Natural disease course modeling of achondroplasia to evaluate the efficacy of recifercept in the absence of a placebo control arm in phase II study.

While randomized, placebo-controlled, double-blinded clinical studies are the gold standard for evaluating the efficacy of investigational drugs, the use of placebo in children with achondroplasia should be limited because it provides no clinical benefit while exhausting study participants' treatment window. Recifercept is an investigational drug for treating children with achondroplasia aged 2-10 years. An alternative efficacy evaluation method, instead of a placebo control arm, was employed in the phase II study. Prior to participating in the phase II study, participants completed a natural history (NH) study. Based on the NH data, a multi-variate linear mixed effects natural disease course model of three anthropometric end points (standing height, sitting height, and arm span) was developed. The model was validated using published growth charts of children with achondroplasia. Subsequently, the model was used to simulate the natural growth trajectories (without any treatment) of the three anthropometric end points for the individuals enrolled in the phase II study. To quantify the efficacy of recifercept, the simulations were compared with the observations post-recifercept treatment in the phase II study. For all the tested doses of recifercept, at the individual level, the observations were comparable to the simulations at 6 and 12 months post-recifercept treatment, suggesting no treatment effect. The results contributed to the decision of terminating recifercept clinical development. This work delivers a framework that could eliminate the need for placebo in clinical trials yet provide sufficient evidence for evaluating the efficacy of an investigational drug.

Higher predation risk for insect prey at low latitudes and elevations.

Biotic interactions underlie ecosystem structure and function, but predicting interaction outcomes is difficult. We tested the hypothesis that biotic interaction strength increases toward the equator, using a global experiment with model caterpillars to measure predation risk. Across an 11,660-kilometer latitudinal gradient spanning six continents, we found increasing predation toward the equator, with a parallel pattern of increasing predation toward lower elevations. Patterns across both latitude and elevation were driven by arthropod predators, with no systematic trend in attack rates by birds or mammals. These matching gradients at global and regional scales suggest consistent drivers of biotic interaction strength, a finding that needs to be integrated into general theories of herbivory, community organization, and life-history evolution.

Evaluating the potential of effluent extracts from pulp and paper mills in Canada, Brazil, and New Zealand to affect fish reproduction: Estrogenic effects in fish.

The authors examined the potential of pulp mill effluent from pulp-producing countries (Canada, Brazil, New Zealand) to affect fish reproduction. Specifically, the estrogenic effects in juvenile rainbow trout (Oncorhynchus mykiss) pulse-exposed to 11 different mill effluent extracts (intraperitoneal injections of solid-phase extraction-dichloromethane nonpolar fraction). The results indicated that effluent extracts were estrogenic in juvenile trout irrespective of the gender, as reflected by increasing level of plasma vitellogenin (VTG; Brazil > New Zealand > Canada). Despite the high variability observed among mills, differences in VTG levels were related to the type of mill process (kraft > elementary chlorine-free kraft > thermomechanical pulping). Moreover, effluent treatments did not appear to significantly decrease VTG induction. A consistent estrogenic effect was observed in those mills that process a combination of feedstocks (softwood and hardwood), with the highest increase in VTG related to eucalyptus feedstock. The results demonstrate significant estrogenic effects of pulp mill effluents on chronically exposed juvenile trout, suggesting that in vivo metabolic activation of precursors is necessary to cause the observed increases in VTG levels. This molecular estrogenic response provides a useful starting point for predicting population-level impacts through the adverse outcome pathway methodology. Environ Toxicol Chem 2017;36:1547-1555. © 2016 SETAC.

Influence of pH and natural organic matter on zinc biosorption in a model lignocellulosic biofuel biorefinery effluent.

The effect of dissolved natural organic matter (NOM) and pH on microbial biosorption of Zn was evaluated in a model lignocellulosic biofuel refinery effluent rich in NOM. Batch culture experiments conducted with two model microorganisms (yeast, Candida tropicalis; bacteria Novosphingobium nitrogenifigens Y88(T)), showed an inhibitory effect of NOM, and an optimum pH for Zn removal at 7.5-8.0. Membrane bioreactors with mixed autochthonous organisms were operated at pH 6.5 and pH 8.0 to better simulate real-world remediation scenarios. More Zn was removed at the high (91%) than at the low (26%) pH, presumably because the higher pH freed negatively-charged functional groups on the cellular biomass for passive Zn binding. Manipulating the pH of bioreactors can significantly improve metal removal in NOM rich wastewater. Such reactors could maintain water quality for closed-cycle biorefineries, leading to reduced water consumption, and a more sustainable biofuel.

Metal biosorption in lignocellulosic biofuel biorefinery effluent: an initial step towards sustainability of water resources.

Biosorption of metals by microorganisms is a promising technology to remove accumulated non-process elements in highly recycled biorefinery process water. Removal of these elements would enable greater water reuse and reduce the environmental impact of effluent discharge. A model lignocellulosic ethanol biorefinery wastewater was created based on pulp mill effluent. This generated a wastewater with an environmentally realistic high loading of dissolved natural organic matter (900 mg/l), a potentially important factor influencing metal biosorption. Analysis of feedstock and pulp mill effluent indicated that Mn and Zn are likely to be problematic in highly recycled lignocellulosic ethanol biorefinery process water. Therefore, the growth of several bacteria and fungi from existing collections, and some isolated from pulp mill effluent were tested in the model wastewater spiked with Mn and Zn (0.2 mM). Wastewater isolates grew the best in the wastewater. Metal uptake varied by species and was much greater for Zn than Mn. A bacterium, Novosphingobium nitrogenifigens Y88(T), removed the most metal per unit biomass, 35 and 17 mg Mn/g. No other organism tested decreased the Mn concentration. A yeast, Candida tropicalis, produced the most biomass and removed the most total metal (38 % of Zn), while uptake per unit biomass was 24 mg Zn/g. These results indicate that microorganisms can remove significant amounts of metals in wastewater with high concentrations of dissolved natural organic matter. Metal sorption by autochthonous microorganisms in an anaerobic bioreactor may be able to extend water reuse and therefore lower the water consumption of future biorefineries.

Evaluating the potential of effluents and wood feedstocks from pulp and paper mills in Brazil, Canada, and New Zealand to affect fish reproduction: chemical profiling and in vitro assessments.

This study investigates factors affecting reproduction in fish exposed to pulp and paper mill effluents by comparing effluents from countries with varying levels of documented effects. To explore the hypothesis of wood as a common source of endocrine disrupting compounds, feedstocks from each country were analyzed. Analyses included in vitro assays for androgenic activity (binding to goldfish testis androgen receptors), estrogenic activity (yeast estrogen screen), and neurotransmitter enzyme inhibition (monoamine oxidase and glutamic acid decarboxylase). Chemical analyses included conventional extractives, known androgens, and gas chromatograph index (GCI) profiles. All effluents and wood contained androgenic activity, particularly in nonpolar fractions, although known androgens were undetected. Effluents with low suspended solids, having undergone conventional biotreatment had lower androgenic activities. Estrogenic activity was only associated with Brazilian effluents and undetected in wood. All effluents and wood inhibited neurotransmitter enzymes, predominantly in polar fractions. Kraft elemental chlorine free mills were associated with the greatest neurotransmitter inhibition. Effluent and wood GCI profiles were correlated with androgenic activity and neurotransmitter enzyme inhibition. Differences in feedstock bioactivities were not reflected in effluents, implying mill factors mitigate bioactive wood components. No differences in bioactivities could be discerned on the basis of country of origin, thus we predict effluents in regions lacking monitoring would affect fish reproduction and therefore recommend implementing such programs.

Effects of substrate composition on the structure of microbial communities in wastewater using fluorescence in situ hybridisation.

The microbial composition in a pulp and paper wastewater aerated lagoon system was analysed using fluorescence in situ hybridisation (FISH) to gain further understanding of the effect of substrate composition on microbial diversity for improved management of wastewater treatment systems. Few experiments have been conducted to tease apart the factors influencing the composition and abundance of certain groups within these wastewaters. Specific probes were used to investigate and enumerate the different bacterial groups present at particular stages through the treatment system over an extended period. Community composition and abundance of specific groups differed through the system however temporal stability was retained despite significant variability in the wastewater. Middle stream wastewater samples were enriched to explore the impact of different carbon/nitrogen/phosphorus (C:N:P) ratios on community composition and provide functionality to groups of micro-organisms within the microbial consortia. Nitrogen and phosphorus conditions did not impact community composition of methanol-fed cultures, which exhibited a dominance of Betaproteobacteria (>75%), namely Methylotrophic bacteria. This was confirmed through 16S rRNA gene sequencing and specific FISH probing, reflecting population observations at the beginning of the treatment system. We conclude that the nutrient and carbon combinations used in the enrichments created an interactive effect, altering the community composition and mimicking the main substrate load in the different stages of the treatment system. Finally, pulp and paper wastewater microbial composition was highly variable across the treatment system but was stable within the time sampled, with the enrichments emulating the substrate loads in the full scale system.

Technological options for the management of biosolids.

BACKGROUND, AIM, AND SCOPE: Large quantities of biosolids (sewage sludge), which are produced from municipal wastewater treatment, are ever-increasing because of the commissioning of new treatment plants and continuous upgrades of the existing facilities. A large proportion of biosolids are currently landfilled. With increasing pressure from regulators and the general public, landfilling of biosolids is being phased out in many countries because of potential secondary pollution caused by leachate and the emission of methane, a potent greenhouse gas. Biosolids contain nutrients and energy that can be used beneficially. Significant efforts have been made recently to develop new technologies to manage biosolids and make useful products from them. In this paper, we provide a review of the technologies in biosolids management. MATERIALS AND METHODS: A survey of literature was conducted. RESULTS: At present, the most common beneficial use of biosolids is agricultural land application because of inherent fertilizer values found in biosolids. Expansion of land application, however, may be limited in the future because of more stringent regulatory requirements and public concern about food chain contamination in some countries. Perceived as a green energy source, the combustion of biosolids has received renewed interest. Anaerobic digestion is generally a more effective method than incineration for energy recovery, and digested biosolids are suitable for further beneficial use through land application. Although conventional incineration systems for biosolid management generally consume more energy than they produce because of the high moisture content in the biosolids, it is expected that more combustion systems, either monocombustion or cocombustion, will be built to cope with the increasing quantity of biosolids. DISCUSSION: Under the increasingly popular low-carbon economy policy, biosolids may be recognized as a renewable fuel and be eligible for 'carbon credits'. Because ash can be used to manufacture construction materials, combustion can provide a complete management for biosolids. A number of advanced thermal conversion technologies (e.g., supercritical water oxidation process and pyrolysis) are under development for biosolids management with a goal to generate useful products, such as higher quality fuels and recovery of phosphorus. With an ever-increasing demand for renewable energy, growing bioenergy crops and forests using biosolids as a fertilizer and soil amendment can not only contribute to the low-carbon economy but also maximize the nutrient and carbon value of the biosolids. CONCLUSIONS: Land application of biosolids achieves a complete reuse of its nutrients and organic carbon at a relatively low cost. Therefore, land application should become a preferred management option where there is available land, the quality of biosolids meet regulatory requirements, and it is socially acceptable. Intensive energy cropping and forest production using biosolids can help us meet the ever-increasing demand for renewable energy, which can eliminate the contamination potential for food sources, a common social concern about land application of biosolids. In recent years, increasing numbers of national and local governments have adopted more stringent regulations toward biosolid management. Under such a political climate, biosolids producers will have to develop multireuse strategies for biosolids to avoid being caught because a single route management practice might be under pressure at a short notice. Conventional incineration systems for biosolids management generally consume more energy than they produce and, although by-products may be used in manufacturing, this process cannot be regarded as a beneficial use of biosolids. However, biosolids are likely to become a source of renewable energy and produce 'carbon credits' under the increasingly popular, low-carbon economy policy. RECOMMENDATIONS AND PERSPECTIVES: To manage biosolids in a sustainable manner, there is a need for further research in the following areas: achieving a higher degree of public understanding and acceptance for the beneficial use of biosolids, developing cost-efficient and effective thermal conversions for direct energy recovery from biosolids, advancing technology for phosphorus recovery, and selecting or breeding crops for efficient biofuel production.