Mechanisms matter: predicting the ecological impacts of global change

The ability of mechanistic models to reliably extrapolate to novel conditions could position them as the gold standard in understanding the impacts of global change, but exactly how mechanistic models can be used most effectively remains to be determined. In this issue, Desforges et al. present a mechanistic physiological model to understand the drivers of muskox population dynamics. We took this as an opportunity to discuss the potential for, and challenges of, using mechanistic models to predict ecological responses to environmental change

Individual-based modelling of elephant population dynamics using remote sensing to estimate food availability

Strategies for the conservation and management of many wild species requires an improved understanding of how population dynamics respond to changes in environmental conditions, including key drivers such as food availability. The development of mechanistic predictive models, in which the underlying processes of a system are modelled, enables a robust understanding of these demographic responses to dynamic environmental conditions. We present an individual-based energy budget model for a mega-herbivore, the African elephant (Loxodonta africana), which relates remotely measured changes in food availability to vital demographic rates of birth and mortality. Elephants require large spaces over which to roam in search of seasonal food, and thus are vulnerable to environmental changes which limit space use or alter food availability. The model is constructed using principles of physiological ecology; uncertain parameter values are calibrated using approximate Bayesian computation. The resulting model fits observed population dynamics data well. The model has critical value in being able to project elephant population size under future environmental conditions and is applicable to other mammalian herbivores with appropriate parameterisation

Human‐driven habitat conversion is a more immediate threat to Amboseli elephants than climate change

Global ecosystem change presents a major challenge to biodiversity conservation, which must identify and prioritize the most critical threats to species persistence given limited available funding. Mechanistic models enable robust predictions under future conditions and can consider multiple stressors in combination. Here we use an individual‐based model (IBM) to predict elephant population size in Amboseli, southern Kenya, under environmental scenarios incorporating climate change and anthropogenic habitat loss. The IBM uses projected food availability as a key driver of elephant population dynamics and relates variation in food availability to changes in vital demographic rates through an energy budget. Habitat loss, rather than climate change, represents the most significant threat to the persistence of the Amboseli elephant population in the 21st century and highlights the importance of collaborations and agreements that preserve space for Amboseli elephants to ensure the population remains resilient to environmental stochasticity

The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754. METHODS: Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought. RESULTS: In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment. CONCLUSION: NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent

Application of TAMSAT-ALERT soil moisture forecasts for planting date decision support in Africa

Deciding when to plant is critical for smallholders in Africa. If they plant too early, farmers risk seedling death if the rains are not established; if they plant too late, there will not be enough rain to sustain the crop through critical development periods. In this study, we present a new decision support tool (DST) that accounts for the trade-off in the risks of early and late planting through advisories based on both short- and long-range forecasts of crop water availability. Unlike most existing operational systems, which are based solely on rainfall, the DST presented here uses ensemble forecasts of soil moisture to estimate the optimal planting date at a local scale. Evaluations using &gt;30,000 observations of planting date and yield in Kenya, Rwanda, Uganda, Zambia and Malawi demonstrate that that planting at the optimal time would increase yield by 7–10% overall, and up to 20% for late planting farmers. The DST has been piloted by One Acre Fund for the 2019–2020, 2020–2021, and 2021–2022 seasons and there is strong demand for the service to be extended further. We conclude from the evaluations and pilots that the planting date DST has the potential to strengthen farmer decision making and hence their resilience to climate variability and change

Type II Endoleak after Endovascular Aneurysm Repair: natural history and treatment outcomes

Published online April 2017Abstract not availableLiana Kumar, Prue Cowled, Margaret Boult, Stuart Howell, and Robert Fitridg

Evaluation of the Response of Intracranial Xenografts to VEGF Signaling Inhibition Using Multiparametric MRI.

Vascular endothelial growth factor A (VEGF-A) is considered one of the most important factors in tumor angiogenesis, and consequently, a number of therapeutics have been developed to inhibit VEGF signaling. Therapeutic strategies to target brain malignancies, both primary brain tumors, particularly in pediatric patients, and metastases, are lacking, but targeting angiogenesis may be a promising approach. Multiparametric MRI was used to investigate the response of orthotopic SF188luc pediatric glioblastoma xenografts to small molecule pan-VEGFR inhibitor cediranib and the effects of both cediranib and cross-reactive human/mouse anti-VEGF-A antibody B20-4.1.1 in intracranial MDA-MB-231 LM2-4 breast cancer xenografts over 48 hours. All therapeutic regimens resulted in significant tumor growth delay. In cediranib-treated SF188luc tumors, this was associated with lower Ktrans (compound biomarker of perfusion and vascular permeability) than in vehicle-treated controls. Cediranib also induced significant reductions in both Ktrans and apparent diffusion coefficient (ADC) in MDA-MB-231 LM2-4 tumors associated with decreased histologically assessed perfusion. B20-4.1.1 treatment resulted in decreased Ktrans, but in the absence of a change in perfusion; a non-significant reduction in vascular permeability, assessed by Evans blue extravasation, was observed in treated tumors. The imaging responses of intracranial MDA-MB-231 LM2-4 tumors to VEGF/VEGFR pathway inhibitors with differing mechanisms of action are subtly different. We show that VEGF pathway blockade resulted in tumor growth retardation and inhibition of tumor vasculature in preclinical models of pediatric glioblastoma and breast cancer brain metastases, suggesting that multiparametric MRI can provide a powerful adjunct to accelerate the development of antiangiogenic therapies for use in these patient populations

The effectiveness of case management for comorbid diabetes type 2 patients; the CasCo study. Design of a randomized controlled trial

BACKGROUND: More than half of the patients with type 2 diabetes (T2DM) patients are diagnosed with one or more comorbid disorders. They can participate in several single-disease oriented disease management programs, which may lead to fragmented care because these programs are not well prepared for coordinating care between programs. Comorbid patients are therefore at risk for suboptimal treatment, unsafe care, inefficient use of health care services and unnecessary costs. Case management is a possible model to counteract fragmented care for comorbid patients. It includes evidence-based optimal care, but is tailored to the individual patients' preferences.The objective of this study is to examine the effectiveness of a case management program, in addition to a diabetes management program, on the quality of care for comorbid T2DM patients. METHODS/DESIGN: The study is a randomized controlled trial among patients with T2DM and at least one comorbid chronic disease (N=230), who already participate in a diabetes management program. Randomization will take place at the level of the patients in general practices. Trained practice nurses (case managers) will apply a case management program in addition to the diabetes management program. The case management intervention is based on the Guided Care model and includes six elements; assessing health care needs, planning care, create access to other care providers and community resources, monitoring, coordinating care and recording of all relevant information. Patients in the control group will continue their participation in the diabetes management program and receive care-as-usual from their general practitioner and other care providers. DISCUSSION: We expect that the case management program, which includes better structured care based on scientific evidence and adjusted to the patients' needs and priorities, will improve the quality of care coordination from both the patients' and caregivers' perspective and will result in less consumption of health care services. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1847. (aut. ref.

Preclinical transgenic and patient-derived xenograft models recapitulate the radiological features of human adamantinomatous craniopharyngioma

To assess the clinical relevance of transgenic and patient-derived xenograft models of adamantinomatous craniopharyngioma (ACP) using serial magnetic resonance imaging (MRI) and high resolution post-mortem microcomputed tomography (μ-CT), with correlation with histology and human ACP imaging. The growth patterns and radiological features of tumors arising in Hesx1(Cre/+) ;Ctnnb1(lox(ex3)/+) transgenic mice, and of patient-derived ACP xenografts implanted in the cerebral cortex, were monitored longitudinally in vivo with anatomical and functional MRI, and by ex vivo μ-CT at study end. Pathological correlates with hematoxylin and eosin stained sections were investigated. Early enlargement and heterogeneity of Hesx1(Cre/+) ;Ctnnb1(lox(ex3)/+) mouse pituitaries was evident at initial imaging at 8 weeks, which was followed by enlargement of a solid tumor, and development of cysts and hemorrhage. Tumors demonstrated MRI features that recapitulated those of human ACP, specifically, T1 -weighted signal enhancement in the solid tumor component following Gd-DTPA administration, and in some animals, hyperintense cysts on FLAIR and T1 -weighted images. Ex vivo μ-CT correlated with MRI findings and identified smaller cysts, which were confirmed by histology. Characteristic histological features, including wet keratin and calcification, were visible on μ-CT and verified by histological sections of patient-derived ACP xenografts. The Hesx1(Cre/+) ;Ctnnb1(lox(ex3)/+) transgenic mouse model and cerebral patient-derived ACP xenografts recapitulate a number of the key radiological features of the human disease and provide promising foundations for in vivo trials of novel therapeutics for the treatment of these tumors