Systematic review of economic evaluations of preparedness strategies and interventions against influenza pandemics

Background

Although public health guidelines have implications for resource allocation, these issues were not explicitly considered in previous WHO pandemic preparedness and response guidance. In order to ensure a thorough and informed revision of this guidance following the H1N1 2009 pandemic, a systematic review of published and unpublished economic evaluations of preparedness strategies and interventions against influenza pandemics was conducted.

Methods

The search was performed in September 2011 using 10 electronic databases, 2 internet search engines, reference list screening, cited reference searching, and direct communication with relevant authors. Full and partial economic evaluations considering both costs and outcomes were included. Conversely, reviews, editorials, and studies on economic impact or complications were excluded. Studies were selected by 2 independent reviewers.

Results

44 studies were included. Although most complied with the cost effectiveness guidelines, the quality of evidence was limited. However, the data sources used were of higher quality in economic evaluations conducted after the 2009 H1N1 pandemic. Vaccination and drug regimens were varied. Pharmaceutical plus non-pharmaceutical interventions are relatively cost effective in comparison to vaccines and/or antivirals alone. Pharmaceutical interventions vary from cost saving to high cost effectiveness ratios. According to ceiling thresholds (Gross National Income per capita), the reduction of non-essential contacts and the use of pharmaceutical prophylaxis plus the closure of schools are amongst the cost effective strategies for all countries. However, quarantine for household contacts is not cost effective even for low and middle income countries.

Conclusion

The available evidence is generally inconclusive regarding the cost effectiveness of preparedness strategies and interventions against influenza pandemics. Studies on their effectiveness and cost effectiveness should be readily implemented in forthcoming events that also involve the developing world. Guidelines for assessing the impact of disease and interventions should be drawn up to facilitate these studies.     

Cultural phylogenetics of the Tupi language family in lowland South America

Background

Recent advances in automated assessment of basic vocabulary lists allow the construction of linguistic phylogenies useful for tracing dynamics of human population expansions, reconstructing ancestral cultures, and modeling transition rates of cultural traits over time.

Methods

Here we investigate the Tupi expansion, a widely-dispersed language family in lowland South America, with a distance-based phylogeny based on 40-word vocabulary lists from 48 languages. We coded 11 cultural traits across the diverse Tupi family including traditional warfare patterns, post-marital residence, corporate structure, community size, paternity beliefs, sibling terminology, presence of canoes, tattooing, shamanism, men''s houses, and lip plugs.

Results/Discussion

The linguistic phylogeny supports a Tupi homeland in west-central Brazil with subsequent major expansions across much of lowland South America. Consistently, ancestral reconstructions of cultural traits over the linguistic phylogeny suggest that social complexity has tended to decline through time, most notably in the independent emergence of several nomadic hunter-gatherer societies. Estimated rates of cultural change across the Tupi expansion are on the order of only a few changes per 10,000 years, in accord with previous cultural phylogenetic results in other language families around the world, and indicate a conservative nature to much of human culture.     

Modulation of ionizing radiation-induced apoptosis by bantam microRNA in Drosophila

In Drosophila, heterozygosity in the pro-apoptotic gene hid significantly reduces apoptosis that is induced by ionizing radiation (IR). Therefore, mechanisms that regulate Hid levels can potentially contribute to life-or-death decision of an irradiated cell. 3′UTR of hid mRNA contains 5 potential binding sites for bantam microRNA. Ectopic expression of ban attenuated apoptosis that results from ectopic expression of hid but the significance of this regulation under physiological conditions remained to be investigated. We report here that ban is needed to limit IR-induced apoptosis in larval imaginal discs. Using tubulin–EGFP ban sensors with ban consensus sequences in the 3′UTR, we find that EGFP decreases following IR, indicating that IR activates ban. Likewise, a tubulin–EGFP reporter with hid-3′UTR is repressed in irradiated discs and this repression requires ban consensus sites in the hid 3′UTR. ban mutant larvae show increased sensitivity to killing by IR, which is suppressed by a mutation in hid. These results can fit into a model in which IR activates ban and ban represses hid to limit IR-induced apoptosis. miRNAs have been shown previously to be induced by radiation but this is the first report that a miRNA is functionally important for radiation responses.     

Deep brain stimulation for neurologic and neuropsychiatric disorders

In the 1960s, ablative stereotactic surgery was employed for a variety of movement disorders and psychiatric conditions. Although largely abandoned in the 1970s because of highly effective drugs, such as levodopa for Parkinson's disease (PD), and a reaction against psychosurgery, the field has undergone a virtual renaissance, guided by a better understanding of brain circuitry and the circuit abnormalities underlying movement disorders such as PD and neuropsychiatric conditions, such as obsessive compulsive disorder. High-frequency electrical deep brain stimulation (DBS) of specific targets, introduced in the early 1990s for tremor, has gained widespread acceptance because of its less invasive, reversible, and adjustable features and is now utilized for an increasing number of brain disorders. This review summarizes the rationale behind DBS and the use of this technique for a variety of movement disorders and neuropsychiatric diseases.     

A mathematical model of thrombopoiesis in rats

A mathematical model of thrombopoiesis in rats is presented. This has four compartments; stem cells, megakaryocytes, thrombocytes and thrombopoietin. A high thrombopoietin concentration influences bone marrow proliferation in three ways. Firstly the stem cells are stimulated and a slow increase in megakaryocyte number follows. Secondly there are additional endomitoses in the (early) megakaryocytes resulting in an increase in megakaryocyte volume. Thirdly the megakaryocyte maturation time is shortened. The parameters of the model are determined from experimental values for the normal, maximum and minimum proliferation rates, maturation times and destruction rates. The model is tested by comparing simulated results for acute and chronic thrombocytopenia and thrombocytosis with experimental curves from the literature. The model and data agree within the limits of experimental error. Not all of the thrombopoietic regulatory system is known yet, so some important alternative hypotheses are investigated and compared with the model. Several hypotheses have been excluded in this way.     

High levels of circulating cardiac proteins indicate cardiac impairment in African children with severe Plasmodium falciparum malaria

A role of the heart in the pathophysiology of severe Plasmodium falciparum malaria has recently been suggested. The objective of the present study was to substantiate this finding in a large group of African children and to correlate results with metabolic conditions in these children. Furthermore, the impact of a potential cardiac impairment on outcome in severe cases was assessed. Results may have important implications on the currently ongoing debate on fluid management in severe malaria patients. Plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), myoglobin and creatine kinase muscle-brain (CK-MB) were compared in 400 African children with severe and mild falciparum malaria. Plasma levels of these markers were correlated with lactate and glucose blood levels, indicators for hypovolemia, and with clinical outcome. Children suffering from severe malaria and children who died (n = 22) exhibited high to very high levels of cardiac markers, respectively. Cardiac factors themselves were not predictive of fatal outcome, while, in multivariate analysis, lactic acidosis was the most important biochemical predictor of death in the severe malaria group. Lactic acidosis and hypoglycemia, however, result in cardiac impairment as defined by elevated levels of circulating cardiac proteins. Our results point to hypovolemia as a major underlying cause of lactic acidosis and hypoglycemia in African children with severe falciparum malaria. These deleterious metabolic conditions contribute to myocardial affection which was evident but not predictive per se of fatal outcome.     

Extinction risk, coloured noise and the scaling of variance

The impact of temporally correlated fluctuating environments (coloured noise) on the extinction risk of populations has become a main focus in theoretical population ecology. In this study we particularly focus on the extinction risk in strongly correlated environments. Here, we found that, in contrast to moderate auto-correlation, the extinction risk was highly dependent on the process of noise generation, in particular on the method of variance scaling. Such scaling is commonly applied to avoid variance-driven biases when comparing the extinction risk under white and coloured noise. We show that for strong auto-correlation often-used scaling techniques lead to a high variability in the variances of the resulting time series and thus to deviations in the subsequent extinction risk. Therefore, we present an alternative scaling method that always delivers the target variance, even in the case of strong auto-correlation. In contrast to earlier techniques, our very intuitive method is not bound to auto-regressive processes but can be applied to all types of coloured noises. We strongly recommend our method to generate time series when the target of interest is the effect of noise colour on extinction risk not obscured by any variance effects.     

Differences in the expression of LPS-receptors are not responsible for the sex-specific immune response after trauma and hemorrhagic shock

Several studies demonstrated a sex-specific cytokine secretion by macrophages following trauma-hemorrhage (T-H) and incubation with lipopolysaccharide A (LPS). Although LPS is known to act via the receptors CD14 and TLR4 on macrophages, it remains unknown whether differences in LPS receptor expression in males and females may be responsible for the gender-specific LPS induced cytokine response following (T-H). To study this, male and proestrus female mice (C3H/HeN) were subjected to trauma (laparotomy) followed by hemorrhage or sham operation. At 2 h thereafter, SMphi and PMphi were harvested and cultured for 2 h. The expression of CD14 and TLR4 was measured by flow cytometry on unstimulated SMphi and PMphi as well as after LPS stimulation. The results indicate that the expression of CD14 and TLR4 on SMphi and PMphi from female and male mice was similar in sham-operated animals and after (T-H). Incubation of macrophages with LPS did not alter CD14 and TLR4 expression in the study groups. Thus, the sex specific LPS induced cytokine secretion after (T-H) is not caused by differences in LPS receptor expression on Mphi of male and female mice.     

Melanocortin-4 receptor gene variant I103 is negatively associated with obesity

Several rare mutations in the melanocortin-4 receptor gene (MC4R) predispose to obesity. For the most common missense variant V103I (rs2229616), however, the previously reported similar carrier frequencies in obese and nonobese individuals are in line with in vitro studies, which have not shown a functional implication of this variant. In the present study, we initially performed a transmission/disequilibrium test on 520 trios with obesity, and we observed a lower transmission rate of the I103 allele (P=.017), which was an unexpected finding. Therefore, we initiated two large case-control studies (N=2,334 and N=661) and combined the data with those from 12 published studies, for a total of 7,713 individuals. The resulting meta-analysis provides evidence for a negative association of the I103 allele with obesity (odds ratio 0.69; 95% confidence interval 0.50-0.96; P=.03), mainly comprising samples of European origin. Additional screening of four other ethnic groups showed comparable I103 carrier frequencies well below 10%. Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I. In our functional in vitro assays, the variant was indistinguishable from the wild-type allele, as was the result in previous studies. This report on an SNP/haplotype that is negatively associated with obesity expands the successful application of meta-analysis of modest effects in common diseases to a variant with a carrier frequency well below 10%. The respective protective effect against obesity implies that variation in the MC4R gene entails both loss and gain of function.