Combined Effects of Tetrakis Hydroxymethyl Phosphonium Chloride and Ammonium on Plankton Community Structure in Blackwater Pond Mesocosms

Flame retardant chemicals enter aquatic systems through municipal and industrial wastewater, and despite being detected in surface waters, most have not been thoroughly assessed for environmental risk. Halogenated flame retardants, known to be persistent and highly toxic to aquatic organisms are being phased out, and replaced with new or under-tested organophosphorus flame retardants. Organophosphorus flame retardants, such as tetrakis hydroxymethyl phosphonium chloride (THPC), often have similar applications to and are generally not as persistent as halogenated flame retardants. Single-species toxicity tests of organophosphorus flame retardants reveal a wide range of toxicity values within the range of environmentally relevant concentrations in surface waters. Additionally, other contaminants from industry and agriculture are likely to accompany flame retardant chemicals in surface waters. For example, THPC may be found in combination with ammonia, which is released directly with THPC in textile effluent and is a common component of agricultural fertilizers. Ammonia is a form of inorganic nitrogen that can stimulate primary production, but in excess can shift phytoplankton community composition to dominance by less edible or harmful species. While the effects of excess nutrients on planktonic communities are well studied, recent findings suggest the presence of nutrients can reduce or enhance the effects of other contaminants on aquatic organisms. Floating, in situ mesocosms were dosed with two levels of THPC (0.08 and 0.8 mg L-1) with or without ammonium (0.3 mg L-1) in a fully crossed design to study the effects of THPC and ammonium in combination on plankton communities. I hypothesized that THPC and ammonium affect plankton communities differently alone than in combination. Water samples were collected weekly over four weeks to assess zooplankton community composition and phytoplankton abundance (as chlorophyll a) in response to treatment additions. The combination of THPC and ammonium influenced community composition, but each factor alone had no effect. Specifically, low THPC+ammonium decreased the proportion of calanoid copepods with a corresponding increase in rotifers due to lower predation pressure compared to each factor alone one to three weeks post exposure. Total zooplankton abundance changed over time across all treatments, decreasing by more than 50% after one and two weeks of exposure before increasing to abundances approximately 27% higher than initial by week 4. Chlorophyll a was not affected by THPC and nutrient addition, but concentrations fluctuated between 5-15 µg L-1 in all treatments throughout the duration of the experiment. The interaction of THPC and ammonium suggests that these contaminants in combination can reduce abundance of large zooplankton such as copepods, thereby limiting a food source for planktivorous fish, and releasing smaller crustacean zooplankton and rotifers from predation and competitive pressure

Limited antigenic diversity of Plasmodium falciparum apical membrane antigen 1 supports the development of effective multi-allele vaccines

BackgroundPolymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies.MethodsWe aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple-antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross-reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence.ResultsWe found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis.ConclusionsAntigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi-allele approach for developing polymorphic antigens as malaria vaccines

Sociodemographic, Anthropometric, and Psychosocial Predictors of Attrition across Behavioral Weight-Loss Trials.

Preventing attrition is a major concern in behavioral weight loss intervention studies. The purpose of this analysis was to identify baseline and six-month predictors associated with participant attrition across three independent clinical trials of behavioral weight loss interventions (PREFER, SELF, and SMART) that were conducted over 10 years. Baseline measures included body mass index, Barriers to Healthy Eating, Beck Depression Inventory-II (BDI), Hunger Satiety Scale (HSS), Binge Eating Scale (BES), Medical Outcome Study Short Form (MOS SF-36 v2) and Weight Efficacy Lifestyle Questionnaire (WEL). We also examined early weight loss and attendance at group sessions during the first 6 months. Attrition was recorded at the end of the trials. Participants included 504 overweight and obese adults seeking weight loss treatment. The sample was 84.92% female and 73.61% white, with a mean (± SD) age of 47.35 ± 9.75 years. After controlling for the specific trial, for every one unit increase in BMI, the odds of attrition increased by 11%. For every year increase in education, the odds of attrition decreased by 10%. Additional predictors of attrition included previous attempts to lose 50–79 lbs, age, not possessing health insurance, and BES, BDI, and HSS scores. At 6 months, the odds of attrition increased by 10% with reduced group session attendance. There was also an interaction between percent weight change and trial (p < .001). Multivariate analysis of the three trials showed education, age, BMI, and BES scores were independently associated with attrition (ps ≤ .01). These findings may inform the development of more robust strategies for reducing attrition

Age, Spatial, and Temporal Variations in Hospital Admissions with Malaria in Kilifi County, Kenya: A 25-Year Longitudinal Observational Study

Background Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children, which has implications for ongoing control strategies. Methods and findings We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked to data on residence and Insecticide Treated Net (ITN) ownership. This included data from 69,104 children admitted to Kilifi County Hospital aged from 3 months to 13 years between 1st January 1990 and 31st December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the predictors; location of residence, calendar time, child’s age, ITN use and Enhanced Vegetation Index (a proxy for soil moisture). The proportion of malaria slide positive admissions declined from 0.56 with 95% confidence interval (95%CI) 0.54 to 0.58 in 1998 to 0.07 95%CI 0.06 to 0.08 in 2009, but then increased again through to 0.24 95%CI 0.22 to 0.25 in 2014. Older children accounted for most of the increase after 2009 (0.035 95%CI (0.030 to 0.040) among young children compared to 0.22 95%CI 0.21 to 0.23 in older children). There was a non-linear relationship between malaria risk and prevalence of ITN use within a 2km radius of an admitted child’s residence such that the predicted malaria positive fraction varied from ~0.4 to <0.1 as the prevalence of ITN use varied from 20% to 80%. In this observational analysis we were unable to determine the cause of the decline in malaria between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use. Conclusion Following a period of reduced transmission a cohort of older children emerged who have increased susceptibility to malaria. Further reductions in malaria transmission are needed to mitigate against the increasing burden among older children and universal ITN coverage is a promising strategy to achieve this

Quantitative Analysis of Immune Response and Erythropoiesis during Rodent Malarial Infection

Malarial infection is associated with complex immune and erythropoietic responses in the host. A quantitative understanding of these processes is essential to help inform malaria therapy and for the design of effective vaccines. In this study, we use a statistical model-fitting approach to investigate the immune and erythropoietic responses in Plasmodium chabaudi infections of mice. Three mouse phenotypes (wildtype, T-cell-deficient nude mice, and nude mice reconstituted with T-cells taken from wildtype mice) were infected with one of two parasite clones (AS or AJ). Under a Bayesian framework, we use an adaptive population-based Markov chain Monte Carlo method and fit a set of dynamical models to observed data on parasite and red blood cell (RBC) densities. Model fits are compared using Bayes' factors and parameter estimates obtained. We consider three independent immune mechanisms: clearance of parasitised RBCs (pRBC), clearance of unparasitised RBCs (uRBC), and clearance of parasites that burst from RBCs (merozoites). Our results suggest that the immune response of wildtype mice is associated with less destruction of uRBCs, compared to the immune response of nude mice. There is a greater degree of synchronisation between pRBC and uRBC clearance than between either mechanism and merozoite clearance. In all three mouse phenotypes, control of the peak of parasite density is associated with pRBC clearance. In wildtype mice and AS-infected nude mice, control of the peak is also associated with uRBC clearance. Our results suggest that uRBC clearance, rather than RBC infection, is the major determinant of RBC dynamics from approximately day 12 post-innoculation. During the first 2–3 weeks of blood-stage infection, immune-mediated clearance of pRBCs and uRBCs appears to have a much stronger effect than immune-mediated merozoite clearance. Upregulation of erythropoiesis is dependent on mouse phenotype and is greater in wildtype and reconstitited mice. Our study highlights the informative power of statistically rigorous model-fitting techniques in elucidating biological systems

Cord blood IgG and the risk of severe Plasmodium falciparum malaria in the first year of life

Young infants are less susceptible to severe episodes of malaria but the targets and mechanisms of protection are not clear. Cord blood antibodies may play an important role in mediating protection but many studies have examined their association with the outcome of infection or non-severe malaria. Here, we investigated whether cord blood IgG to Plasmodium falciparum merozoite antigens and antibody-mediated effector functions were associated with reduced odds of developing severe malaria at different time points during the first year of life. We conducted a case-control study of well-defined severe falciparum malaria nested within a longitudinal birth cohort of Kenyan children. We measured cord blood total IgG levels against five recombinant merozoite antigens and antibody function in the growth inhibition activity and neutrophil antibody-dependent respiratory burst assays. We also assessed the decay of maternal antibodies during the first 6months of life. The mean antibody half-life range was 2.51months (95% confidence interval (CI): 2.19-2.92) to 4.91months (95% CI: 4.47-6.07). The rate of decline of maternal antibodies was inversely proportional to the starting concentration. The functional assay of antibody-dependent respiratory burst activity predicted significantly reduced odds of developing severe malaria during the first 6months of life (Odds ratio (OR) 0.07, 95% CI: 0.007-0.74, P=0.007). Identification of the targets of antibodies mediating antibody-dependent respiratory burst activity could contribute to the development of malaria vaccines that protect against severe episodes of malaria in early infancy

Haemoglobin C and S Role in Acquired Immunity against Plasmodium falciparum Malaria

A recently proposed mechanism of protection for haemoglobin C (HbC; β6Glu→Lys) links an abnormal display of PfEMP1, an antigen involved in malaria pathogenesis, on the surface of HbC infected erythrocytes together with the observation of reduced cytoadhesion of parasitized erythrocytes and impaired rosetting in vitro. We investigated the impact of this hypothesis on the development of acquired immunity against Plasmodium falciparum variant surface antigens (VSA) encoding PfEMP1 in HbC in comparison with HbA and HbS carriers of Burkina Faso. We measured: i) total IgG against a single VSA, A4U, and against a panel of VSA from severe malaria cases in human sera from urban and rural areas of Burkina Faso of different haemoglobin genotypes (CC, AC, AS, SC, SS); ii) total IgG against recombinant proteins of P. falciparum asexual sporozoite, blood stage antigens, and parasite schizont extract; iii) total IgG against tetanus toxoid. Results showed that the reported abnormal cell-surface display of PfEMP1 on HbC infected erythrocytes observed in vitro is not associated to lower anti- PfEMP1 response in vivo. Higher immune response against the VSA panel and malaria antigens were observed in all adaptive genotypes containing at least one allelic variant HbC or HbS in the low transmission urban area whereas no differences were detected in the high transmission rural area. In both contexts the response against tetanus toxoid was not influenced by the β-globin genotype. These findings suggest that both HbC and HbS affect the early development of naturally acquired immunity against malaria. The enhanced immune reactivity in both HbC and HbS carriers supports the hypothesis that the protection against malaria of these adaptive genotypes might be at least partially mediated by acquired immunity against malaria

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Predictors of anti-convulsant treatment failure in children presenting with malaria and prolonged seizures in Kampala, Uganda

BACKGROUND: In endemic areas, falciparum malaria remains the leading cause of seizures in children presenting to emergency departments. In addition, seizures in malaria have been shown to increase morbidity and mortality in these patients. The management of seizures in malaria is sometimes complicated by the refractory nature of these seizures to readily available anti-convulsants. The objective of this study was to determine predictors of anti-convulsant treatment failure and seizure recurrence after initial control among children with malaria. METHODS: In a previous study, the efficacy and safety of buccal midazolam was compared to that of rectal diazepam in the treatment of prolonged seizures in children aged three months to 12 years in Kampala, Uganda. For this study, predictive models were used to determine risk factors for anti-convulsant treatment failure and seizure recurrence among the 221 of these children with malaria. RESULTS: Using predictive models, focal seizures (OR 3.21; 95% CI 1.42-7.25, p = 0.005), cerebral malaria (OR 2.43; 95% CI 1.20-4.91, p = 0.01) and a blood sugar >or=200 mg/dl at presentation (OR 2.84; 95% CI 1.11-7.20, p = 0.02) were independent predictors of treatment failure (seizure persistence beyond 10 minutes or recurrence within one hour of treatment). Predictors of seizure recurrence included: 1) cerebral malaria (HR 3.32; 95% CI 1.94-5.66, p < 0.001), 2) presenting with multiple seizures (HR 2.45; 95% CI 1.42-4.23, p = 0.001), 3) focal seizures (HR 2.86; 95% CI 1.49-5.49, p = 0.002), 4) recent use of diazepam (HR 2.43; 95% CI 1.19-4.95, p = 0.01) and 5) initial control of the seizure with diazepam (HR 1.96; 95% CI 1.16-3.33, p = 0.01). CONCLUSION: Specific predictors, including cerebral malaria, can identify patients with malaria at risk of anti-convulsant treatment failure and seizure recurrence