Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson's disease and depression.

Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson's disease (PD) as well as treatments for attention deficit hyperactivity disorder (ADHD) and depression. Model genetic organisms such as Drosophila melanogaster may enhance the detection of new drugs via modifier or 'enhancer/suppressor' screens, but this technique has not been applied to processes relevant to psychiatry. To identify new aminergic drugs in vivo, we used a mutation in the Drosophila vesicular monoamine transporter (dVMAT) as a sensitized genetic background and performed a suppressor screen. We fed dVMAT mutant larvae ∼ 1000 known drugs and quantitated rescue (suppression) of an amine-dependent locomotor deficit in the larva. To determine which drugs might specifically potentiate neurotransmitter release, we performed an additional secondary screen for drugs that require presynaptic amine storage to rescue larval locomotion. Using additional larval locomotion and adult fertility assays, we validated that at least one compound previously used clinically as an antineoplastic agent potentiates the presynaptic function of aminergic circuits. We suggest that structurally similar agents might be used to development treatments for PD, depression and ADHD, and that modifier screens in Drosophila provide a new strategy to screen for neuropsychiatric drugs. More generally, our findings demonstrate the power of physiologically based screens for identifying bioactive agents for select neurotransmitter systems

Can data in optometric practice be used to provide an evidence base for ophthalmic public health?

Purpose: The purpose of this paper is to investigate the potential of using primary care optometry data to support ophthalmic public health, research and policy making. Methods: Suppliers of optometric electronic patient record systems (EPRs) were interviewed to gather information about the data present in commercial software programmes and the feasibility of data extraction. Researchers were presented with a list of metrics that might be included in an optometric practice dataset via a survey circulated by email to 102 researchers known to have an interest in eye health. Respondents rated the importance of each metric for research. A further survey presented the list of metrics to 2000 randomly selected members of the College of Optometrists. The optometrists were asked to specify how likely they were to enter information about each metric in a routine sight test consultation. They were also asked if data were entered as free text, menus or a combination of these. Results: Current EPRs allowed the input of data relating to the metrics of interest. Most data entry was free text. There was a good match between high priority metrics for research and those commonly recorded in optometric practice. Conclusions: Although there were plenty of electronic data in optometric practice, this was highly variable and often not in an easily analysed format. To facilitate analysis of the evidence for public health purposes a UK based minimum dataset containing standardised clinical information is recommended. Further research would be required to develop suitable coding for the individual metrics included. The dataset would need to capture information from all sectors of the population to ensure effective planning of any future interventions

Droplet-based electro-coalescence for probing threshold disjoining pressure

In this work, we investigate the coalescence of emulsion droplets in a controlled electric field. Two contacting droplets stabilized by surfactants can be forced to coalesce into a combined one when the applied voltage is above a critical value. The critical voltages change with the types, concentrations of surfactants and temperature. By exploring the drainage of a thin oil film trapped between emulsions, we interpret that the coalescence occurs as the electric compression overcomes the disjoining pressure barrier and squeezes the film to a critical thickness. Based on this, we have devised an approach to probe the threshold disjoining pressure which can help predict the emulsion stability and surfactant efficacy quantitatively. We have confirmed the validity of our approach for measuring the threshold disjoining pressure by comparing the result with other proven tests that involve centrifugation and thermal heating. Our approach is simple, reliable and robust in predicting emulsion stability and will facilitate the design of emulsion-based formulations by accelerating the testing of emulsion stability.postprin

Sparse Deterministic Approximation of Bayesian Inverse Problems

We present a parametric deterministic formulation of Bayesian inverse problems with input parameter from infinite dimensional, separable Banach spaces. In this formulation, the forward problems are parametric, deterministic elliptic partial differential equations, and the inverse problem is to determine the unknown, parametric deterministic coefficients from noisy observations comprising linear functionals of the solution. We prove a generalized polynomial chaos representation of the posterior density with respect to the prior measure, given noisy observational data. We analyze the sparsity of the posterior density in terms of the summability of the input data's coefficient sequence. To this end, we estimate the fluctuations in the prior. We exhibit sufficient conditions on the prior model in order for approximations of the posterior density to converge at a given algebraic rate, in terms of the number $N$ of unknowns appearing in the parameteric representation of the prior measure. Similar sparsity and approximation results are also exhibited for the solution and covariance of the elliptic partial differential equation under the posterior. These results then form the basis for efficient uncertainty quantification, in the presence of data with noise

Exploring the Use of Cost-Benefit Analysis to Compare Pharmaceutical Treatments for Menorrhagia

Background: The extra-welfarist theoretical framework tends to focus on health-related quality of life, whilst the welfarist framework captures a wider notion of well-being. EQ-5D and SF-6D are commonly used to value outcomes in chronic conditions with episodic symptoms, such as heavy menstrual bleeding (clinically termed menorrhagia). Because of their narrow-health focus and the condition’s periodic nature these measures may be unsuitable. A viable alternative measure is willingness to pay (WTP) from the welfarist framework. Objective: We explore the use of WTP in a preliminary cost-benefit analysis comparing pharmaceutical treatments for menorrhagia. Methods: A cost-benefit analysis was carried out based on an outcome of WTP. The analysis is based in the UK primary care setting over a 24-month time period, with a partial societal perspective. Ninety-nine women completed a WTP exercise from the ex-ante (pre-treatment/condition) perspective. Maximum average WTP values were elicited for two pharmaceutical treatments, levonorgestrel-releasing intrauterine system (LNG-IUS) and oral treatment. Cost data were offset against WTP and the net present value derived for treatment. Qualitative information explaining the WTP values was also collected. Results: Oral treatment was indicated to be the most cost-beneficial intervention costing £107 less than LNG-IUS and generating £7 more benefits. The mean incremental net present value for oral treatment compared with LNG-IUS was £113. The use of the WTP approach was acceptable as very few protests and non-responses were observed. Conclusion: The preliminary cost-benefit analysis results recommend oral treatment as the first-line treatment for menorrhagia. The WTP approach is a feasible alternative to the conventional EQ-5D/SF-6D approaches and offers advantages by capturing benefits beyond health, which is particularly relevant in menorrhagia

Can disordered mobile phone use be considered a behavioral addiction? An update on current evidence and a comprehensive model for future research

Despite the many positive outcomes, excessive mobile phone use is now often associated with potentially harmful and/or disturbing behaviors (e.g., symptoms of deregulated use, negative impact on various aspects of daily life such as relationship problems, and work intrusion). Problematic mobile phone use (PMPU) has generally been considered as a behavioral addiction that shares many features with more established drug addictions. In light of the most recent data, the current paper reviews the validity of the behavioral addiction model when applied to PMPU. On the whole, it is argued that the evidence supporting PMPU as an addictive behavior is scarce. In particular, it lacks studies that definitively show behavioral and neurobiological similarities between mobile phone addiction and other types of legitimate addictive behaviors. Given this context, an integrative pathway model is proposed that aims to provide a theoretical framework to guide future research in the field of PMPU. This model highlights that PMPU is a heterogeneous and multi-faceted condition

Ocean forced variability of Totten Glacier mass loss

This is the author accepted manuscript. The final version is available from the Geological Society of London via the DOI in this record.A large volume of the East Antarctic Ice Sheet drains through the Totten Glacier (TG) and is thought to be a potential source of substantial global sea level rise over the coming centuries. We show the surface velocity and heightof the floating part of TG, which buttresses the grounded component, have varied substantially over two decades (1989–2011), with variations in surface height strongly anti-correlated with simulated basal melt rates (r=0.70, p<0.05). Coupled glacier/ice-shelf simulations confirm ice flow and thickness respond to both basal melting of the ice shelf and grounding on bed obstacles. We conclude the observed variability of TG is primarily ocean-driven. Ocean warming in this region will lead to enhanced ice-sheet dynamism and loss of upstream grounded ice.This work was supported by, Australian Antarctic Division projects 3103, 4077, 4287 and 4346, National Computing Infrastructure grant m68, NSF grant ANT-0733025, NASA grant NNX09AR52G (Operation Ice Bridge), NERC grant NE/F016646/1, NERC fellowship NE/G012733/2, the Jackson School of Geoscience, the Jet Propulsion Laboratory and the G. Unger Vetlesen Foundation. This research was also supported by the Australian Government’s Cooperative Research Centres Programme through the Antarctic Climate & Ecosystems Cooperative Research Centre. The work is also supported under the Australian Research Councils Special Research Initiative for Antarctic Gateway Partnership SR140300001. Landsat 4 and 7 images courtesy of the U.S. Geological Survey. This is UTIG contribution 2486. Thanks to Benoit Legresy for useful discussions

Dissolved noble gases and stable isotopes as tracers of preferential fluid flow along faults in the Lower Rhine Embayment, Germany

Groundwater in shallow unconsolidated sedimentary aquifers close to the Bornheim fault in the Lower Rhine Embayment (LRE), Germany, has relatively low δ2H and δ18O values in comparison to regional modern groundwater recharge, and 4He concentrations up to 1.7 × 10−4 cm3 (STP) g–1 ± 2.2 % which is approximately four orders of magnitude higher than expected due to solubility equilibrium with the atmosphere. Groundwater age dating based on estimated in situ production and terrigenic flux of helium provides a groundwater residence time of ∼107 years. Although fluid exchange between the deep basal aquifer system and the upper aquifer layers is generally impeded by confining clay layers and lignite, this study’s geochemical data suggest, for the first time, that deep circulating fluids penetrate shallow aquifers in the locality of fault zones, implying  that sub-vertical fluid flow occurs along faults in the LRE. However, large hydraulic-head gradients observed across many faults suggest that they act as barriers to lateral groundwater flow. Therefore, the geochemical data reported here also substantiate a conduit-barrier model of fault-zone hydrogeology in unconsolidated sedimentary deposits, as well as corroborating the concept that faults in unconsolidated aquifer systems can act as loci for hydraulic connectivity between deep and shallow aquifers. The implications of fluid flow along faults in sedimentary basins worldwide are far reaching and of particular concern for carbon capture and storage (CCS) programmes, impacts of deep shale gas recovery for shallow groundwater aquifers, and nuclear waste storage sites where fault zones could act as potential leakage pathways for hazardous fluids

Population-Based Precision Cancer Screening: A Symposium on Evidence, Epidemiology, and Next Steps

Precision medicine, an emerging approach for disease treatment that takes into account individual variability in genes, environment, and lifestyle, is under consideration for preventive interventions, including cancer screening. On September 29, 2015, the National Cancer Institute sponsored a symposium entitled “Precision Cancer Screening in the General Population: Evidence, Epidemiology, and Next Steps”. The goal was two-fold: to share current information on the evidence, practices, and challenges surrounding precision screening for breast, cervical, colorectal, lung, and prostate cancers, and to allow for in-depth discussion among experts in relevant fields regarding how epidemiology and other population sciences can be used to generate evidence to inform precision screening strategies. Attendees concluded that the strength of evidence for efficacy and effectiveness of precision strategies varies by cancer site, that no one research strategy or methodology would be able or appropriate to address the many knowledge gaps in precision screening, and that issues surrounding implementation must be researched as well. Additional discussion needs to occur to identify the high priority research areas in precision cancer screening for pertinent organs and to gather the necessary evidence to determine whether further implementation of precision cancer screening strategies in the general population would be feasible and beneficial

A hypothetico-deductive approach to assessing the social function of chemical signalling in a non-territorial solitary carnivore

The function of chemical signalling in non-territorial solitary carnivores is still relatively unclear. Studies on territorial solitary and social carnivores have highlighted odour capability and utility, however the social function of chemical signalling in wild carnivore populations operating dominance hierarchy social systems has received little attention. We monitored scent marking and investigatory behaviour of wild brown bears Ursus arctos, to test multiple hypotheses relating to the social function of chemical signalling. Camera traps were stationed facing bear ‘marking trees’ to document behaviour by different age sex classes in different seasons. We found evidence to support the hypothesis that adult males utilise chemical signalling to communicate dominance to other males throughout the non-denning period. Adult females did not appear to utilise marking trees to advertise oestrous state during the breeding season. The function of marking by subadult bears is somewhat unclear, but may be related to the behaviour of adult males. Subadults investigated trees more often than they scent marked during the breeding season, which could be a result of an increased risk from adult males. Females with young showed an increase in marking and investigation of trees outside of the breeding season. We propose the hypothesis that females engage their dependent young with marking trees from a young age, at a relatively ‘safe’ time of year. Memory, experience, and learning at a young age, may all contribute towards odour capabilities in adult bears