Mark Shirley

GENETIC BASIS OF A BETWEEN-ENVIRONMENT TRADE-OFF INVOLVING RESISTANCE TO CADMIUM IN DROSOPHILA MELANOGASTER

In a replicated, laboratory, natural selection experiment Drosophila melanogaster populations were maintained for 20 generations either on unpolluted medium or on polluted medium containing cadmium chloride at a concentration of 80 μg/ml. Lines maintained on polluted medium evolved resistance. In comparison with unpolluted lines, their juvenile survivorship increased from 35% to 46%, developmental period decreased from 13.7 days to 13.0 days, and fecundity increased from 3 to 29 eggs per two‐day period. Emergence weights, however, did not change. By contrast the “environmental” effect of moving susceptible flies onto polluted medium was that after two generations survivorship fell 62%, developmental period increased 40%, and fecundity fell 97%. Emergence weights fell 31% in females and 28% in males. Resistant lines paid a fitness cost in unpolluted environments, with fecundity being reduced by 44% and emergence weights being reduced by 4% in females and 6% in males. Developmental period, however, was unaffected. Analyses of crosses and backcrosses between the lines suggested that the evolved cadmium resistance was due to a single sex‐linked gene. Levels of dominance were calculated, and in each life‐history character the resistant allele was found to be completely dominant. Because the life‐history effects appear to be produced by a single gene, it is probable that they all depend on the same metabolic pathway. Metallothionein production is a likely candidate because this is known to be controlled by genes on the X‐chromosome. The study adds to a small number of examples of single or closely linked genes with large antagonistic pleiotropic effects on life histories. The result here is a between‐environment trade‐off, allowing animals increased fitness in polluted environments, but only at the cost of reduced growth and reproduction in unpolluted environments.

Visualization, modelling and prediction in soil microbiology

The introduction of new approaches for characterizing microbial communities and imaging soil environments has benefited soil microbiology by providing new ways of detecting and locating microorganisms. Consequently, soil microbiology is poised to progress from simply cataloguing microbial complexity to becoming a systems science. A systems approach will enable the structures of microbial communities to be characterized and will inform how microbial communities affect soil function. Systems approaches require accurate analyses of the spatio–temporal properties of the different microenvironments present in soil. In this Review we advocate the need for the convergence of the experimental and theoretical approaches that are used to characterize and model the development of microbial communities in soils.

Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer

BACKGROUND Complete surgical removal of the prostate, radical prostatectomy, is the most frequently used treatment option for men with localised prostate cancer. The use of laparoscopic (keyhole) and robot-assisted surgery has improved operative safety but the comparative effectiveness and cost-effectiveness of these options remains uncertain. OBJECTIVE This study aimed to determine the relative clinical effectiveness and cost-effectiveness of robotic radical prostatectomy compared with laparoscopic radical prostatectomy in the treatment of localised prostate cancer within the UK NHS. DATA SOURCES MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index and Cochrane Central Register of Controlled Trials were searched from January 1995 until October 2010 for primary studies. Conference abstracts from meetings of the European, American and British Urological Associations were also searched. Costs were obtained from NHS sources and the manufacturer of the robotic system. Economic model parameters and distributions not obtained in the systematic review were derived from other literature sources and an advisory expert panel. REVIEW METHODS Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies of men with clinically localised prostate cancer (cT1 or cT2); outcome measures included adverse events, cancer related, functional, patient driven and descriptors of care. Two reviewers abstracted data and assessed the risk of bias of the included studies. For meta-analyses, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness was assessed using a discrete-event simulation model. RESULTS The searches identified 2722 potentially relevant titles and abstracts, from which 914 reports were selected for full-text eligibility screening. Of these, data were included from 19,064 patients across one RCT and 57 non-randomised comparative studies, with very few studies considered at low risk of bias. The results of this study, although associated with some uncertainty, demonstrated that the outcomes were generally better for robotic than for laparoscopic surgery for major adverse events such as blood transfusion and organ injury rates and for rate of failure to remove the cancer (positive margin) (odds ratio 0.69; 95% credible interval 0.51 to 0.96; probability outcome favours robotic prostatectomy = 0.987). The predicted probability of a positive margin was 17.6% following robotic prostatectomy compared with 23.6% for laparoscopic prostatectomy. Restriction of the meta-analysis to studies at low risk of bias did not change the direction of effect but did decrease the precision of the effect size. There was no evidence of differences in cancer-related, patient-driven or dysfunction outcomes. The results of the economic evaluation suggested that when the difference in positive margins is equivalent to the estimates in the meta-analysis of all included studies, robotic radical prostatectomy was on average associated with an incremental cost per quality-adjusted life-year that is less than threshold values typically adopted by the NHS (£30,000) and becomes further reduced when the surgical capacity is high. LIMITATIONS The main limitations were the quantity and quality of the data available on cancer-related outcomes and dysfunction. CONCLUSIONS This study demonstrated that robotic prostatectomy had lower perioperative morbidity and a reduced risk of a positive surgical margin compared with laparoscopic prostatectomy although there was considerable uncertainty. Robotic prostatectomy will always be more costly to the NHS because of the fixed capital and maintenance charges for the robotic system. Our modelling showed that this excess cost can be reduced if capital costs of equipment are minimised and by maintaining a high case volume for each robotic system of at least 100-150 procedures per year. This finding was primarily driven by a difference in positive margin rate. There is a need for further research to establish how positive margin rates impact on long-term outcomes. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Disease threats posed by alien species: the role of a poxvirus in the decline of the native red squirrel in Britain

Red squirrels are declining in the United Kingdom. Competition from, and squirrel poxvirus (SQPV) disease carried by, grey squirrels are assumed to be determining the decline. We analyse the incidence of disease and changes in distribution of the two species in Cumbria, from 1993 to 2003 and compare these to the predictions of an individual-based (IB) spatially explicit disease model simulating the dynamics of both squirrel species and SQPV in the landscape. Grey squirrels increased whilst red squirrels declined over 10 years. The incidence of disease in red squirrels was related to the time since grey squirrels arrived in the landscape. Analysis of rates of decline in red squirrel populations in other areas showed that declines are 17-25 times higher in regions where SQPV is present in grey squirrel populations than in those where it is not. The IB model predicted spatial overlap of 3-4 years between the species that was also observed in the field. The model predictions matched the observed data best when contact rates and rates of infection between the two species were low. The model predicted that a grey squirrel population control of >60% effective kill was needed to stop the decline in red squirrel populations in Cumbria.

The LCROSS Cratering Experiment

Watering the Moon About a year ago, a spent upper stage of an Atlas rocket was deliberately crashed into a crater at the south pole of the Moon, ejecting a plume of debris, dust, and vapor. The goal of this event, the Lunar Crater Observation and Sensing Satellite (LCROSS) experiment, was to search for water and other volatiles in the soil of one of the coldest places on the Moon: the permanently shadowed region within the Cabeus crater. Using ultraviolet, visible, and near-infrared spectroscopy data from accompanying craft, Colaprete et al. (p. 463; see the news story by Kerr; see the cover) found evidence for the presence of water and other volatiles within the ejecta cloud. Schultz et al. (p. 468) monitored the different stages of the impact and the resulting plume. Gladstone et al. (p. 472), using an ultraviolet spectrograph onboard the Lunar Reconnaissance Orbiter (LRO), detected H2, CO, Ca, Hg, and Mg in the impact plume, and Hayne et al. (p. 477) measured the thermal signature of the impact and discovered that it had heated a 30 to 200 square-meter region from ∼40 kelvin to at least 950 kelvin. Paige et al. (p. 479) mapped cryogenic zones predictive of volatile entrapment, and Mitrofanov et al. (p. 483) used LRO instruments to confirm that surface temperatures in the south polar region persist even in sunlight. In all, about 155 kilograms of water vapor was emitted during the impact; meanwhile, the LRO continues to orbit the Moon, sending back a stream of data to help us understand the evolution of its complex surface structures. A controlled spacecraft impact into a crater in the lunar south pole plunged through the lunar soil, revealing water and other volatiles. As its detached upper-stage launch vehicle collided with the surface, instruments on the trailing Lunar Crater Observation and Sensing Satellite (LCROSS) Shepherding Spacecraft monitored the impact and ejecta. The faint impact flash in visible wavelengths and thermal signature imaged in the mid-infrared together indicate a low-density surface layer. The evolving spectra reveal not only OH within sunlit ejecta but also other volatile species. As the Shepherding Spacecraft approached the surface, it imaged a 25- to-30-meter–diameter crater and evidence of a high-angle ballistic ejecta plume still in the process of returning to the surface—an evolution attributed to the nature of the impactor.

Bacillus Calmette-Guérin vaccination reduces the severity and progression of tuberculosis in badgers

Control of bovine tuberculosis (TB) in cattle has proven particularly challenging where reservoirs of infection exist in wildlife populations. In Britain and Ireland, control is hampered by a reservoir of infection in Eurasian badgers (Meles meles). Badger culling has positive and negative effects on bovine TB in cattle and is difficult, costly and controversial. Here we show that Bacillus Calmette-Guérin (BCG) vaccination of captive badgers reduced the progression, severity and excretion of Mycobacterium bovis infection after experimental challenge. In a clinical field study, BCG vaccination of free-living badgers reduced the incidence of positive serological test results by 73.8 per cent. In common with other species, BCG did not appear to prevent infection of badgers subjected to experimental challenge, but did significantly reduce the overall disease burden. BCG vaccination of badgers could comprise an important component of a comprehensive programme of measures to control bovine TB in cattle.

Comparative cost-effectiveness of robot-assisted and standard laparoscopic prostatectomy as alternatives to open radical prostatectomy for treatment of men with localised prostate cancer: a health technology assessment from the perspective of the UK National Health Service.

BACKGROUND Robot-assisted laparoscopic prostatectomy is increasingly used compared with a standard laparoscopic technique, but it remains uncertain whether potential benefits offset higher costs. OBJECTIVE To determine the cost-effectiveness of robotic prostatectomy. DESIGN, SETTING, AND PARTICIPANTS We conducted a care pathway description and model-based cost-utility analysis. We studied men with localised prostate cancer able to undergo either robotic or laparoscopic prostatectomy for cure. We used data from a meta-analysis, other published literature, and costs from the UK National Health Service and commercial sources. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Care received by men for 10 yr following radical prostatectomy was modelled. Clinical events, their effect on quality of life, and associated costs were synthesised assuming 200 procedures were performed annually. RESULTS AND LIMITATIONS Over 10 yr, robotic prostatectomy was on average (95% confidence interval [CI]) £1412 (€1595) (£1304 [€1473] to £1516 [€1713]) more costly than laparoscopic prostatectomy but more effective with mean (95% CI) gain in quality-adjusted life-years (QALYs) of 0.08 (0.01-0.15). The incremental cost-effectiveness ratio (ICER) was £18 329 (€20 708) with an 80% probability that robotic prostatectomy was cost effective at a threshold of £30 000 (€33 894)/QALY. The ICER was sensitive to the throughput of cases and the relative positive margin rate favouring robotic prostatectomy. CONCLUSIONS Higher costs of robotic prostatectomy may be offset by modest health gain resulting from lower risk of early harms and positive margin, provided >150 cases are performed each year. Considerable uncertainty persists in the absence of directly comparative randomised data.

Descriptive epidemiology of congenital heart disease in Northern England.

Congenital heart disease (CHD) is the most prevalent group of congenital anomalies. There is considerable variation in the reported epidemiology of CHD, mainly attributable to methodological differences. Using register-based data, the current study describes the epidemiology of CHD in a geographically well-defined population of the North of England during 1985-2003. The total prevalence of CHD was 85.9 per 10 000 births and terminations of pregnancy for fetal anomaly. Livebirth prevalence was 79.7 per 10 000 livebirths. Both total and livebirth prevalence increased during the study period. Ninety-two per cent of affected pregnancies resulted in a livebirth, 5% were terminated, 2% resulted in a stillbirth, and 1% in a late miscarriage. Almost a quarter (23%) of cases had one or more coincident anomalies of other organs, with chromosomal abnormalities the most frequent group. A total of 89.2% of cases survived to 1 year and the survival improved during the study period. This population-based study has demonstrated an increasing trend in both prevalence and survival among children with CHD.

BCG vaccination reduces risk of tuberculosis infection in vaccinated badgers and unvaccinated badger cubs.

Wildlife is a global source of endemic and emerging infectious diseases. The control of tuberculosis (TB) in cattle in Britain and Ireland is hindered by persistent infection in wild badgers (Meles meles). Vaccination with Bacillus Calmette-Guérin (BCG) has been shown to reduce the severity and progression of experimentally induced TB in captive badgers. Analysis of data from a four-year clinical field study, conducted at the social group level, suggested a similar, direct protective effect of BCG in a wild badger population. Here we present new evidence from the same study identifying both a direct beneficial effect of vaccination in individual badgers and an indirect protective effect in unvaccinated cubs. We show that intramuscular injection of BCG reduced by 76% (Odds ratio = 0.24, 95% confidence interval (CI) 0.11–0.52) the risk of free-living vaccinated individuals testing positive to a diagnostic test combination to detect progressive infection. A more sensitive panel of tests for the detection of infection per se identified a reduction of 54% (Odds ratio = 0.46, 95% CI 0.26–0.88) in the risk of a positive result following vaccination. In addition, we show the risk of unvaccinated badger cubs, but not adults, testing positive to an even more sensitive panel of diagnostic tests decreased significantly as the proportion of vaccinated individuals in their social group increased (Odds ratio = 0.08, 95% CI 0.01–0.76; P = 0.03). When more than a third of their social group had been vaccinated, the risk to unvaccinated cubs was reduced by 79% (Odds ratio = 0.21, 95% CI 0.05–0.81; P = 0.02).

Where diseases and networks collide: lessons to be learnt from a study of the 2001 foot-and-mouth disease epidemic

This paper uses a graph-theoretical approach to investigate the properties of the observed network of disease transmission in the 2001 foot-and-mouth epidemic in the United Kingdom. This analysis revealed both global and local heterogeneity in the contact pattern between the infected premises in the first 3 weeks of the disease. In particular, the global heterogeneity contributed to the failure of the culling strategy imposed by the UK government. However, a more effective strategy targeting selective deletion of key premises in the network was not available once the epidemic had begun. We recommend that post-hoc analyses of this sort should become part of preventative and proactive policy rather than part of a reaction to an ongoing crisis.