional, Ekkapongpisit, Maneerat, additional, Cruz, Cintia, additional, Callery, James J, additional, Boyd, Simon, additional, Anunsittichai, Orawan, additional, Hongsuwan, Maliwan, additional, Singhaboot, Yutatirat, additional, Pagornrat, Watcharee, additional, Tuntipaiboontana, Runch, additional, Kruabkontho, Varaporn, additional, Ngernseng, Thatsanun, additional, Tubprasert, Jaruwan, additional, Abdad, Mohammad Yazid, additional, Keayarsa, Srisuda, additional, Madmanee, Wanassanan, additional, Aguiar, Renato S, additional, Santos, Franciele M, additional, Batty, Elizabeth M, additional, Hanboonkunupakarn, Pongtorn, additional, Hanboonkunupakarn, Borimas, additional, Sookprome, Sakol, additional, Poovorawan, Kittiyod, additional, Imwong, Mallika, additional, Taylor, Walter R J, additional, Chotivanich, Vasin, additional, Sangketchon, Chunlanee, additional, Ruksakul, Wiroj, additional, Chotivanich, Kesinee, additional, Pukrittayakamee, Sasithon, additional, Dondorp, Arjen M, additional, Day, Nicholas P J, additional, Teixeira, Mauro M, additional, Piyaphanee, Watcharapong, additional, Phumratanaprapin, Weerapong, additional, and White, Nicholas J, additional

Published
2023
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215. Activity of Ivermectin and Its Metabolites against Asexual Blood Stage Plasmodium falciparum and Its Interactions with Antimalarial Drugs

Author

Yipsirimetee, Achaporn, primary, Tipthara, Phornpimon, additional, Hanboonkunupakarn, Borimas, additional, Tripura, Rupam, additional, Lek, Dysoley, additional, Kümpornsin, Krittikorn, additional, Lee, Marcus C. S., additional, Sattabongkot, Jetsumon, additional, Dondorp, Arjen M., additional, White, Nicholas J., additional, Kobylinski, Kevin C., additional, Tarning, Joel, additional, and Chotivanich, Kesinee, additional

Published
2023
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220. Carer reported perceptions of child vulnerability and self-reported health self-efficacy in siblings of children with chronic physical illness

Author

White, Nicholas

Abstract

Objective - This study aimed to explore whether parental perceptions of child vulnerability were elevated in siblings of children with chronic illness, and to examine the effect of such beliefs on children’s own health self-efficacy and psychological adjustment. Design - Cross sectional questionnaire methodology. Setting - Two major hospitals in the United Kingdom with specialist paediatric services. Participants - 35 parent/child pairs from families with children who experienced difficulties relating to cancer or cardiological problems. Main Outcome Measures -Parents were asked to complete the child vulnerability scale (Forsyth, Horwitz, Leventhal, Burger & Leaf, 1996), and the Strengths and Difficulties Questionnaire (Parent Form - Goodman, 1997). Siblings were asked to complete items from the School Health Self-Efficacy Scale (Froman & Owen, 1991). Results - Siblings were not more likely to be perceived as ‘vulnerable’ to a statistically significant level. No substantial relationship existed between parental vulnerability perceptions and children’s health self-efficacy beliefs. Self-efficacy was found to be significantly higher than the community sample. Both constructs were correlated with psychological outcomes. Sibling adjustment was found to be significantly different from that expected from community samples for emotional symptoms. Use of exploratory correlation suggested that self-efficacy beliefs might to some extent moderate the relationship between vulnerability and emotional symptoms. Conclusions - While siblings of children with physical illness do experience difficulties, health self-efficacy is a valuable potential source of resilience for young people in the context of family illness.

Published
2005

221. Purinergic signalling in malignant melanoma

Author

White, Nicholas

Subjects
616.99477
Abstract

Malignant melanoma is an aggressive cancer that originates from melanocytes, the pigment producing cells of the skin. The incidence of melanoma is increasing and the outcome for patients with advanced disease remains poor. New therapies for melanoma are in urgently needed as no current systemic treatment is effective. Interactions between the nervous system and epidermal melanocytes have been suspected on the basis of their common embryological origin from the neural crest. Both melanocytes and melanomas are innervated by autonomic nerves with acetylcholine and noradrenaline acting as transmitter molecules. It is now well established that the purine nucleotide adenosine triphosphate (ATP) is a co-transmitter with noradrenaline in sympathetic nerves and with acetylcholine in parasympathetic nerves. ATP acts on extracellular receptors which have been characterised to consist of a number of subtypes. ATP acting on these receptors is involved with both rapid signalling in neurotransmission and also long term signalling in cell proliferation, differentiation and apoptosis.

Published
2005

224. Low-Mass X-Ray Binaries, Millisecond Radio Pulsars, and the Cosmic Star Formation Rate

Author

White, Nicholas E. and Ghosh, Pranab

Subjects
Astrophysics
Abstract

We report on the implications of the peak in the cosmic star-formation rate (SFR) at redshift z ~ 1.5 for the resulting population of low-mass X-ray binaries(LMXB) and for that of their descendants, the millisecond radio pulsars (MRP). Since the evolutionary timescales of LMXBs, their progenitors, and their descendants are thought be significant fractions of the time-interval between the SFR peak and the present epoch, there is a lag in the turn-on of the LMXB population, with the peak activity occurring at z ~ 0.5 - 1.0. The peak in the MRP population is delayed further, occurring at z < 0.5. We show that the discrepancy between the birthrate of LMXBs and MRPs, found under the assumption of a stead-state SFR, can be resolved for the population as a whole when the effects of a time-variable SFR are included. A discrepancy may persist for LMXBs with short orbital periods, although a detailed population synthesis will be required to confirm this. Further, since the integrated X-ray luminosity distribution of normal galaxies is dominated by X-ray binaries, it should show strong luminosity evolution with redshift. In addition to an enhancement near the peak (z ~ 1.5) of the SFR due to the prompt turn-on of the relatively short-lived massive X-ray binaries and young supernova remnants, we predict a second enhancement by a factor ~10 at a redshift between ~ 0.5 and ~ 1 due to the delayed turn-on of the LMXB population. Deep X-ray observations of galaxies out to z ~ 1 by AXAF will be able to observe this enhancement, and, by determining its shape as a function of redshift, will provide an important new method for constraining evolutionary models of X-ray binaries., Comment: 13 pages, including 1 figure. Accepted for publication in ApJ Letters

Published
1998
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225. On the Amplitude of Burst Oscillations in 4U 1636-54: Evidence for Nuclear Powered Pulsars

Author

Strohmayer, Tod E., Zhang, William, Swank, Jean H., White, Nicholas E., and Lapidus, Iosif

Subjects
Astrophysics
Abstract

We present a study of 581 Hz oscillations observed during a thermonuclear X-ray burst from the low mass X-ray binary (LMXB) 4U 1636-54 with the Rossi X-ray Timing Explorer (RXTE). We argue that the combination of large pulsed amplitudes near burst onset and the spectral evidence for localized emission during the rise strongly supports rotational modulation as the mechanism for the oscillations. We discuss how theoretical interpretation of spin modulation amplitudes, pulse profiles and pulse phase spectroscopy can provide constraints on the masses and radii of neutron stars. We also discuss the implication of these findings for the beat frequency models of kHz X-ray variability in LMXB., Comment: AASTEX Latex, 13 pages including 5 figures. Accepted for publication in the Astrophysical Journal Letters

Published
1998
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236. Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis

Author

Saito, Makoto, Mansoor, Rashid, Kennon, Kalynn, Anvikar, Anupkumar R., Ashley, Elizabeth A., Chandramohan, Daniel, Cohee, Lauren M., D’Alessandro, Umberto, Genton, Blaise, Gilder, Mary Ellen, Juma, Elizabeth, Kalilani-Phiri, Linda, Kuepfer, Irene, Laufer, Miriam K., Lwin, Khin Maung, Meshnick, Steven R., Mosha, Dominic, Muehlenbachs, Atis, Mwapasa, Victor, Mwebaza, Norah, Nambozi, Michael, Ndiaye, Jean-Louis A., Nosten, François, Nyunt, Myaing, Ogutu, Bernhards, Parikh, Sunil, Paw, Moo Kho, Phyo, Aung Pyae, Pimanpanarak, Mupawjay, Piola, Patrice, Rijken, Marcus J., Sriprawat, Kanlaya, Tagbor, Harry K., Tarning, Joel, Tinto, Halidou, Valéa, Innocent, Valecha, Neena, White, Nicholas J., Wiladphaingern, Jacher, Stepniewska, Kasia, McGready, Rose, and Guérin, Philippe J.

Published
2020
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239. Correction to: The use of ultrasensitive quantitative-PCR to assess the impact of primaquine on asymptomatic relapse of Plasmodium vivax infections: a randomized, controlled trial in Lao PDR

Author

Phommasone, Koukeo, van Leth, Frank, Imwong, Mallika, Henriques, Gisela, Pongvongsa, Tiengkham, Adhikari, Bipin, Peto, Thomas J., Promnarate, Cholrawee, Dhorda, Mehul, Sirithiranont, Pasathorn, Mukaka, Mavuto, Peerawaranun, Pimnara, Day, Nicholas P. J., Cobelens, Frank, Dondorp, Arjen M., Newton, Paul N., White, Nicholas J., von Seidlein, Lorenz, and Mayxay, Mayfong

Published
2020
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240. The use of ultrasensitive quantitative-PCR to assess the impact of primaquine on asymptomatic relapse of Plasmodium vivax infections: a randomized, controlled trial in Lao PDR

Author

Phommasone, Koukeo, van Leth, Frank, Imwong, Mallika, Henriques, Gisela, Pongvongsa, Tiengkham, Adhikari, Bipin, Peto, Thomas J., Promnarate, Cholrawee, Dhorda, Mehul, Sirithiranont, Pasathorn, Mukaka, Mavuto, Peerawaranun, Pimnara, Day, Nicholas P. J., Cobelens, Frank, Dondorp, Arjen M., Newton, Paul N., White, Nicholas J., von Seidlein, Lorenz, and Mayxay, Mayfong

Published
2020
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241. The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis

Author

Chan, Xin Hui S., Haeusler, Ilsa L., Win, Yan Naung, Pike, James, Hanboonkunupakarn, Borimas, Hanafiah, Maryam, Lee, Sue J., Djimdé, Abdoulaye, Fanello, Caterina I., Kiechel, Jean-René, Lacerda, Marcus VG, Ogutu, Bernhards, Onyamboko, Marie A., Siqueira, André M., Ashley, Elizabeth A., Taylor, Walter RJ, and White, Nicholas J.

Subjects
Drugs -- Adverse and side effects, Malaria -- Drug therapy, Cardiovascular diseases -- Risk factors, Biological sciences
Abstract

Background Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. Methods and findings Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged [greater than or equal to]12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia ([less than or equal to]50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged Conclusions While caution is advised in the use of amodiaquine in patients aged [greater than or equal to]12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria., Author(s): Xin Hui S. Chan 1,2,*, Ilsa L. Haeusler 3, Yan Naung Win 1,4, James Pike 1, Borimas Hanboonkunupakarn 1,5, Maryam Hanafiah 1, Sue J. Lee 1,2, Abdoulaye Djimdé 6, [...]

Published
2021
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