Sediment Spatial Distribution and Quality Assessment of Metals in Chinook Salmon and Resident Killer Whale Marine Habitat in British Columbia, Canada.

At-risk resident killer whale (Orcinus orca) populations of the northeastern Pacific, Canada, and their main prey, Chinook Salmon (Oncorhynchus tshawytscha), are exposed to a variety of contaminants including chemical elements from both natural and anthropogenic sources, which may be constraining their recovery. Concentrations of 36 chemical elements in subtidal surface sediments (1-435 m depth) collected from 98 sites along the British Columbia coast were used to characterize coast-wide patterns, and a subset of metals (mercury (Hg), cadmium (Cd), arsenic (As), nickel (Ni), copper (Cu), and lead (Pb)) were selected to assess Chinook Salmon and resident killer whale marine habitat quality. Principal component analysis (PCA) showed a dominance of Hg, antimony (Sb), Pb, Cu, and zinc (Zn) for Prince Rupert Harbour, Victoria Harbour, and Burrard Inlet, suggesting local sources. Based on the PCA, geochemical properties such as total organic carbon (TOC), acid volatile sulfide (AVS), and pH explained the spatial distribution of all elements in sediment (p < 0.001). Mercury, Cd, As, Ni, Cu, and Pb hotspots were identified along the coast of Vancouver Island, the central and north coast, in the Strait of Georgia, and Haida Gwaii. Bischof Island of Haida Gwaii and Ardmillan Bay on the central coast were most contaminated and enriched by Cd, determined by geoaccumulation index (Igeo) and enrichment factor (EF), respectively. Marine habitat quality was assessed by comparing metal concentrations to Canadian Sediment Quality Guidelines (SQGs). Chinook Salmon populations may be indirectly affected by metal toxicity (As > Cd and Cu > Ni > Hg > Pb) to lower trophic level prey species. Toxicity related impacts to benthic organisms as a result of exposure to elevated Cd and As concentrations in Northern Resident Killer Whale critical habitat and to Hg, Cd, As, Ni, Cu, and Pb concentrations in Southern Resident Killer Whale critical habitat may indirectly pose a threat to resident killer whale populations, highlighting a need for management actions to reduce risks associated with these metals.

Xanthomatous hypophysitis causing hypogonadotropic hypogonadism resulting in delayed presentation of slipped capital femoral epiphysis.

An 18-year-old man who underwent bilateral pinning of his hip joints after a left unstable Slipped Capital Femoral Epiphysis (right pinned prophylactically) was noted to have delayed secondary sexual characteristics and post-operative diabetes insipidus. The patient also described a history of fatigue, headache and polydipsia for the past 4 years. Endocrine investigations revealed reduced androgen levels, hypocortisolism, a borderline normal Serum ACE and secondary hypothyroidism. Magnetic Resonance Imaging of the pituitary gland identified an enhancing mass and a thickened stalk which trans-nasal endoscopic biopsy found to be necrotic with pus. Histology confirmed a diagnosis of Xanthomatous Hypophysitis, an inflammatory condition likely related to a partial rupture of a Rathke cleft cyst. The patient was subsequently commenced on Androgen, Thyroxine, Desmopressin and Hydrocortisone therapy with on-going endocrine follow-up. Although endocrine dysfunction & hypogonadism has been recognised to be a risk factor for SCFE at an atypically older age, due to reduced androgen levels leading to a weakened physeal plate, this is the first known case of a Xanthomatous Hypophysitis resulting in pituitary dysfunction and eventual SCFE. This case highlights that an increased range of pituitary disorders should be considered in late presentations of SCFE; and vice versa the risk of SCFE should be considered in patients with prolonged hypogonadotropic hypogonadism.

Resurgence of malaria infection after mass treatment: a simulation study.

BACKGROUND: Field studies are evaluating if mass drug administration (MDA) might shorten the time to elimination of Plasmodium falciparum malaria, when vector control measures and reactive surveillance strategies are scaled-up. A concern with this strategy is that there may be resurgence of transmission following MDA. METHODS: A conceptual model was developed to classify possible outcomes of an initial period of MDA, followed by continuously implementing other interventions. The classification considered whether elimination or a new endemic stable state is achieved, and whether changes are rapid, transient, or gradual. These categories were informed by stability analyses of simple models of vector control, case management, and test-and-treat interventions. Individual-based stochastic models of malaria transmission (OpenMalaria) were then used to estimate the probability and likely rates of resurgence in realistic settings. Effects of concurrent interventions, including routine case management and test-and-treat strategies were investigated. RESULTS: Analysis of the conceptual models suggest resurgence will occur after MDA unless transmission potential is very low, or the post-MDA prevalence falls below a threshold, which depends on both transmission potential and on the induction of bistability. Importation rates are important only when this threshold is very low. In most OpenMalaria simulations the approximately stable state achieved at the end of the simulations was independent of inclusion of MDA and the final state was unaffected by importation of infections at plausible rates. Elimination occurred only with high effective coverage of case management, low initial prevalence, and high intensity test-and-treat. High coverage of case management but not by test-and-treat induced bistability. Where resurgence occurred, its rate depended mainly on transmission potential (not treatment rates). CONCLUSIONS: A short burst of high impact MDA is likely to be followed by resurgence. To avert resurgence, concomitant interventions need either to substantially reduce average transmission potential or to be differentially effective in averting or clearing infections at low prevalence. Case management at high effective coverage has this differential effect, and should suffice to avert resurgence caused by imported cases at plausible rates of importation. Once resurgence occurs, its rate depends mainly on transmission potential, not on treatment strategies.

Theory of reactive interventions in the elimination and control of malaria.

BACKGROUND: Reactive case detection (RCD) is an integral part of many malaria control and elimination programmes and can be conceived of as a way of gradually decreasing transmission. However, it is unclear under what circumstances RCD may have a substantial impact on prevalence, how likely it is to lead to local elimination, or how effective it needs to be to prevent reintroduction after transmission has been interrupted. METHODS: Analyses and simulations of a discrete time compartmental susceptible-infectious-susceptible (SIS) model were used to understand the mechanisms of how RCD changes transmission dynamics and estimate the impact of RCD programmes in a range of settings with varying patterns of transmission potential and programme characteristics. Prevalence survey data from recent studies in Zambia were used to capture the effects of spatial clustering of patent infections. RESULTS: RCD proved most effective at low prevalence. Increasing the number of index cases followed was more important than increasing the number of neighbours tested per index case. Elimination was achieved only in simulations of situations with very low transmission intensity and following many index cases. However, RCD appears to be helpful in maintaining the disease-free state after achieving malaria elimination (through other interventions). CONCLUSION: RCD alone can eliminate malaria in only a very limited range of settings, where transmission potential is very low, and improving the coverage of RCD has little effect on this range. In other settings, it is likely to reduce disease burden. RCD may also help maintain the disease-free state in the face of imported infections. Prevalence survey data can be used to estimate a targeting ratio (the ratio of prevalence found through RCD to that in the general population) which is an important determinant of the effect of RCD.

Validating team communication data using a transmission-duration threshold and voice activity detection algorithm.

The processes underlying team effectiveness can be understood by analyzing the temporal dynamics of team communication sequences. The results of such analyses have shown that the complexity of team communication is associated with team performance on task-related variables, and hence communication complexity statistics have been proposed for use as measures for real-time feedback on team performance. In two analyses of historical team communication sequences, we found that filtering via use of a transmission-duration threshold and voice activity detection algorithm resulted in significant changes in complexity relative to not filtering the data or using a transmission-duration filter alone. The use of these filtering techniques showed significant effects on the complexity of communication sequences in both a laboratory-based experiment, with participants with little experience with voice communication protocols, and in a mission simulation with trained military operators. There was also a significant non-linear relationship between the complexity of communication sequences and task performance. However, an analysis of the impact of the changes in communication dynamics gained through filtering did not demonstrate that the changed temporal dynamics of filtered data better explained team performance. It is concluded that pre-filtering of invalid communication data should be included during the data cleaning stage of statistical analysis as a matter of good scientific practice. Furthermore, such use of filtering will ensure that inferences made about the relationship between the complexity of communication between team members and their performance are not confounded by the presence of invalid communication events.

Public health impact and cost-effectiveness of the RTS,S/AS01 malaria vaccine: a systematic comparison of predictions from four mathematical models.

BACKGROUND: The phase 3 trial of the RTS,S/AS01 malaria vaccine candidate showed modest efficacy of the vaccine against Plasmodium falciparum malaria, but was not powered to assess mortality endpoints. Impact projections and cost-effectiveness estimates for longer timeframes than the trial follow-up and across a range of settings are needed to inform policy recommendations. We aimed to assess the public health impact and cost-effectiveness of routine use of the RTS,S/AS01 vaccine in African settings. METHODS: We compared four malaria transmission models and their predictions to assess vaccine cost-effectiveness and impact. We used trial data for follow-up of 32 months or longer to parameterise vaccine protection in the group aged 5-17 months. Estimates of cases, deaths, and disability-adjusted life-years (DALYs) averted were calculated over a 15 year time horizon for a range of levels of Plasmodium falciparum parasite prevalence in 2-10 year olds (PfPR2-10; range 3-65%). We considered two vaccine schedules: three doses at ages 6, 7·5, and 9 months (three-dose schedule, 90% coverage) and including a fourth dose at age 27 months (four-dose schedule, 72% coverage). We estimated cost-effectiveness in the presence of existing malaria interventions for vaccine prices of US$2-10 per dose. FINDINGS: In regions with a PfPR2-10 of 10-65%, RTS,S/AS01 is predicted to avert a median of 93,940 (range 20,490-126,540) clinical cases and 394 (127-708) deaths for the three-dose schedule, or 116,480 (31,450-160,410) clinical cases and 484 (189-859) deaths for the four-dose schedule, per 100,000 fully vaccinated children. A positive impact is also predicted at a PfPR2-10 of 5-10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2-10 of 10-65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18-211) per clinical case averted and $80 (44-279) per DALY averted for the three-dose schedule, and of $25 (16-222) and $87 (48-244), respectively, for the four-dose schedule. Higher ICERs were estimated at low PfPR2-10 levels. INTERPRETATION: We predict a significant public health impact and high cost-effectiveness of the RTS,S/AS01 vaccine across a wide range of settings. Decisions about implementation will need to consider levels of malaria burden, the cost-effectiveness and coverage of other malaria interventions, health priorities, financing, and the capacity of the health system to deliver the vaccine. FUNDING: PATH Malaria Vaccine Initiative; Bill & Melinda Gates Foundation; Global Good Fund; Medical Research Council; UK Department for International Development; GAVI, the Vaccine Alliance; WHO.

Climate change-contaminant interactions in marine food webs: Toward a conceptual framework.

Climate change is reshaping the way in which contaminants move through the global environment, in large part by changing the chemistry of the oceans and affecting the physiology, health, and feeding ecology of marine biota. Climate change-associated impacts on structure and function of marine food webs, with consequent changes in contaminant transport, fate, and effects, are likely to have significant repercussions to those human populations that rely on fisheries resources for food, recreation, or culture. Published studies on climate change-contaminant interactions with a focus on food web bioaccumulation were systematically reviewed to explore how climate change and ocean acidification may impact contaminant levels in marine food webs. We propose here a conceptual framework to illustrate the impacts of climate change on contaminant accumulation in marine food webs, as well as the downstream consequences for ecosystem goods and services. The potential impacts on social and economic security for coastal communities that depend on fisheries for food are discussed. Climate change-contaminant interactions may alter the bioaccumulation of two priority contaminant classes: the fat-soluble persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), as well as the protein-binding methylmercury (MeHg). These interactions include phenomena deemed to be either climate change dominant (i.e., climate change leads to an increase in contaminant exposure) or contaminant dominant (i.e., contamination leads to an increase in climate change susceptibility). We illustrate the pathways of climate change-contaminant interactions using case studies in the Northeastern Pacific Ocean. The important role of ecological and food web modeling to inform decision-making in managing ecological and human health risks of chemical pollutants contamination under climate change is also highlighted. Finally, we identify the need to develop integrated policies that manage the ecological and socioeconomic risk of greenhouse gases and marine pollutants.

A stochastic model for the probability of malaria extinction by mass drug administration.

BACKGROUND: Mass drug administration (MDA) has been proposed as an intervention to achieve local extinction of malaria. Although its effect on the reproduction number is short lived, extinction may subsequently occur in a small population due to stochastic fluctuations. This paper examines how the probability of stochastic extinction depends on population size, MDA coverage and the reproduction number under control, R c . A simple compartmental model is developed which is used to compute the probability of extinction using probability generating functions. The expected time to extinction in small populations after MDA for various scenarios in this model is calculated analytically. RESULTS: The results indicate that mass drug administration (Firstly, R c must be sustained at R c  < 1.2 to avoid the rapid re-establishment of infections in the population. Secondly, the MDA must produce effective cure rates of >95% to have a non-negligible probability of successful elimination. Stochastic fluctuations only significantly affect the probability of extinction in populations of about 1000 individuals or less. The expected time to extinction via stochastic fluctuation is less than 10 years only in populations less than about 150 individuals. Clustering of secondary infections and of MDA distribution both contribute positively to the potential probability of success, indicating that MDA would most effectively be administered at the household level. CONCLUSIONS: There are very limited circumstances in which MDA will lead to local malaria elimination with a substantial probability.

Identification of Spilled Oil from the MV Marathassa (Vancouver, Canada 2015) Using Alkyl PAH Isomer Ratios.

On the morning of April 9, 2015, citizens in Vancouver (British Columbia, Canada) awoke to the sight and smell of oil on the shores of popular downtown beaches. Because the oil also had spread over the shallow seawater intakes for the Vancouver Aquarium, a preliminary screening of samples was performed as a prompt, first response to assess the risks to the Aquarium collection and guide the emergency operational response. A subsequent, more detailed examination for the presence of spilled oil in sediment, biota and water samples from the Vancouver Harbour region was then conducted based on the analysis of a large suite of alkanes, petroleum biomarkers, parent polycyclic aromatic hydrocarbons (PAHs) and alkyl PAH isomers. Most of the commonly applied biomarker ratios exhibit similar values for the spilled oil, Alberta oil (the main petroleum source for British Columbia), and pre-spill and un-oiled sediment samples. In contrast, alkyl PAH isomer ratios showed a clear distinction between the spilled oil and pre-spill samples, with the largest differences shown by isomers of the methyl fluoranthene/pyrene alkyl PAH series. This novel use of alkyl PAH isomers for fingerprinting petroleum helped to confirm the grain carrier MV Marathassa as the source of the oil that affected beach and mussel samples to document definitively the spread of the oil and to establish which samples contained a mix of the oil and hydrocarbons linked to historical activities. Finally, an initial evaluation of the biological risks of the MV Marathassa oil spill in Vancouver Harbour showed that oiled beach sediments had priority parent PAH concentrations that are likely to harm marine life.

A Risk-Based Characterization of Sediment Contamination by Legacy and Emergent Contaminants of Concern in Coastal British Columbia, Canada.

Sediments have long been used to help describe pollution sources, contaminated sites, trends over time, and habitat quality for marine life. We collected surficial sediments from 12 sites at an average seawater depth of 25 m in three near-urban areas of the Salish Sea (British Columbia, Canada) to investigate habitat quality for marine life, including heavily contaminated killer whales. Samples were analyzed using high-resolution instrumentation for a wide variety of congeners of polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs), hexabromocyclododecane (HBCDD), polybrominated biphenyls, polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans, organochlorine pesticides, and polychlorinated naphthalenes (PCNs). The top six contaminant classes detected in sediments were ∑PCB > ∑PBDE > ∑PCDD/F > DDT > ∑HBCDD > ∑PCN. Near-urban harbor sediments had up to three orders of magnitude higher concentrations of contaminants than more remote sites. With limited tools available to characterize biological risks associated with complex mixtures in the real world, we applied several available approaches to prioritize the pollutant found in our study: (1) sediment quality guidelines from the Canadian Council of Ministers of the Environment where available; (2) US NOAA effects range low and other international guidelines; (3) total TEQ for dioxin-like PCBs for the protection of mammals; and (4) the calculation of risk quotients. Our findings provide an indication of the state of contamination of coastal environments in British Columbia and guidance for chemical regulations and priority setting, as well as management actions including best-practices, dredging, disposal at sea, and source control. In this regard, the legacy PCB and the emergent PBDEs should command continued priority monitoring.

Oil Spills and Marine Mammals in British Columbia, Canada: Development and Application of a Risk-Based Conceptual Framework.

Marine mammals are inherently vulnerable to oil spills. We developed a conceptual framework to evaluate the impacts of potential oil exposure on marine mammals and applied it to 21 species inhabiting coastal British Columbia (BC), Canada. Oil spill vulnerability was determined by examining both the likelihood of species-specific (individual) oil exposure and the consequent likelihood of population-level effects. Oil exposure pathways, ecology, and physiological characteristics were first used to assign species-specific vulnerability rankings. Baleen whales were found to be highly vulnerable due to blowhole breathing, surface filter feeding, and invertebrate prey. Sea otters (Enhydra lutris) were ranked as highly vulnerable due to their time spent at the ocean surface, dense pelage, and benthic feeding techniques. Species-specific vulnerabilities were considered to estimate the likelihood of population-level effects occurring after oil exposure. Killer whale (Orcinus orca) populations were deemed at highest risk due to small population sizes, complex social structure, long lives, slow reproductive turnover, and dietary specialization. Finally, we related the species-specific and population-level vulnerabilities. In BC, vulnerability was deemed highest for Northern and Southern Resident killer whales and sea otters, followed by Bigg's killer whales and Steller sea lions (Eumetopias jubatus). Our findings challenge the typical "indicator species" approach routinely used and underscore the need to examine marine mammals at a species and population level for risk-based oil spill predictions. This conceptual framework can be combined with spill probabilities and volumes to develop more robust risk assessments and may be applied elsewhere to identify vulnerability themes for marine mammals.

Polychlorinated Biphenyl-Related Alterations of the Expression of Essential Genes in Harbour Seals (Phoca vitulina) from Coastal Sites in Canada and the United States.

As long-lived marine mammals found throughout the temperate coastal waters of the North Pacific and Atlantic Oceans, harbour seals (Phoca vitulina) have become an invaluable sentinel of food-web contamination. Their relatively high trophic position predisposes harbour seals to the accumulation of harmful levels of persistent organic pollutants (POPs). We obtained skin/blubber biopsy samples from live-captured young harbour seals from various sites in the northeastern Pacific (British Columbia, Canada, and Washington State, USA) as well as the northwestern Atlantic (Newfoundland and Quebec, Canada). We developed harbour seal-specific primers to investigate the potential impact of POP exposure on the expression of eight important genes. We found correlations between the blubber mRNA levels of three of our eight target genes and the dominant persistent organic pollutant in seals [polychlorinated biphenyls (PCBs)] including estrogen receptor alpha (Esr1: r 2 = 0.12, p = 0.038), thyroid hormone receptor alpha (Thra: r 2 = 0.16; p = 0.028), and glucocorticoid receptor (Nr3c1: r 2 = 0.12; p = 0.049). Age, sex, weight, and length were not confounding factors on the expression of genes. Although the population-level consequences are unclear, our results suggest that PCBs are associated with alterations of the expression of genes responsible for aspects of metabolism, growth and development, and immune function. Collectively, these results provide additional support for the use of harbour seals as indicators of coastal food-web contamination.

ARMADA: Using motif activity dynamics to infer gene regulatory networks from gene expression data.

Analysis of gene expression data remains one of the most promising avenues toward reconstructing genome-wide gene regulatory networks. However, the large dimensionality of the problem prohibits the fitting of explicit dynamical models of gene regulatory networks, whereas machine learning methods for dimensionality reduction such as clustering or principal component analysis typically fail to provide mechanistic interpretations of the reduced descriptions. To address this, we recently developed a general methodology called motif activity response analysis (MARA) that, by modeling gene expression patterns in terms of the activities of concrete regulators, accomplishes dramatic dimensionality reduction while retaining mechanistic biological interpretations of its predictions (Balwierz, 2014). Here we extend MARA by presenting ARMADA, which models the activity dynamics of regulators across a time course, and infers the causal interactions between the regulators that drive the dynamics of their activities across time. We have implemented ARMADA as part of our ISMARA webserver, ismara.unibas.ch, allowing any researcher to automatically apply it to any gene expression time course. To illustrate the method, we apply ARMADA to a time course of human umbilical vein endothelial cells treated with TNF. Remarkably, ARMADA is able to reproduce the complex observed motif activity dynamics using a relatively small set of interactions between the key regulators in this system. In addition, we show that ARMADA successfully infers many of the key regulatory interactions known to drive this inflammatory response and discuss several novel interactions that ARMADA predicts. In combination with ISMARA, ARMADA provides a powerful approach to generating plausible hypotheses for the key interactions between regulators that control gene expression in any system for which time course measurements are available.

Food Web Bioaccumulation Model for Resident Killer Whales from the Northeastern Pacific Ocean as a Tool for the Derivation of PBDE-Sediment Quality Guidelines.

Resident killer whale populations in the NE Pacific Ocean are at risk due to the accumulation of pollutants, including polybrominated diphenyl ethers (PBDEs). To assess the impact of PBDEs in water and sediments in killer whale critical habitat, we developed a food web bioaccumulation model. The model was designed to estimate PBDE concentrations in killer whales based on PBDE concentrations in sediments and the water column throughout a lifetime of exposure. Calculated and observed PBDE concentrations exceeded the only toxicity reference value available for PBDEs in marine mammals (1500 µg/kg lipid) in southern resident killer whales but not in northern resident killer whales. Temporal trends (1993-2006) for PBDEs observed in southern resident killer whales showed a doubling time of ≈5 years. If current sediment quality guidelines available in Canada for polychlorinated biphenyls are applied to PBDEs, it can be expected that PBDE concentrations in killer whales will exceed available toxicity reference values by a large margin. Model calculations suggest that a PBDE concentration in sediments of approximately 1.0 µg/kg dw produces PBDE concentrations in resident killer whales that are below the current toxicity reference value for 95 % of the population, with this value serving as a precautionary benchmark for a management-based approach to reducing PBDE health risks to killer whales. The food web bioaccumulation model may be a useful risk management tool in support of regulatory protection for killer whales.

Mercury Accumulation in Harbour Seals from the Northeastern Pacific Ocean: The Role of Transplacental Transfer, Lactation, Age and Location.

Mercury (Hg) bioaccumulates in the aquatic food chain in the form of methylmercury, a compound well known for its neurotoxicity. We analyzed total mercury (THg) in hair collected from 209 harbour seals captured at 10 sites in British Columbia (Canada) and Washington State (USA) between 2003 and 2010. In addition, laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) allowed for a highly refined analysis of THg accumulation over time by examining nine whiskers taken from 4- to 6-week-old pups. We estimate that THg concentrations in pups increased sharply at a point corresponding to mid- to late gestation of their time in utero (4.7 ± 0.8 and 6.6 ± 1.3 µg/g dry weight (dw), respectively), and then again at the onset of nursing (8.1 ± 1.3 µg/g dw). These abrupt changes highlight the importance of both pre- and post-natal THg transfer from the mother to the growing fetus and the newborn pup. While THg levels varied among sites, hair analyses from seals collected at the same site demonstrated the influence of age in THg accumulation with pups (5.3 ± 0.3 µg/g) and juveniles (4.5 ± 0.5 µg/g) having lower levels than those in adults (8.3 ± 0.8 µg/g). Our results revealed that 33 % of the pups sampled (n = 167) had THg levels that surpassed a mammalian hair threshold for neurochemical alterations. This study suggests that Hg could represent a health concern to marine wildlife, especially as atmospheric emissions of this toxic element from human activities in the Pacific Rim and worldwide continue.

The time-course of protection of the RTS,S vaccine against malaria infections and clinical disease.

BACKGROUND: Recent publications have reported follow-up of the RTS,S/AS01 malaria vaccine candidate Phase III trials at 11 African sites for 32 months (or longer). This includes site- and time-specific estimates of incidence and efficacy against clinical disease with four different vaccination schedules. These data allow estimation of the time-course of protection against infection associated with two different ages of vaccination, both with and without a booster dose. METHODS: Using an ensemble of individual-based stochastic models, each trial cohort in the Phase III trial was simulated assuming many different hypothetical profiles for the vaccine efficacy against infection in time, for both the primary course and boosting dose and including the potential for either exponential or non-exponential decay. The underlying profile of protection was determined by Bayesian fitting of these model predictions to the site- and time-specific incidence of clinical malaria over 32 months (or longer) of follow-up. Using the same stochastic models, projections of clinical efficacy in each of the sites were modelled and compared to available observed trial data. RESULTS: The initial protection of RTS,S immediately following three doses is estimated as providing an efficacy against infection of 65 % (when immunizing infants aged 6-12 weeks old) and 91 % (immunizing children aged 5-17 months old at first vaccination). This protection decays relatively rapidly, with an approximately exponential decay for the 6-12 weeks old cohort (with a half-life of 7.2 months); for the 5-17 months old cohort a biphasic decay with a similar half-life is predicted, with an initial rapid decay followed by a slower decay. The boosting dose was estimated to return protection to an efficacy against infection of 50-55 % for both cohorts. Estimates of clinical efficacy by trial site are consistent with those reported in the trial for all cohorts. CONCLUSIONS: The site- and time-specific clinical observations from the RTS,S/AS01 trial data allowed a reasonably precise estimation of the underlying vaccine protection against infection which is consistent with common underlying efficacy and decay rates across the trial sites. This calibration suggests that the decay in efficacy against clinical disease is more rapid than that against infection because of age-shifts in the incidence of disease. The dynamical models predict that clinical effectiveness will continue to decay and that likely effects beyond the time-scale of the trial will be small.

Age-shifting in malaria incidence as a result of induced immunological deficit: a simulation study.

Effective population-level interventions against Plasmodium falciparum malaria lead to age-shifts, delayed morbidity or rebounds in morbidity and mortality whenever they are deployed in ways that do not permanently interrupt transmission. When long-term intervention programmes target specific age-groups of human hosts, the age-specific morbidity rates ultimately adjust to new steady-states, but it is very difficult to study these rates and the temporal dynamics leading up to them empirically because the changes occur over very long time periods. This study investigates the age and magnitude of age- and time- shifting of incidence induced by either pre-erythrocytic vaccination (PEV) programmes or seasonal malaria chemo-prevention (SMC), using an ensemble of individual-based stochastic simulation models of P. falciparum dynamics. The models made various assumptions about immunity decay, transmission heterogeneity and were parameterized with data on both age-specific infection and disease incidence at different levels of exposure, on the durations of different stages of the parasite life-cycle and on human demography. Effects of transmission intensity, and of levels of access to malaria treatment were considered. While both PEV and SMC programmes are predicted to have overall strongly positive health effects, a shift of morbidity into older children is predicted to be induced by either programme if transmission levels remain static and not reduced by other interventions. Predicted shifting of burden continue into the second decade of the programme. Even if long-term surveillance is maintained it will be difficult to avoid mis-attribution of such long-term changes in age-specific morbidity patterns to other factors. Conversely, short-lived transient changes in incidence measured soon after introduction of a new intervention may give over-positive views of future impacts. Complementary intervention strategies could be designed to specifically protect those age-groups at risk from burden shift.

Distribution of malaria exposure in endemic countries in Africa considering country levels of effective treatment.

BACKGROUND: Malaria prevalence, clinical incidence, treatment, and transmission rates are dynamically interrelated. Prevalence is often considered a measure of malaria transmission, but treatment of clinical malaria reduces prevalence, and consequently also infectiousness to the mosquito vector and onward transmission. The impact of the frequency of treatment on prevalence in a population is generally not considered. This can lead to potential underestimation of malaria exposure in settings with good health systems. Furthermore, these dynamical relationships between prevalence, treatment, and transmission have not generally been taken into account in estimates of burden. METHODS: Using prevalence as an input, estimates of disease incidence and transmission [as the distribution of the entomological inoculation rate (EIR)] for Plasmodium falciparum have now been made for 43 countries in Africa using both empirical relationships (that do not allow for treatment) and OpenMalaria dynamic micro-simulation models (that explicitly include the effects of treatment). For each estimate, prevalence inputs were taken from geo-statistical models fitted for the year 2010 by the Malaria Atlas Project to all available observed prevalence data. National level estimates of the effectiveness of case management in treating clinical attacks were used as inputs to the estimation of both EIR and disease incidence by the dynamic models. RESULTS AND CONCLUSIONS: When coverage of effective treatment is taken into account, higher country level estimates of average EIR and thus higher disease burden, are obtained for a given prevalence level, especially where access to treatment is high, and prevalence relatively low. These methods provide a unified framework for comparison of both the immediate and longer-term impacts of case management and of preventive interventions.

Computer-assessed performance of psychomotor skills in endoscopic otolaryngology surgery: construct validity of the Dundee Endoscopic Psychomotor Otolaryngology Surgery Trainer (DEPOST).

BACKGROUND: This study was undertaken to introduce and establish the value of the Dundee Endoscopic Psychomotor Otolaryngology Surgery Trainer (DEPOST) as a customisable, objective real-time scoring system for trainee assessment. The construct validity of the system was assessed by comparing the performance of experienced otolaryngologists with that of otolaryngology trainees, junior doctors and medical students. METHODS: Forty two subjects (13 Consultants, 8 senior trainees, 13 junior trainees and 8 junior doctors/medical students) completed a single test on DEPOST. The test involved using a 30° rigid endoscope and a probe with position sensor, to identify a series of lights in a complex 3-dimensional model. The system scored subjects for time, success rate, and economy of movement (distance travelled). An analysis of variance and correlation analysis were used for the data analysis, with statistical significance set at 0.05. RESULTS: Increasing experience led to significantly improved performance with the DEPOST (p < 0.01). Senior trainees' results were significantly better than those of consultant otolaryngologists in success rate and time (p < 0.05 & p < 0.05). Consultants were the most efficient in their movement (p = 0.051) CONCLUSIONS: The system provides an accurate and customisable assessment of endoscopic skill in otolaryngologists. The DEPOST system has construct validity, with master surgeons and senior trainees completing the tasks more accurately without sacrificing execution time, success rate or efficiency of movement.

Manufacturing doubt about endocrine disrupter science--A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012".

We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford-Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.