Empirical correlation of triggered activity and spatial and temporal re-entrant substrates with arrhythmogenicity in a murine model for Jervell and Lange-Nielsen syndrome

KCNE1 encodes the β-subunit of the slow component of the delayed rectifier K+ current. The Jervell and Lange-Nielsen syndrome is characterized by sensorineural deafness, prolonged QT intervals, and ventricular arrhythmogenicity. Loss-of-function mutations in KCNE1 are implicated in the JLN2 subtype. We recorded left ventricular epicardial and endocardial monophasic action potentials (MAPs) in intact, Langendorff-perfused mouse hearts. KCNE1−/− but not wild-type (WT) hearts showed not only triggered activity and spontaneous ventricular tachycardia (VT), but also VT provoked by programmed electrical stimulation. The presence or absence of VT was related to the following set of criteria for re-entrant excitation for the first time in KCNE1−/− hearts: Quantification of APD90, the MAP duration at 90% repolarization, demonstrated alterations in (1) the difference, ∆APD90, between endocardial and epicardial APD90 and (2) critical intervals for local re-excitation, given by differences between APD90 and ventricular effective refractory period, reflecting spatial re-entrant substrate. Temporal re-entrant substrate was reflected in (3) increased APD90 alternans, through a range of pacing rates, and (4) steeper epicardial and endocardial APD90 restitution curves determined with a dynamic pacing protocol. (5) Nicorandil (20 µM) rescued spontaneous and provoked arrhythmogenic phenomena in KCNE1−/− hearts. WTs remained nonarrhythmogenic. Nicorandil correspondingly restored parameters representing re-entrant criteria in KCNE1−/− hearts toward values found in untreated WTs. It shifted such values in WT hearts in similar directions. Together, these findings directly implicate triggered electrical activity and spatial and temporal re-entrant mechanisms in the arrhythmogenesis observed in KCNE1−/− hearts

Malaria transmission pattern resilience to climatic variability is mediated by insecticide-treated nets

<p>Abstract</p> <p>Background</p> <p>Malaria is an important public-health problem in the archipelago of Vanuatu and climate has been hypothesized as important influence on transmission risk. Beginning in 1988, a major intervention using insecticide-treated bed nets (ITNs) was implemented in the country in an attempt to reduce <it>Plasmodium </it>transmission. To date, no study has addressed the impact of ITN intervention in Vanuatu, how it may have modified the burden of disease, and whether there were any changes in malaria incidence that might be related to climatic drivers.</p> <p>Methods and findings</p> <p>Monthly time series (January 1983 through December 1999) of confirmed <it>Plasmodium falciparum </it>and <it>Plasmodium vivax </it>infections in the archipelago were analysed. During this 17 year period, malaria dynamics underwent a major regime shift around May 1991, following the introduction of bed nets as a control strategy in the country. By February of 1994 disease incidence from both parasites was reduced by at least 50%, when at most 20% of the population at risk was covered by ITNs. Seasonal cycles, as expected, were strongly correlated with temperature patterns, while inter-annual cycles were associated with changes in precipitation. Following the bed net intervention, the influence of environmental drivers of malaria dynamics was reduced by 30–80% for climatic forces, and 33–54% for other factors. A time lag of about five months was observed for the qualitative change ("regime shift") between the two parasites, the change occurring first for <it>P. falciparum</it>. The latter might be explained by interspecific interactions between the two parasites within the human hosts and their distinct biology, since <it>P. vivax </it>can relapse after a primary infection.</p> <p>Conclusion</p> <p>The Vanuatu ITN programme represents an excellent example of implementing an infectious disease control programme. The distribution was undertaken to cover a large, local proportion (~80%) of people in villages where malaria was present. The successful coverage was possible because of the strategy for distribution of ITNs by prioritizing the free distribution to groups with restricted means for their acquisition, making the access to this resource equitable across the population. These results emphasize the need to implement infectious disease control programmes focusing on the most vulnerable populations.</p

Can universal insecticide-treated net campaigns achieve equity in coverage and use? the case of northern Nigeria

<p>Abstract</p> <p>Background</p> <p>Insecticide-treated nets (ITNs) are effective tools for malaria prevention and can significantly reduce severe disease and mortality due to malaria, especially among children under five in endemic areas. However, ITN coverage and use remain low and inequitable among different socio-economic groups in sub-Saharan Africa, particularly in Nigeria. Several strategies have been proposed to increase coverage and use and reduce inequity in Nigeria, including free distribution campaigns recently conducted by the Nigerian federal government. Using data from the first post-campaign survey, the authors investigated the effect of the mass free distribution campaigns in achieving equity in household ownership and use of ITNs.</p> <p>Methods</p> <p>A post-campaign survey was undertaken in November 2009 in northern Nigeria to assess the effect of the campaigns in addressing equity across different socio-economic groups. The survey included 987 households randomly selected from 60 clusters in Kano state. Using logistic regression and the Lorenz concentration curve and index, the authors assessed equity in ITN coverage and use.</p> <p>Results</p> <p>ITN ownership coverage increased from 10% before the campaigns to 70%-a more than fivefold increase. The campaigns reduced the ownership coverage gap by 75%, effectively reaching parity among wealth quintiles (Concentration index 0.02, 95% CI (-0.02 ; 0.05) versus 0.21 95%CI (0.08 ; 0.34) before the campaigns). ITN use (individuals reporting having slept under an ITN the night before the survey visit) among individuals from households owning at least one ITN, was 53.1% with no statistically significant difference between the lowest, second, third and fourth wealth quintiles and the highest wealth quintile (lowest: odds ratio (OR) 0.87, 95% confidence interval (CI) (0.67 ; 1.13); second: OR 0.85, 95% CI (0.66 ; 1.24); third: OR 1.10 95% CI (0.86 ; 1.4) and fourth OR 0.91 95% CI (0.72 ; 1.15).</p> <p>Conclusion</p> <p>The campaign had a significant impact by increasing ITN coverage and reducing inequity in ownership and use. Free ITN distribution campaigns should be sustained to increase equitable coverage. These campaigns should be supplemented with other ITN distribution strategies to cover newborns and replace aging nets.</p

Effects of community-level bed net coverage on malaria morbidity in Lilongwe, Malawi

Abstract Background The protective effect of insecticide-treated bed nets against individual-level malaria transmission is well known, however community-level effects are less understood. Protective effects from community-level bed net use against malaria transmission have been observed in clinical trials, however, the relationship is less clear outside of a controlled research setting. The objective of this research was to investigate the effect of community-level bed net use against malaria transmission outside of a bed net clinical trial setting in Lilongwe, Malawi following national efforts to scale-up ownership of long-lasting, insecticide-treated bed nets. Methods An annual, cross-sectional, household-randomized, malaria transmission intensity survey was conducted in Lilongwe, Malawi (2011–2013). Health, demographic, and geographic-location data were collected. Participant blood samples were tested for Plasmodium falciparum presence. The percentage of people sleeping under a bed net within 400-m and 1-km radii of all participants was measured. Mixed effects logistic regression models were used to measure the relationship between malaria prevalence and surrounding bed net coverage. Each year, 800 people were enrolled (400 <5 years; 200 5–19 years; 200 ≥20 years; total n = 2400). Results From 2011 to 2013, malaria prevalence declined from 12.9 to 5.6%, while bed net use increased from 53.8 to 78.6%. For every 1% increase in community bed net coverage, malaria prevalence decreased among children under 5 years old [adjusted odds ratio: 0.98 (0.96, 1.00)]. Similar effects were observed in participants 5–19 years [unadjusted odds ratio: 0.98 (0.97, 1.00)]; the effect was attenuated after adjusting for individual-level bed net use. Community coverage was not associated with malaria prevalence among adults ≥20 years. Supplemental analyses identified more pronounced indirect protective effects from community-level bed net use against malaria transmission among children under 5 years who were sleeping under a bed net [adjusted odds ratio: 0.97 (0.94, 0.99)], compared to children who were not sleeping under a bed net [adjusted odds ratio: 0.99 (0.97, 1.01)]. Conclusions Malawi’s efforts to scale up ownership of long-lasting, insecticide-treated bed nets are effective in increasing reported use. Increased community-level bed net coverage appears to provide additional protection against malaria transmission beyond individual use in a real-world context

Microfluidic high performance liquid chromatography-chip hyphenation to inductively coupled plasma-mass spectrometry

The Agilent Chip Cube Interface is a microfluidic chip-based technology originally designed for nanospray molecular mass spectrometry in which the sample enrichment, nano-column, tubing, connectors and spray tip were integrated into a single biocompatible chip. Here we describe the hyphenation of the Chip Cube Interface to ICP-MS via modification of the standard HPLC chip design and a new total consumption nebuliser suitable for flow rates as low as 300nLmin-1. The potential of the instrument to eliminate common nanoLC - ICP-MS shortcomings such as leaks, blockages and band-broadening was demonstrated via analysis of cyanocobalamin in equine plasma. The method was linear over three orders of magnitude with an r2 of 0.9999, the peak area repeatability was 1.9% (n=7), and the detection limit was 14ngmL-1. This novel configuration of the Chip Cube Interface coupled to ICP-MS is a suitable platform for the analysis of biomolecules associated with trace metals and speciation applications

School mental health services: signpost for out-of-school service utilization in adolescents with mental disorders? : a nationally representative United States cohort

Background: School mental health services are important contact points for children and adolescents with mental disorders, but their ability to provide comprehensive treatment is limited. The main objective was to estimate in mentally disordered adolescents of a nationally representative United States cohort the role of school mental health services as guide to mental health care in different out-of-school service sectors. Methods: Analyses are based on weighted data (N = 6483) from the United States National Comorbidity Survey Replication Adolescent Supplement (participants' age: 13–18 years). Lifetime DSM-IV mental disorders were assessed using the fully structured WHO CIDI interview, complemented by parent report. Adolescents and parents provided information on mental health service use across multiple sectors, based on the Service Assessment for Children and Adolescents. Results: School mental health service use predicted subsequent out-of-school service utilization for mental disorders i) in the medical specialty sector, in adolescents with affective (hazard ratio (HR) = 3.01, confidence interval (CI) = 1.77–5.12), anxiety (HR = 3.87, CI = 1.97–7.64), behavior (HR = 2.49, CI = 1.62–3.82), substance use (HR = 4.12, CI = 1.87–9.04), and eating (HR = 10.72, CI = 2.31–49.70) disorders, and any mental disorder (HR = 2.97, CI = 1.94–4.54), and ii) in other service sectors, in adolescents with anxiety (HR = 3.15, CI = 2.17–4.56), behavior (HR = 1.99, CI = 1.29–3.06), and substance use (HR = 2.48, CI = 1.57–3.94) disorders, and any mental disorder (HR = 2.33, CI = 1.54–3.53), but iii) not in the mental health specialty sector. Conclusions: Our findings indicate that in the United States, school mental health services may serve as guide to out-of-school service utilization for mental disorders especially in the medical specialty sector across various mental disorders, thereby highlighting the relevance of school mental health services in the trajectory of mental care. In light of the missing link between school mental health services and mental health specialty services, the promotion of a stronger collaboration between these sectors should be considered regarding the potential to improve and guarantee adequate mental care at early life stages

Best practices for an insecticide-treated bed net distribution programme in sub-Saharan eastern Africa

<p>Abstract</p> <p>Insecticide-treated bed nets are the preeminent malaria control means; though there is no consensus as to a best practice for large-scale insecticide-treated bed net distribution. In order to determine the paramount distribution method, this review assessed literature on recent insecticide treated bed net distribution programmes throughout sub-Saharan Eastern Africa. Inclusion criteria were that the study had taken place in sub-Saharan Eastern Africa, targeted malaria prevention and control, and occurred between 1996 and 2007. Forty-two studies were identified and reviewed. The results indicate that distribution frameworks varied greatly; and consequently so did outcomes of insecticide-treated bed net use. Studies revealed consistent inequities between urban and rural populations; which were most effectively alleviated through a free insecticide-treated bed net delivery and distribution framework. However, cost sharing through subsidies was shown to increase programme sustainability, which may lead to more long-term coverage. Thus, distribution should employ a catch up/keep up programme strategy. The catch-up programme rapidly scales up coverage, while the keep-up programme maintains coverage levels. Future directions for malaria should include progress toward distribution of long-lasting insecticide-treated nets.</p