The interaction between seasonality and pulsed interventions against malaria in their effects on the reproduction number.

The basic reproduction number (R0) is an important quantity summarising the dynamics of an infectious disease, as it quantifies how much effort is needed to control transmission. The relative change in R0 due to an intervention is referred to as the effect size. However malaria and other diseases are often highly seasonal and some interventions have time-varying effects, meaning that simple reproduction number formulae cannot be used. Methods have recently been developed for calculating R0 for diseases with seasonally varying transmission. I extend those methods to calculate the effect size of repeated rounds of mass drug administration, indoor residual spraying and other interventions against Plasmodium falciparum malaria in seasonal settings in Africa. I show that if an intervention reduces transmission from one host to another by a constant factor, then its effect size is the same in a seasonal as in a non-seasonal setting. The optimal time of year for drug administration is in the low season, whereas the best time for indoor residual spraying or a vaccine which reduces infection rates is just before the high season. In general, the impact of time-varying interventions increases with increasing seasonality, if carried out at the optimal time of year. The effect of combinations of interventions that act at different stages of the transmission cycle is roughly the product of the separate effects. However for individual time-varying interventions, it is necessary to use methods such as those developed here rather than inserting the average efficacy into a simple formula.The work was funded by a fellowship from the UK Medical Research Council, grant number G1002284. http://www.mrc.ac.uk/index.htm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Quantum dot conjugated nanobodies for multiplex imaging of protein dynamics at synapses

Neurons communicate with each other through synapses, which show enrichment for specialized receptors. Although many studies have explored spatial enrichment and diffusion of these receptors in dissociated neurons using single particle tracking, much less is known about their dynamic properties at synapses in complex tissue like brain slices. Here we report the use of smaller and highly specific quantum dots conjugated with a recombinant single domain antibody fragment (VHH fragment) against green fluorescent protein to provide information on diffusion of adhesion molecules at the growth cone and neurotransmitter receptors at synapses. Our data reveals that QD-nanobodies can measure neurotransmitter receptor dynamics at both excitatory and inhibitory synapses in primary neuronal cultures as well as in ex vivo rat brain slices. We also demonstrate that this approach can be applied to tagging multiple proteins to simultaneously monitor their behavior. Thus, we provide a strategy for multiplex imaging of tagged membrane proteins to study their clustering, diffusion and transport both in vitro as well as in native tissue environments such as brain slices

Methods for estimating the case fatality ratio for a novel, emerging infectious disease.

During the course of an epidemic of a potentially fatal disease, it is important that the case fatality ratio be well estimated. The authors propose a novel method for doing so based on the Kaplan-Meier survival procedure, jointly considering two outcomes (death and recovery), and evaluate its performance by using data from the 2003 epidemic of severe acute respiratory syndrome in Hong Kong, People's Republic of China. They compare this estimate obtained at various points in the epidemic with the case fatality ratio eventually observed; with two commonly quoted, naïve estimates derived from cumulative incidence and mortality statistics at single time points; and with estimates in which a parametric mixture model is used. They demonstrate the importance of patient characteristics regarding outcome by analyzing subgroups defined by age at admission to the hospital

Gradual acquisition of immunity to severe malaria with increasing exposure

Previous analyses have suggested that immunity to non-cerebral severe malaria due to Plasmodium falciparum is acquired after only a few infections, whereas longitudinal studies show that some children experience multiple episodes of severe disease, suggesting that immunity may not be acquired so quickly. We fitted a mathematical model for the acquisition and loss of immunity to severe disease to the age distribution of severe malaria cases stratified by symptoms from a range of transmission settings in Tanzania, combined with data from several African countries on the age distribution and overall incidence of severe malaria. We found that immunity to severe disease was acquired more gradually with exposure than previously thought. The model also suggests that physiological changes, rather than exposure, may alter the symptoms of disease with increasing age, suggesting that a later age at infection would be associated with a higher proportion of cases presenting with cerebral malaria regardless of exposure. This has consequences for the expected pattern of severe disease as transmission changes. Careful monitoring of the decline in immunity associated with reduced transmission will therefore be needed to ensure rebound epidemics of severe and fatal malaria are avoided

On the relationship between fundamental measurements in TCP flows

This paper considers fundamental measurements which drive TCP flows: throughput, RTT and loss. It is clear that throughput is, in some sense, a function of both RTT and loss. In their seminal paper Padyhe et al [1] begin with a mathematical model of the TCP sliding window evolution process and come up with an equation showing that TCP throughput is (roughly) proportional to 1/RTT√p where p is the probability of packet loss. Their equation is shown to be consistent with data gathered on several links. This paper takes the opposite approach and analyses a large number of packet traces from well-known sources in order to create a data-driven estimate of the functions which relate TCP, loss and RTT. Regression analysis is used to fit models to connect the quantities. The fitted models show different behaviour from that expected in [1]

Measuring the Relationships between Internet Geography and RTT

When designing distributed systems and Internet protocols, designers can benefit from statistical models of the Internet that can be used to estimate their performance. However, it is frequently impossible for these models to include every property of interest. In these cases, model builders have to select a reduced subset of network properties, and the rest will have to be estimated from those available. In this paper we present a technique for the analysis of Internet round trip times (RTT) and its relationship with other geographic and network properties. This technique is applied on a novel dataset comprising ∼19 million RTT measurements derived from ∼200 million RTT samples between ∼54 thousand DNS servers. Our main contribution is an information-theoretical analysis that allows us to determine the amount of information that a given subset of geographic or network variables (such as RTT or great circle distance between geolocated hosts) gives about other variables of interest. We then provide bounds on the error that can be expected when using statistical estimators for the variables of interest based on subsets of other variables

Key traveller groups of relevance to spatial malaria transmission: a survey of movement patterns in four sub-Saharan African countries

Background: As malaria prevalence declines in many parts of the world due to widescale control efforts and as drug-resistant parasites begin to emerge, a quantitative understanding of human movement is becoming increasingly relevant to malaria control. However, despite its importance, significant knowledge gaps remain regarding human movement, particularly in sub-Saharan Africa. Methods: A quantitative survey of human movement patterns was conducted in four countries in sub-Saharan Africa: Mali, Burkina Faso, Zambia, and Tanzania, with three to five survey locations chosen in each country. Questions were included on demographic and trip details, malaria risk behaviour, children accompanying travellers, and mobile phone usage to enable phone signal data to be better correlated with movement. A total of 4352 individuals were interviewed and 6411 trips recorded. Results: A cluster analysis of trips highlighted two distinct traveller groups of relevance to malaria transmission: women travelling with children (in all four countries) and youth workers (in Mali). Women travelling with children were more likely to travel to areas of relatively high malaria prevalence in Mali (OR = 4.46, 95 % CI = 3.42–5.83), Burkina Faso (OR = 1.58, 95 % CI = 1.23–1.58), Zambia (OR = 1.50, 95 % CI = 1.20–1.89), and Tanzania (OR = 2.28, 95 % CI = 1.71–3.05) compared to other travellers. They were also more likely to own bed nets in Burkina Faso (OR = 1.77, 95 % CI = 1.25–2.53) and Zambia (OR = 1.74, 95 % CI = 1.34 2.27), and less likely to own a mobile phone in Mali (OR = 0.50, 95 % CI = 0.39–0.65), Burkina Faso (OR = 0.39, 95 % CI = 0.30–0.52), and Zambia (OR = 0.60, 95 % CI = 0.47–0.76). Malian youth workers were more likely to travel to areas of relatively high malaria prevalence (OR = 23, 95 % CI = 17–31) and for longer durations (mean of 70 days cf 21 days, p < 0.001) compared to other travellers. Conclusions: Women travelling with children were a remarkably consistent traveller group across all four countries surveyed. They are expected to contribute greatly towards spatial malaria transmission because the children they travel with tend to have high parasite prevalence. Youth workers were a significant traveller group in Mali and are expected to contribute greatly to spatial malaria transmission because their movements correlate with seasonal rains and hence peak mosquito densities. Interventions aimed at interrupting spatial transmission of parasites should consider these traveller groups

A model of parity-dependent immunity to placental malaria

C1 - Journal Articles RefereedPlasmodium falciparum placental infection during pregnancy is harmful for both mother and child. Protection from placental infection is parity-dependent, that is, acquired over consecutive pregnancies. However, the infection status of the placenta can only be assessed at delivery. Here, to better understand the mechanism underlying this parity-dependence, we fitted a model linking malaria dynamics within the general population to observed placental histology. Our results suggest that immunity resulting in less prolonged infection is a greater determinant of the parity-specific patterns than immunity that prevents placental sequestration. Our results also suggest the time when maternal blood first flows into the placenta is a high-risk period. Therefore, preventative strategies implementable before or early in pregnancy, such as insecticide-treated net usage in women of child-bearing age or any future vaccine, could substantially reduce the number of women who experience placental infection

Age-related differences in affective control and its association with mental health difficulties

Difficulties in regulating affect are core characteristics of a wide range of mental health conditions and are associated with deficits in cognitive control, particularly in affective contexts, affective control. The current study explored how affective control relates to mental health over the course of adolescence. We developed an Affective Control Task, which was administered to young adolescents (11–14 years; n = 29); mid-adolescents (15–18 years; n = 31), and adults (22–30 years; n = 31). The task required individuals to sort cards according to continuously changing rules: color, number, or item type. There was a neutral condition in which items were shapes, and an affective condition, in which items were emotional facial expressions. Better affective control was associated with fewer mental health difficulties (p < .001, R^{2} = .15). Affective control partially accounted for the association between age group and mental health problems, z = 2.61, p = .009, Akaike information criterion = 484, with the association being strongest in young adolescents, r (27) = −.44, p = .018. Affective control further accounted for variance in the association between self-reported (but not experimental) emotion regulation and mental health (z = −3.44, p < .001, Akaike information criterion = 440). Poor affective control, especially in young adolescents, is associated with more mental health problems and higher levels of emotion regulation difficulties. Improving affective control therefore may constitute a promising target for prevention