Quantum superposition at the half-metre scale.

The quantum superposition principle allows massive particles to be delocalized over distant positions. Though quantum mechanics has proved adept at describing the microscopic world, quantum superposition runs counter to intuitive conceptions of reality and locality when extended to the macroscopic scale, as exemplified by the thought experiment of Schrödinger's cat. Matter-wave interferometers, which split and recombine wave packets in order to observe interference, provide a way to probe the superposition principle on macroscopic scales and explore the transition to classical physics. In such experiments, large wave-packet separation is impeded by the need for long interaction times and large momentum beam splitters, which cause susceptibility to dephasing and decoherence. Here we use light-pulse atom interferometry to realize quantum interference with wave packets separated by up to 54 centimetres on a timescale of 1 second. These results push quantum superposition into a new macroscopic regime, demonstrating that quantum superposition remains possible at the distances and timescales of everyday life. The sub-nanokelvin temperatures of the atoms and a compensation of transverse optical forces enable a large separation while maintaining an interference contrast of 28 per cent. In addition to testing the superposition principle in a new regime, large quantum superposition states are vital to exploring gravity with atom interferometers in greater detail. We anticipate that these states could be used to increase sensitivity in tests of the equivalence principle, measure the gravitational Aharonov-Bohm effect, and eventually detect gravitational waves and phase shifts associated with general relativity.

Transmission scenarios for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and how to tell them apart.

Detection of human cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection internationally is a global public health concern. Rigorous risk assessment is particularly challenging in a context where surveillance may be subject to under-ascertainment and a selection bias towards more severe cases. We would like to assess whether the virus is capable of causing widespread human epidemics, and whether self-sustaining transmission is already under way. Here we review possible transmission scenarios for MERS-CoV and their implications for risk assessment and control. We discuss how existing data, future investigations and analyses may help in reducing uncertainty and refining the public health risk assessment and present analytical approaches that allow robust assessment of epidemiological characteristics, even from partial and biased surveillance data. Finally, we urge that adequate data be collected on future cases to permit rigorous assessment of the transmission characteristics and severity of MERS-CoV, and the public health threat it may pose. Going beyond minimal case reporting, open international collaboration, under the guidance of the World Health Organization and the International Health Regulations, will impact on how this potential epidemic unfolds and prospects for control.

Immunity to non-cerebral severe malaria is acquired after one or two infections.

In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.

Influence of rearing and lay risk factors on propensity for feather damage in laying hens.

1. Feather pecking is one of the major problems facing the egg industry in non-cage systems and is set to become even more of an issue with the European Union ban on the keeping of laying hens in barren battery cages which comes into force in 2012 and the prospect of a ban on beak-trimming. Reducing feather pecking without resorting to beak treatment is an important goal for the poultry industry. 2. We report here a longitudinal study that included over 335,500 birds from 22 free range and organic laying farms. Accelerated failure time models and proportional hazards models were used to examine the effects of a wide range of factors (management, environment and bird) on development of substantial feather damage in lay. Particular emphasis was placed on risk factors during rear and on practices that could feasibly be changed or implemented. 3. The age at which a flock exhibits substantial feather damage could be predicted both by factors in the environment and by early symptoms in the birds themselves. Factors that were associated with earlier onset of severe feather damage included the presence of chain feeders, raised levels of carbon dioxide and ammonia, higher sound and light levels, particularly in younger birds. Increased feather damage (even very slight) in birds at 17-20 weeks of age was also highly predictive of the time of onset of severe feather damage during lay. Increased feed intake also indicated that a flock was at risk of early severe feather damage. 4. Birds that stayed on the same farm for rearing and lay showed later onset of serious feather damage than those that experienced a change in farm from rearing to lay. However, an increased number of changes between rearing and lay (feeder type, drinker type, light intensity etc) was not associated with earlier onset of serious feather damage. Further research needs to be done on the role of the transition from rearing to lay as a risk factor for FP in lay.

Synaptic weighting in single flux quantum neuromorphic computing.

Josephson junctions act as a natural spiking neuron-like device for neuromorphic computing. By leveraging the advances recently demonstrated in digital single flux quantum (SFQ) circuits and using recently demonstrated magnetic Josephson junction (MJJ) synaptic circuits, there is potential to make rapid progress in SFQ-based neuromorphic computing. Here we demonstrate the basic functionality of a synaptic circuit design that takes advantage of the adjustable critical current demonstrated in MJJs and implement a synaptic weighting element. The devices were fabricated with a restively shunted Nb/AlOx-Al/Nb process that did not include MJJs. Instead, the MJJ functionality was tested by making multiple circuits and varying the critical current, but not the external shunt resistance, of the oxide Josephson junction that represents the MJJ. Experimental measurements and simulations of the fabricated circuits are in good agreement.

The foot-and-mouth epidemic in Great Britain: pattern of spread and impact of interventions.

We present an analysis of the current foot-and-mouth disease epidemic in Great Britain over the first 2 months of the spread of the virus. The net transmission potential of the pathogen and the increasing impact of control measures are estimated over the course of the epidemic to date. These results are used to parameterize a mathematical model of disease transmission that captures the differing spatial contact patterns between farms before and after the imposition of movement restrictions. The model is used to make predictions of future incidence and to simulate the impact of additional control strategies. Hastening the slaughter of animals with suspected infection is predicted to slow the epidemic, but more drastic action, such as "ring" culling or vaccination around infection foci, is necessary for more rapid control. Culling is predicted to be more effective than vaccination.

Insect population control using a dominant, repressible, lethal genetic system.

A major modification to the sterile insect technique is described, in which transgenic insects homozygous for a dominant, repressible, female-specific lethal gene system are used. We demonstrate two methods that give the required genetic characteristics in an otherwise wild-type genetic background. The first system uses a sex-specific promoter or enhancer to drive the expression of a repressible transcription factor, which in turn controls the expression of a toxic gene product. The second system uses non-sex-specific expression of the repressible transcription factor to regulate a selectively lethal gene product. Both methods work efficiently in Drosophila melanogaster, and we expect these principles to be widely applicable to more economically important organisms.

Cross-species interactions between malaria parasites in humans.

The dynamics of multiple Plasmodium infections in asymptomatic children living under intense malaria transmission pressure provide evidence for a density-dependent regulation that transcends species as well as genotype. This regulation, in combination with species- and genotype-specific immune responses, results in nonindependent, sequential episodes of infection with each species.

Specificity of the Toxoplasma gondii-altered behaviour to definitive versus non-definitive host predation risk.

The hypothesis that the parasite Toxoplasma gondii manipulates the behaviour of its intermediate rat host in order to increase its chance of being predated specifically by its feline definitive host, rather than a non-definitive host predator species, was tested. The impact of a range of therapeutic drugs, previously demonstrated to be effective in preventing the development of T. gondii-associated behavioural and cognitive alterations in rats, on definitive-host predator specificity was also tested. Using a Y-shaped maze design, we demonstrated that T. gondii-associated behavioural changes, apparently aimed to increase predation rate, do appear to be specific to that of the feline definitive host--there were significant and consistent differences between the (untreated) infected and uninfected rats groups where T. gondii-infected rats tended to choose the definitive host feline-predator-associated maze arm and nest-box significantly more often than a maze arm or nest-box treated with non-definitive host predator (mink) odour. Drug treatment of infected rats prevented any such host-specificity from being displayed. We discuss our results in terms of their potential implications both for T. gondii epidemiology and the evolution of parasite-altered behaviour.

Refined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning.

CYD-TDV is the first licensed dengue vaccine for individuals 9-45 (or 60) years of age. Using 12% of the subjects enroled in phase-2b and phase-3 trials for which baseline serostatus was measured, the vaccine-induced protection against virologically confirmed dengue during active surveillance (0-25 months) was found to vary with prior exposure to dengue. Because age and dengue exposure are highly correlated in endemic settings, refined insight into how efficacy varies by serostatus and age is essential to understand the increased risk of hospitalisation observed among vaccinated individuals during the long-term follow-up and to develop safe and effective vaccination strategies. Here we apply machine learning to impute the baseline serostatus for subjects with post-dose 3 titres but missing baseline serostatus. We find evidence for age dependence in efficacy independent of serostatus and estimate that among 9-16 year olds, CYD-TDV is protective against serotypes 1, 3 and 4 regardless of baseline serostatus.

Early warning of footpad dermatitis and hockburn in broiler chicken flocks using optical flow, bodyweight and water consumption.

Footpad dermatitis and hockburn are serious welfare and economic issues for the production of broiler (meat) chickens. The authors here describe the use of an inexpensive camera system that monitors the movements of broiler flocks throughout their lives and suggest that it is possible to predict, even in young birds, the cross-sectional prevalence at slaughter of footpad dermatitis and hockburn before external signs are visible. The skew and kurtosis calculated from the authors' camera-based optical flow system had considerably more power to predict these outcomes in the 50 flocks reported here than water consumption, bodyweight or mortality and therefore have the potential to inform improved flock management through giving farmers early warning of welfare issues. Further trials are underway to establish the generality of the results.

Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour.

With increasing pressure to understand transmissible agents, renewed recognition of infectious causation of both acute and chronic diseases is occurring. Epidemiological and neuropathological studies indicate that some cases of schizophrenia may be associated with environmental factors, such as exposure to the ubiquitous protozoan Toxoplasma gondii. Reasons for this include T. gondii's ability to establish persistent infection within the central nervous system, its ability to manipulate intermediate host behaviour, the occurrence of neurological and psychiatric symptoms in some infected individuals, and an association between infection with increased incidence of schizophrenia. Moreover, several of the medications used to treat schizophrenia and other psychiatric disease have recently been demonstrated in vitro to possess anti-parasitic, and in particular anti-T. gondii, properties. Our aim here was thus to test the hypothesis that the anti-psychotic and mood stabilizing activity of some medications may be achieved, or at least augmented, through their in vivo inhibition of T. gondii replication and invasion in infected individuals. In particular we predicted, using the epidemiologically and clinically applicable rat-T. gondii model system, and following a previously described and neurologically characterized 'feline attraction' protocol that haloperidol (an anti-psychotic used in the treatment of mental illnesses including schizophrenia) and/or valproic acid (a mood stabilizer used in the treatment of mental illnesses including schizophrenia), would be, at least, as effective in preventing the development of T. gondii-associated behavioural and cognitive alterations as the standard anti-T. gondii chemotherapeutics pyrimethamine with Dapsone. We demonstrate that, while T. gondii appears to alter the rats' perception of predation risk turning their innate aversion into a 'suicidal' feline attraction, anti-psychotic drugs prove as efficient as anti-T. gondii drugs in preventing such behavioural alterations. Our results have important implications regarding the aetiology and treatment of such disorders.

Adherence to antiretroviral therapy and its impact on clinical outcome in HIV-infected patients.

We analyse data on patient adherence to prescribed regimens and surrogate markers of clinical outcome for 168 human immunodeficiency virus infected patients treated with antiretroviral therapy. Data on patient adherence consisted of dose-timing measurements collected for an average of 12 months per patient via electronic monitoring of bottle opening events. We first discuss how such data can be presented to highlight suboptimal adherence patterns and between-patient differences, before introducing two novel methods by which such data can be statistically modelled. Correlations between adherence and subsequent measures of viral load and CD4+T-cell counts are then evaluated. We show that summary measures of short-term adherence, which incorporate pharmacokinetic and pharmacodynamic data on the monitored regimen, predict suboptimal trends in viral load and CD4+T-cell counts better than measures based on adherence data alone.

Environmental and management factors affecting the welfare of chickens on commercial farms in the United Kingdom and Denmark stocked at five densities.

Data from a large commercial-scale experiment in which 10 major broiler producer companies stocked whole houses of birds at 30, 34, 38, 42, and 46 kg/m2 were analyzed to identify 1) temperature and humidity profiles achieved throughout the growth cycle, 2) management practices and equipment that contributed to observed variation in environmental conditions, and 3) the extent to which environmental variables affected bird welfare. The study involved a total of 2.7 million birds in 114 houses on commercial farms with measurement of a wide range of environmental and bird variables. Much of the variation in broiler health and welfare was associated with the percentage of time a company could maintain house temperature and RH within limits recommended by the breeder company. RH in the first week of life was particularly important to later health, suggesting that better control of humidity might lead to improved welfare. Key management factors affecting bird welfare were those relating to good ventilation and air control such as the type of ventilation, type of drinker, numbers of stockmen, and litter type. Controlling the environment, particularly temperature, humidity, and air and litter quality, is crucial to broiler chicken welfare. This does not mean that stocking density is unimportant, but lowering stocking density on its own, without regard to the environment the birds experience, is not sufficient. Genuine improvements in bird welfare will come from setting standards that combine stocking density, safeguards on the environment, and the genetic makeup of the birds.

Exploration of the power of routine surveillance data to assess the impacts of industry-led badger culling on bovine tuberculosis incidence in cattle herds.

In the UK, badgers (Meles meles) are a well-known reservoir of infection, and there has been lively debate about whether badger culling should play a role within the British Government's strategy to control and eventually eradicate tuberculosis (TB) in cattle. The key source of information on the potential for badger culling to reduce cattle TB in high-cattle-TB-incidence areas remains the Randomised Badger Culling Trial (RBCT). In late 2013, two pilot areas were subjected to industry-led badger culls. These culls differed importantly from RBCT culling in that free-ranging as well as cage-trapped badgers were shot, and culling took place over a longer time period. Their impacts will be harder to evaluate because culling was not randomised between comparable areas for subsequent comparisons of culling versus no culling. However, the authors present calculations that explore the power of routine surveillance data to assess the impacts of industry-led badger culling on cattle TB incidence. The rollout of industry-led culling as a component of a national cattle TB control policy would be controversial. The best possible estimates of the effects of such culling on confirmed cattle TB incidence should be made available to inform all stakeholders and policy-makers.

Bovine Tuberculosis Risk Factors for British Herds Before and After the 2001 Foot-and-Mouth Epidemic: What have we Learned from the TB99 and CCS2005 Studies?

Over the last couple of decades, the UK experienced a substantial increase in the incidence and geographical spread of bovine tuberculosis (TB), in particular since the epidemic of foot-and-mouth disease (FMD) in 2001. The initiation of the Randomized Badger Culling Trial (RBCT) in 1998 in south-west England provided an opportunity for an in-depth collection of questionnaire data (covering farming practices, herd management and husbandry, trading and wildlife activity) from herds having experienced a TB breakdown between 1998 and early 2006 and randomly selected control herds, both within and outside the RBCT (the so-called TB99 and CCS2005 case-control studies). The data collated were split into four separate and comparable substudies related to either the pre-FMD or post-FMD period, which are brought together and discussed here for the first time. The findings suggest that the risk factors associated with TB breakdowns may have changed. Higher Mycobacterium bovis prevalence in badgers following the FMD epidemic may have contributed to the identification of the presence of badgers on a farm as a prominent TB risk factor only post-FMD. The strong emergence of contact/trading TB risk factors post-FMD suggests that the purchasing and movement of cattle, which took place to restock FMD-affected areas after 2001, may have exacerbated the TB problem. Post-FMD analyses also highlighted the potential impact of environmental factors on TB risk. Although no unique and universal solution exists to reduce the transmission of TB to and among British cattle, there is an evidence to suggest that applying the broad principles of biosecurity on farms reduces the risk of infection. However, with trading remaining as an important route of local and long-distance TB transmission, improvements in the detection of infected animals during pre- and post-movement testing should further reduce the geographical spread of the disease.

Demographic approaches to the estimation of incidence of HIV-1 infection among adults from age-specific prevalence data in stable endemic conditions.

OBJECTIVE: To develop methods for estimating the incidence of HIV-1 infection among adults from age-specific prevalence data derived in stable endemic conditions. METHODS: Two methods are proposed. The first method is the Cumulative Incidence and Survival Method which treats HIV-1 prevalence at any given age as the cumulative incidence of new infections at each preceding age, adjusted for mortality. A model for age-specific incidence is fitted to the data using maximum likelihood techniques. The other method is the Constant Prevalence Method whereby the incidence of new infections within a time interval (t-r, t) is calculated as the difference, after adjusting for mortality, between observed prevalence levels at two successive age intervals, whose mean ages are r years apart. The two methods were applied to data from Kampala, Uganda. RESULTS: Plausible estimates of age-specific and cumulative HIV-1 incidence were obtained from each of the methods. Estimates of HIV-1 incidence are sensitive to assumptions regarding the length of the survival period after infection and the stability of the epidemic. CONCLUSIONS: Reasonable estimates of HIV-1 incidence can be obtained from prevalence data derived in near-stable conditions. With the Constant Prevalence Method, these conditions may be relaxed if large sample sizes are available and age-reporting is good. The methods proposed could be used in the design and implementation of HIV-1 prevention trials. Cumulative incidence is a better indication of demographic impact than average age-specific incidence.

PIP: Two methods to estimate the incidence of HIV-1 infection among adults from age-specific prevalence data derived in stable endemic conditions are presented and tested on data from Kampala, Uganda. The Cumulative Incidence and Survival Method is first proposed which treats HIV-1 prevalence at any given age as the cumulative incidence of new infections at each preceding age, adjusted for mortality. A model for age-specific incidence is fitted to the data using maximum likelihood techniques. The Constant Prevalence Method is then presented in which the incidence of new infections within a given time interval is calculated as the difference, after adjusting for mortality, between observed prevalence levels at two successive age intervals, whose mean ages are a specified number of years apart. Plausible estimates of age-specific and cumulative HIV-1 incidence were obtained from each method.

Estimating HIV incidence from age-specific prevalence data: comparison with concurrent cohort estimates in a study of male factory workers, Harare, Zimbabwe.

OBJECTIVE: To compare HIV incidence estimates from cross-sectional age-specific prevalence data with concurrent cohort estimates and to examine the sensitivity of the estimates to changes in age-categorization and survivorship assumptions. METHODS: Two previously described methods of estimating HIV incidence from cross-sectional prevalence data - the cumulative incidence and survival (CIS) and constant prevalence (CP) methods - are applied using data from a study of male factory workers in Harare, Zimbabwe. The methods are applied under two alternative groupings of the HIV prevalence data and under alternative survivorship assumptions: (a) Weibull distribution providing the best fit to the HIV prevalence data using the CIS method; (b) Weibull distribution matching data from an HIV natural history cohort study in Uganda; and (c) survivorship pattern as in (b) with survival periods reducing with increasing age at infection. Age-specific, age-standardized and cumulative HIV incidence estimates are calculated. The results are compared with concurrent longitudinal estimates from 3 years of follow-up of the Harare cohort (1993-1995). RESULTS: Age-standardized HIV incidence was estimated at 2.02 per 100 man years (95% CI, 1.57-2.47) in the cohort study. There was evidence of recent variability in HIV incidence in these data. Estimates from the cross-sectional methods ranged from 1.98 to 2.74 per 100 man years and were sensitive to changes in age-categorization of the HIV prevalence data and changes in survivorship assumptions. The cross-sectional estimates were higher at central ages and lower at older ages than the cohort estimates. The age-specific estimates from the CIS method were less sensitive to changes in age grouping than those from the CP method. CONCLUSIONS: HIV incidence remains high in Harare. Incidence estimates broadly consistent with cohort estimates can be obtained from single-round cross-sectional HIV prevalence data in established epidemics - even when the underlying assumption of stable endemic prevalence is not fully met. Estimates based on cross-sectional surveys should therefore be explored when reliable longitudinal estimates cannot be obtained. More data on post-HIV infection survivorship distributions in sub-Saharan Africa would facilitate the improvement of estimates of incidence based on cross-sectional surveys.

Comparison of the effectiveness of non-nucleoside reverse transcriptase inhibitor-containing and protease inhibitor-containing regimens using observational databases.

OBJECTIVES: To compare the effectiveness of first protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. METHODS: Data were analysed from three large HIV patient databases: Apache HIV Insight (APACHE), Target Management Services (TMS) and Clinical Partners (CP). The effectiveness of therapy was the time taken for HIV-1 RNA to fall below detectable levels on first highly active antiretroviral therapy regimen (PI- or NNRTI-containing) and the subsequent time to failure (two consecutive detectable measurements). Comparisons were made using proportional hazards models, adjusting for differences in age, sex, previous reverse transcriptase inhibitor use, calendar year and baseline viral load and CD4 T-cell count. RESULTS: The type of regimen was not associated with time to undetectable viral load in any of the three databases, all of which had high power to detect a difference. PI-containing regimens were significantly less likely to fail after reaching undetectable viral loads for APACHE and CP patients (relative hazard, 1.7; 95% confidence interval, 1.3--2.1 and relative hazard, 1.6; 95% confidence interval, 1.0--2.5 respectively). These results remained significant after allowing for an unmeasured confounder with moderate effect on risk. No significant association between time to failure and regimen was found for TMS patients, possibly due to low power (67% to detect a relative hazard of 1.5). No difference was found between regimens in the time taken for an increase of > 100 x 10(9)cells/l in CD4 T-cell count. In the APACHE database, those on NNRTI-containing regimens were more likely to have a failing CD4 T-cell response. CONCLUSIONS: PI-containing regimens have a lower risk of treatment failure than NNRTI-containing regimens.