PLoS clinical trials最新文献

Objective: The candidate malaria vaccine RTS,S/AS02A is a recombinant protein containing part of the circumsporozoite protein (CSP) sequence of Plasmodium falciparum, linked to the hepatitis B surface antigen and formulated in the proprietary adjuvant system AS02A. In a recent trial conducted in children younger than age five in southern Mozambique, the vaccine demonstrated significant and sustained efficacy against both infection and clinical disease. In a follow-up study to the main trial, breakthrough infections identified in the trial were examined to determine whether the distribution of csp sequences was affected by the vaccine and to measure the multiplicity of infecting parasite genotypes.

Design: P. falciparum DNA from isolates collected during the trial was used for genotype studies.

Setting: The main trial was carried out in the Manhiça district, Maputo province, Mozambique, between April 2003 and May 2004.

Participants: Children from the two cohorts of the main trial provided parasite isolates as follows: children from Cohort 1 who were admitted to hospital with clinical malaria; children from Cohort 1 who were parasite-positive in a cross-sectional survey at study month 8.5; children from Cohort 2 identified as parasite-positive during follow-up by active detection of infection.

Outcome: Divergence of DNA sequence encoding the CSP T cell-epitope region sequence from that of the vaccine sequence was measured in 521 isolates. The number of distinct P. falciparum genotypes was also determined.

Results: We found no evidence that parasite genotypes from children in the RTS,S/AS02A arm were more divergent than those receiving control vaccines. For Cohort 1 (survey at study month 8.5) and Cohort 2, infections in the vaccine group contained significantly fewer genotypes than those in the control group, (p = 0.035, p = 0.006), respectively, for the two cohorts. This was not the case for children in Cohort 1 who were admitted to hospital (p = 0.478).

Conclusions: RTS,S/AS02A did not select for genotypes encoding divergent T cell epitopes in the C-terminal region of CSP in this trial. In both cohorts, there was a modest reduction in the mean number of parasite genotypes harboured by vaccinated children compared with controls, but only among those with asymptomatic infections.

Objectives: To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda.

Design: Randomized single-blind controlled trial.

Setting: Tororo, Uganda, an area of high-level malaria transmission.

Participants: Children aged one to ten years with confirmed uncomplicated P. falciparum malaria.

Interventions: Amodiaquine + artesunate or artemether-lumefantrine.

Outcome measures: Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.

Results: Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether-lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether-lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%-24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether-lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%-25.2%). Amodiaquine + artesunate and artemether-lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens.

Conclusions: Amodiaquine + artesunate and artemether-lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether-lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.

Objective: The objective of this trial, the Leiden 85-Plus Occupational Therapy Intervention Study (LOTIS), was to assess whether unsolicited occupational therapy, as compared to no therapy, can decelerate the increase in disability in high-risk elderly people.

Design: This was a randomised controlled trial with 2-y follow-up.

Setting: The study took place in the municipality of Leiden in the Netherlands.

Participants: The participants were 402 community-dwelling 85-y-old people, with a Mini-Mental State Examination score of >18 points at baseline.

Interventions: Participants in the intervention group were visited by an occupational therapist who provided training and education about assistive devices that were already present and who gave recommendations and information about procedures, possibilities, and costs of assistive devices and community-based services. Control participants were not visited by an occupational therapist.

Outcome measures: The primary outcome measure was the score achieved on the Groningen Activity Restriction Scale. Secondary outcome measures included self-evaluations of well-being and feelings of loneliness.

Results: THE PARTICIPANTS WERE EVENLY DIVIDED BETWEEN THE TWO GROUPS: 202 participants were allocated to the intervention group and 200 participants to the control group. Of the 202 participants randomised to occupational therapy, 55 participants declined the proposed intervention. An occupational therapist indicated that of the remaining 147 participants, 66 (45%) needed an occupational therapy intervention. A total of 44 new assistive devices and five community-based services were implemented. During follow-up there was a progressive increase in disability in the intervention group (mean annual increase, 2.0 points; SE 0.2; p < 0.001) and control group (mean annual increase, 2.1 points; SE 0.2; p < 0.001). The increase in disability was not significantly different between study groups (0.08 points; 95% CI, -1.1-1.2; p = 0.75). There was also no difference between study groups for any of the secondary outcome measures.

Conclusion: Unsolicited occupational therapy in high-risk elderly participants does not decelerate the increase in disability over time.

Objectives: We investigated whether reducing post-methionine homocysteine concentrations via various treatments other than folic acid affects vascular function, as measured through flow-mediated dilation (FMD) of the brachial artery. High fasting and post-methionine homocysteine concentrations are associated with cardiovascular disease risk, but homocysteine might be a surrogate marker for low folate status.

Design: This was a randomized, placebo-controlled, double-blind, crossover study.

Setting: The study took place at Wageningen University in Wageningen in the Netherlands.

Participants: Participants were 39 apparently healthy men and women, aged 50-70 y.

Interventions: Participants ingested 10 mg of folic acid, 3 g of betaine, 5 g of serine, and placebo together with an oral methionine load. Each supplement was tested on two different days.

Outcome measures: On each of the eight treatment days, plasma homocysteine concentrations and FMD were measured before (t = 0 h, fasting) and 6 h (t = 6 h) after methionine loading.

Results: The mean (+/- SD) fasting homocysteine concentrations averaged over the eight test days were 9.6 +/- 2.1 micromol/l. Mean fasting FMD was 3.1 +/- 2.4 FMD%. A methionine load with placebo increased homocysteine concentrations by 17.2 +/- 9.3 micromol/l at 6 h after loading, similar to the increase following methionine loading with folic acid. A methionine load together with betaine and with serine increased homocysteine by 10.4 +/- 2.8 micromol/l (p < 0.001 relative to placebo) and by 12.1 +/- 8.2 micromol/l (p < 0.001 relative to placebo), respectively. Methionine loading with placebo did not affect FMD, and neither did methionine loading with folic acid, betaine, or serine; differences relative to placebo were +0.7 FMD% (95%CI, -0.6; 1.9), +0.2 FMD% (-1.0; 1.3), and +0.3 FMD% (-0.8; 1.4), respectively.

Conclusions: Experimentally induced acute changes in homocysteine concentrations did not affect FMD in healthy volunteers. This implies that potential adverse effects of high homocysteine concentrations on the cardiovascular system are not mediated through vascular function. However, homocysteine or folate may affect cardiovascular disease risk through other mechanisms.