Composite endpoints for malaria case-management: not simplifying the picture?

Rapid diagnostic tests (RDTs) for infection with Plasmodium spp. offer two main potential advantages related to malaria treatment: 1) ensuring that individuals with malaria are promptly treated with an effective artemisinin-based combination therapy, and 2) ensuring that individuals without malaria do not receive an anti-malarial they do not need (and instead receive a more appropriate treatment). Some studies of the impact of RDTs on malaria case management have combined these two different successes into a binary outcome describing 'correct management'. However combining correct management of positives and negatives into a single summary measure can be misleading. The problems, which are analogous to those encountered in the evaluation of diagnostic tests, can largely be avoided if data for patients with and without malaria are presented and analysed separately. Where a combined metric is necessary, then one of the established approaches to summarise the performance of diagnostic tests could be considered, although these are not without their limitations. Two graphical approaches to help understand case management performance are illustrated

Prevalence of pulmonary tuberculosis in western China in 2010–11: a population-based, cross-sectional survey

Background Progress in tuberculosis control in China has been the slowest in western areas, which have the highest prevalence. We assessed the prevalence of pulmonary tuberculosis in the Xinjiang province, China, 10 years after introduction of a control programme based on directly observed treatment, short course. Methods In this population-based, cross-sectional survey, we used a multistage stratifi ed random cluster sample design to estimate the prevalence of smear-positive and bacteriologically confi rmed (either smear positive or culture positive, or both) pulmonary tuberculosis among adults (aged ≥15 years) in Xinjiang who had been resident in their household for the last 6 months. The screening strategy and diagnosis followed WHO guidelines. We estimated prevalence by combining inverse probability weighting and multiple imputation of missing data. We compared our prevalence survey estimates with the ones from the 2010 China national pulmonary tuberculosis survey and the ones from a provincial pulmonary survey done in Xinjiang in 2000. The new smear-positive pulmonary tuberculosis notifi cation rate in 2011 in Xinjiang was obtained to allow the calculation of patient diagnosis rate (PDR). Findings Between Sept 1, 2010, and July 31, 2011, 31 081 individuals were eligible, of whom 29 835 (96·0%) participated in the survey. We identifi ed 50 (0·2%) smear-positive and 101 (0·3%) bacteriologically confi rmed pulmonary tuberculosis cases. The weighted prevalence of smear-positive pulmonary tuberculosis was 170 (95% CI 103–233) per 100 000 people and of bacteriologically confi rmed pulmonary tuberculosis was 430 (249–611) per 100 000 people. Compared with 2000 Xinjiang survey estimates, the prevalence of smear-positive pulmonary tuberculosis has decreased by 26·4% (from 231 [95% CI 148–314] per 100 000 people), whereas the prevalence of bacteriologically confi rmed pulmonary tuberculosis has increased by 17·8% (from 365 [237–493] per 100 000 people). In each age group and sex, the pulmonary tuberculosis prevalence was higher in the 2010–11 Xinjiang survey than in the 2010 national survey. The PDR in 2011 was 0·34 (95% CI 0·25–0·44). Interpretation Despite progress in other parts of China, the prevalence of pulmonary tuberculosis in Xinjiang remains high. The very low PDR suggests poor access to diagnosis and care. Further studies are needed to understand the barriers to diagnosis and care of this population, and eff orts are urgently needed to enhance tuberculosis screening in this area

The addition of artesunate to chloroquine for treatment of Plasmodium falciparum malaria in Gambian children delays, but does not prevent treatment failure.

In a randomized controlled trial, chloroquine monotherapy was compared with the combination of artesunate and chloroquine for treating uncomplicated Plasmodium falciparum malaria in 536 Gambian children. Chloroquine-treated children exhibited a 28-day clinical failure rate of 15% (95% confidence interval [CI] = 9.2-22%) compared with 11% (7.8-15%) among children receiving the combination (P = 0.08, by Wilcoxon test). Seventy-three percent of chloroquine-treated children exhibited parasitemia during follow-up compared with 49% of children receiving the combination (relative risk = 1.5, 95% CI = 1.3-1.7; chi2 = 21.18, P < 0.001). A significant reduction in clinical and parasitologic treatment failure in the combination group occurred in the first two weeks following treatment, but this was eroded over weeks three and four of follow-up. The impact of combination therapy on the transmission of chloroquine-resistant parasites is discussed. Chloroquine plus artesunate is not sufficiently efficacious to justify its introduction as a replacement for chloroquine monotherapy in The Gambia

Prevention of the Recurrence of Anaemia in Gambian Children Following Discharge from Hospital

BACKGROUND: In malaria endemic countries, children who have experienced an episode of severe anaemia are at increased risk of a recurrence of anaemia. There is a need to find ways of protecting these at risk children from malaria and chemoprevention offers a potential way of achieving this objective. METHODS: During the 2003 and 2004 malaria transmission seasons, 1200 Gambian children with moderate or severe anaemia (Hb concentration <7 g/dL) were randomised to receive either monthly sulfadoxine-pyrimethamine (SP) or placebo until the end of the malaria transmission season in which they were enrolled, in a double-blind trial. All study subjects were treated with oral iron for 28 days and morbidity was monitored through surveillance at health centres. The primary endpoint was the proportion of children with moderate or severe anaemia at the end of the transmission season. Secondary endpoints included the incidence of clinical episodes of malaria during the surveillance period, outpatient attendances, the prevalence of parasitaemia and splenomegaly, nutritional status at the end of the malaria transmission season and compliance with the treatment regimen. RESULTS: The proportions of children with a Hb concentration of <7 g/dL at the end of the malaria transmission season were similar in the two study groups, 14/464 (3.0%) in children who received at least one dose of SP and 16/471 (3.4%) in those who received placebo, prevalence ratio 0.89 (0.44,1.8) P = 0.742. The protective efficacy of SP against episodes of clinical malaria was 53% (95% CI 37%, 65%). Treatment with SP was safe and well tolerated; no serious adverse events related to SP administration were observed. Mortality following discharge from hospital was low among children who received SP or placebo (6 in the SP group and 9 in the placebo group respectively). CONCLUSIONS: Intermittent treatment with SP did not reduce the proportion of previously anaemic children with moderate or severe anaemia at the end of the malaria season, although it prevented malaria. The combination of appropriate antimalarial treatment plus one month of iron supplementation and good access to healthcare during follow-up proved effective in restoring haemoglobin to an acceptable level in the Gambian setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT00131716

Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN). METHODS AND FINDINGS: An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia ≥ 5,000/µl, was 2.88 (95% confidence interval [CI] 2.70-3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78-0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%-74%) (p<0.001). There was a 69% (95% CI 6%-90%) reduction in incidence of severe malaria (p = 0.04) and a 46% (95% CI 7%-69%) (p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%-77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%-70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65-1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72-0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3-3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded. CONCLUSIONS: IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission. TRIAL REGISTRATION: ClinicalTrials.govNCT00738946. Please see later in the article for the Editors' Summary

situ particle size distributions and volume concentrations from a LISST-100 laser particle sizer and a digital floc

Abstract A LISST-100 in situ laser particle sizer was deployed together with a digital floc camera during field work in the Newark Bay area (USA) and along the Apennine margin (the Adriatic Sea, Italy). The purpose of these simultaneous deployments was to investigate how well in situ particle (floc) sizes and volume concentrations from the two different instruments compared. In the Adriatic Sea the two instruments displayed the same temporal variation, but the LISST provided lower estimates of floc size by a factor of 2-3, compared to the DFC. In the Newark Bay area, the LISST provided higher values of floc size by up to a factor of 2. When floc size was computed using only the overlapping size bins from the two instruments the discrepancy disappeared. The reason for the discrepancy in size was found to be related to several issues: First, the LISST measured particles in the 2.5-500 mm range, whereas the camera measured particles in the 135-9900 mm range, so generally the LISST should provide lower estimates of floc size, as it measures the smaller particles. Second, in the Newark Bay area scattering from particles 4500 mm generally caused the LISST to overestimate the volume of particles in its largest size bin, thereby increasing apparent floc size. Relative to the camera, the LISST generally provided estimates of total floc volume that were lower by a factor of 3. Factors that could explain this discrepancy are errors arising from the accuracy of the LISST volume conversion coefficient and image processing. Regardless of these discrepancies, the shapes of the size spectra from the instruments were similar in the regions of overlap and could be matched by multiplying with an appropriate correction coefficient. This facilitated merging of the size spectra from the LISST and the DFC, yielding size spectra in the 2.5-9900 mm range. The merged size spectra generally had one or more peaks in the coarse end of the spectrum, presumably due to the presence of flocs. The fine end (o100 mm) of the spectrum displayed a flat tail with equal concentration of particles in all size classes. Size spectra with this shape indicate that the classical Junge model for description of in situ particle size spectra is reasonable for particles smaller than 100 mm but not for larger particles. Floc fraction was computed for the merged spectra by using a diameter-to-mass conversion and found to vary between 0.34 and 0.95, within the range reported by other authors.

Large-scale delivery of seasonal malaria chemoprevention to children under 10 in Senegal: an economic analysis.

Seasonal Malaria Chemoprevention (SMC) is recommended for children under 5 in the Sahel and sub-Sahel. The burden in older children may justify extending the age range, as has been done effectively in Senegal. We examine costs of door-to-door SMC delivery to children up to 10 years by community health workers (CHWs). We analysed incremental financial and economic costs at district level and below from a health service perspective. We examined project accounts and prospectively collected data from 405 CHWs, 46 health posts, and 4 district headquarters by introducing questionnaires in advance and completing them after each monthly implementation round. Affordability was explored by comparing financial costs of SMC to relevant existing health expenditure levels. Costs were disaggregated by administration month and by health service level. We used linear regression models to identify factors associated with cost variation between health posts. The financial cost to administer SMC to 180 000 children over one malaria season, reaching ∼93% of children with all three intended courses of SMC was $234 549 (constant 2010 USD) or$0.50 per monthly course administered. Excluding research-participation incentives, the financial cost was $0.32 per resident (all ages) in the catchment area, which is 1.2$278 922 or $0.59 per course administered and varied widely between health posts, from$0.38 to $2.74 per course administered. Substantial economies of scale across health posts were found, with the smallest health posts incurring highest average costs per monthly course administered. SMC for children up to 10 is likely to be affordable, particularly where it averts substantial curative care costs. Estimates of likely costs and cost-effectiveness of SMC in other contexts must account for variation in average costs across delivery months and health posts

Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization

<p>Abstract</p> <p>Background</p> <p>Calcitonin gene-related peptide (CGRP), a neuropeptide released from trigeminal nerves, is implicated in the underlying pathology of temporomandibular joint disorder (TMD). Elevated levels of CGRP in the joint capsule correlate with inflammation and pain. CGRP mediates neurogenic inflammation in peripheral tissues by increasing blood flow, recruiting immune cells, and activating sensory neurons. The goal of this study was to investigate the capability of CGRP to promote peripheral and central sensitization in a model of TMD.</p> <p>Results</p> <p>Temporal changes in protein expression in trigeminal ganglia and spinal trigeminal nucleus were determined by immunohistochemistry following injection of CGRP in the temporomandibular joint (TMJ) capsule of male Sprague-Dawley rats. CGRP stimulated expression of the active forms of the MAP kinases p38 and ERK, and PKA in trigeminal ganglia at 2 and 24 hours. CGRP also caused a sustained increase in the expression of c-Fos neurons in the spinal trigeminal nucleus. In contrast, levels of P2X₃in spinal neurons were only significantly elevated at 2 hours in response to CGRP. In addition, CGRP stimulated expression of GFAP in astrocytes and OX-42 in microglia at 2 and 24 hours post injection.</p> <p>Conclusions</p> <p>Our results demonstrate that an elevated level of CGRP in the joint, which is associated with TMD, stimulate neuronal and glial expression of proteins implicated in the development of peripheral and central sensitization. Based on our findings, we propose that inhibition of CGRP-mediated activation of trigeminal neurons and glial cells with selective non-peptide CGRP receptor antagonists would be beneficial in the treatment of TMD.</p

Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Mali: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria. However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs). Whether IPTc provides additional protection to children sleeping under an ITN has not been established. METHODS AND FINDINGS: To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali. After screening, eligible children aged 3-59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos. Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008. Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period. The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up. Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition. Cox regression was used to compare incidence rates between intervention and control arms. The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up. During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45). A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76-2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29-0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%-85%) (p<0.001) on the primary endpoint. There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%-99%) (p = 0.001). IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%-92%) (p<0.001) during the intervention period and by 46% (95% CI 31%-68%) (p<0.001) at the end of the intervention period. The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%-67%) (p<0.007) at the end of intervention period. The frequencies of adverse events were similar between the two arms. There was no drug-related serious adverse event. CONCLUSIONS: IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN. SP+AQ was safe and well tolerated. These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT00738946. Please see later in the article for the Editors' Summary

Vulnerability and resilience of living marine resources to the Deepwater Horizon oil spill : an overview

Funding for the project was primarily provided by the Gulf of Mexico Research Initiative through several of its research centers.The 2010 Deepwater Horizon (DWH) oil well blowout in the Gulf of Mexico (GoM) was the largest and perhaps most consequential accidental marine oil spill in global history. This paper provides an overview of a Research Topic consisting of four additional papers that: (1) assemble time series data for ecosystem components in regions impacted by the spill, and (2) interpret temporal changes related to the vulnerability of species and ecosystems to DWH and the ensuing resilience to perturbation. Time series abundance data for many taxa pre-date DWH, often by decades, thus allowing an assessment of population- and community-level impacts. We divided the north central GoM into four interconnected “eco-types”: the coastal/nearshore, continental shelf, open-ocean pelagic and deep benthic. Key taxa in each eco-type were evaluated for their vulnerability to the circumstances of the DWH spill based on population overlap with oil, susceptibility to oil contamination, and other factors, as well their imputed resilience to population-level impacts, based on life history metrics, ecology and post-spill trajectories. Each taxon was scored as low, medium, or high for 13 vulnerability attributes and 11 resilience attributes to produce overall vulnerability and resilience scores, which themselves were also categorical (i.e., low, medium, or high). The resulting taxon-specific V-R scores provide important guidance on key species to consider and monitor in the event of future spills similar to DWH. Similar analyses may also guide resource allocation to collect baseline data on highly vulnerable taxa or those with low resilience potential in other ecosystems. For some species, even a decade of observation has been insufficient to document recovery given chronic, long-term exposure to DWH oil remaining in all eco-types and because of impacts to the reproductive output of long-lived species. Due to the ongoing threats of deep-water blowouts, continued surveillance of populations affected by DWH is warranted to document long-term recovery or change in system state. The level of population monitoring in the open-ocean and deep benthic eco-types has historically been low and is inconsistent with the continued migration of the oil industry to the ultra-deep (≥1,500 m) where the majority of leasing, exploration, and production now occurs.Publisher PDFPeer reviewe