Time to abandon the hygiene hypothesis: new perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene.

AIMS: To review the burden of allergic and infectious diseases and the evidence for a link to microbial exposure, the human microbiome and immune system, and to assess whether we could develop lifestyles which reconnect us with exposures which could reduce the risk of allergic disease while also protecting against infectious disease. METHODS: Using methodology based on the Delphi technique, six experts in infectious and allergic disease were surveyed to allow for elicitation of group judgement and consensus view on issues pertinent to the aim. RESULTS: Key themes emerged where evidence shows that interaction with microbes that inhabit the natural environment and human microbiome plays an essential role in immune regulation. Changes in lifestyle and environmental exposure, rapid urbanisation, altered diet and antibiotic use have had profound effects on the human microbiome, leading to failure of immunotolerance and increased risk of allergic disease. Although evidence supports the concept of immune regulation driven by microbe-host interactions, the term 'hygiene hypothesis' is a misleading misnomer. There is no good evidence that hygiene, as the public understands, is responsible for the clinically relevant changes to microbial exposures. CONCLUSION: Evidence suggests a combination of strategies, including natural childbirth, breast feeding, increased social exposure through sport, other outdoor activities, less time spent indoors, diet and appropriate antibiotic use, may help restore the microbiome and perhaps reduce risks of allergic disease. Preventive efforts must focus on early life. The term 'hygiene hypothesis' must be abandoned. Promotion of a risk assessment approach (targeted hygiene) provides a framework for maximising protection against pathogen exposure while allowing spread of essential microbes between family members. To build on these findings, we must change public, public health and professional perceptions about the microbiome and about hygiene. We need to restore public understanding of hygiene as a means to prevent infectious disease

Improved timed-mating, non-invasive method using fewer unproven female rats with pregnancy validation via early body mass increases

For studies requiring accurate conception-timing, reliable, efficient methods of detecting oestrus reduce time and costs, whilst improving welfare. Standard methods use vaginal cytology to stage cycle, and breeders are paired–up using approximately five proven females with proven males to achieve at least one conception on a specific day. We describe an alternative, fast, consistent, non-invasive method of timed-mating using detection of lordosis behaviour in Wistar and Lister-Hooded rats that used unproven females with high success rates. Rats under reverse-lighting had body masses recorded pre-mating, day (d) 3-4, d8, d10 and d18 of pregnancy. Using only the presence of the oestrus dance to time-mate females for 24-hrs, 89% Wistar and 88% Lister-Hooded rats successfully conceived. We did not observe behavioural oestrus in Sprague-Dawleys without males present. Significant body mass increases following mating distinguished pregnant from non-pregnant rats, as early as d4 of pregnancy (10% ± 1.0 increase cf 3% ± 1.2). The pattern of increases throughout gestation was similar for all pregnant rats until late pregnancy, when there were smaller increases for primi- and multiparous rats (32% ± 2.5; 25% ± 2.4), whereas nulliparous rats had highest gains (38% ± 1.5). This method demonstrated a distinct refinement of the previous timed-mating common practice used, as disturbance of females was minimised. Only the number required of nulli-, primi- or multiparous rats were mated, and body mass increases validated pregnancy status. This new breeding-management method is now established practice for two strains of rat and resulted in a reduction in animal use

Gastric Malignancy Survival in Zambia, Southern Africa: A two year follow up study

Background: Gastric cancer poses a significant global health burden. It is the second most common cause of cancer death worldwide and the ninth leading cause of cancer mortality in Zambia, at a rate of 3.8/100,000; comparable to USA (2/100,000) and UK (3.4/100,000). Survival data on gastric malignancy in Zambia is not known.Objectives: To provide preliminary survival rates of patients with histologically proven gastric adenocarcinoma in Zambia.Study Design: Using our prospective gastric cancer research database, we conducted a retrospective audit of patients diagnosed with gastric cancer at the University Teaching Hospital, Zambia, from June 2010 until January 2012. We contacted patients or their relatives using phone numbers provided at time of enrollment.Main Outcomes: We reviewed age, sex, demographic data (income, education), body mass index, symptoms, duration of symptoms, treatment (surgery, chemotherapy, radiotherapy or combination) and survival outcome.  Analysis was performed using Kaplan-Meier models and log rank test.Results: Fifty one patients were diagnosed with gastric adenocarcinoma during the study period, but follow-up data were available for 50. Median survival was 142 days. Age, sex, income, education, BMI, tumor location, and treatment modality were not significantly associated with overall survival. In Cox regression models, covariates associated with survival were a history of regular alcohol intake (HR 0.49, 95%CI 0.26,0.92; P=0.025) and intestinal type cancer histology (HR 0.40, 95%CI 0.19,0.83; P=0.01).Conclusion: Prognosis of newly diagnosed gastric cancer in Zambia is poor with significant mortality within 1 yearof diagnosis, particularly among patients with weight loss and dysphagia

Versatile regularisation toolkit for iterative image reconstruction with proximal splitting algorithms

Ill-posed image recovery requires regularisation to ensure stability. The presented open-source regularisation toolkit consists of state-of-the-art variational algorithms which can be embedded in a plug-and-play fashion into the general framework of proximal splitting methods. The packaged regularisers aim to satisfy various prior expectations of the investigated objects, e.g., their structural characteristics, smooth or non-smooth surface morphology. The flexibility of the toolkit helps with the design of more advanced model-based iterative reconstruction methods for different imaging modalities while operating with simpler building blocks. The toolkit is written for CPU and GPU architectures and wrapped for Python/MATLAB. We demonstrate the functionality of the toolkit in application to Positron Emission Tomography (PET) and X-ray synchrotron computed tomography (CT)

A Microsoft-Excel-based tool for running and critically appraising network meta-analyses--an overview and application of NetMetaXL.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.BACKGROUND: The use of network meta-analysis has increased dramatically in recent years. WinBUGS, a freely available Bayesian software package, has been the most widely used software package to conduct network meta-analyses. However, the learning curve for WinBUGS can be daunting, especially for new users. Furthermore, critical appraisal of network meta-analyses conducted in WinBUGS can be challenging given its limited data manipulation capabilities and the fact that generation of graphical output from network meta-analyses often relies on different software packages than the analyses themselves. METHODS: We developed a freely available Microsoft-Excel-based tool called NetMetaXL, programmed in Visual Basic for Applications, which provides an interface for conducting a Bayesian network meta-analysis using WinBUGS from within Microsoft Excel. . This tool allows the user to easily prepare and enter data, set model assumptions, and run the network meta-analysis, with results being automatically displayed in an Excel spreadsheet. It also contains macros that use NetMetaXL's interface to generate evidence network diagrams, forest plots, league tables of pairwise comparisons, probability plots (rankograms), and inconsistency plots within Microsoft Excel. All figures generated are publication quality, thereby increasing the efficiency of knowledge transfer and manuscript preparation. RESULTS: We demonstrate the application of NetMetaXL using data from a network meta-analysis published previously which compares combined resynchronization and implantable defibrillator therapy in left ventricular dysfunction. We replicate results from the previous publication while demonstrating result summaries generated by the software. CONCLUSIONS: Use of the freely available NetMetaXL successfully demonstrated its ability to make running network meta-analyses more accessible to novice WinBUGS users by allowing analyses to be conducted entirely within Microsoft Excel. NetMetaXL also allows for more efficient and transparent critical appraisal of network meta-analyses, enhanced standardization of reporting, and integration with health economic evaluations which are frequently Excel-based.CC is a recipient of a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (funding reference number—CGV 121171) and is a trainee on the Canadian Institutes of Health Research Drug Safety and Effectiveness Network team grant (funding reference number—116573). BH is funded by a New Investigator award from the Canadian Institutes of Health Research and the Drug Safety and Effectiveness Network. This research was partly supported by funding from CADTH as part of a project to develop Excel-based tools to support the conduct of health technology assessments. This research was also supported by Cornerstone Research Group

Genes Are Often Sheltered from the Global Histone Hyperacetylation Induced by HDAC Inhibitors

Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (∼9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi

X-ray Absorption and Reflection in Active Galactic Nuclei

X-ray spectroscopy offers an opportunity to study the complex mixture of emitting and absorbing components in the circumnuclear regions of active galactic nuclei, and to learn about the accretion process that fuels AGN and the feedback of material to their host galaxies. We describe the spectral signatures that may be studied and review the X-ray spectra and spectral variability of active galaxies, concentrating on progress from recent Chandra, XMM-Newton and Suzaku data for local type 1 AGN. We describe the evidence for absorption covering a wide range of column densities, ionization and dynamics, and discuss the growing evidence for partial-covering absorption from data at energies > 10 keV. Such absorption can also explain the observed X-ray spectral curvature and variability in AGN at lower energies and is likely an important factor in shaping the observed properties of this class of source. Consideration of self-consistent models for local AGN indicates that X-ray spectra likely comprise a combination of absorption and reflection effects from material originating within a few light days of the black hole as well as on larger scales. It is likely that AGN X-ray spectra may be strongly affected by the presence of disk-wind outflows that are expected in systems with high accretion rates, and we describe models that attempt to predict the effects of radiative transfer through such winds, and discuss the prospects for new data to test and address these ideas.Comment: Accepted for publication in the Astronomy and Astrophysics Review. 58 pages, 9 figures. V2 has fixed an error in footnote

Shining light on data-poor coastal fisheries

This is the final version. Available on open access from Frontiers Media via the DOI in this recordData Availability Statement: VIIRS Boat Detection data productmade available open access by the Earth Observation Group, Payne Institute for Public Policy (https://eogdata.mines.edu/vbd/). The other datasets presented in this article are not readily available because data requests need to be made directly to the WCS Myanmar offices. Requests to access the datasets should be directed to WCS Myanmar, [email protected] fisheries provide livelihoods and sustenance for millions of people globally but are often poorly documented. Data scarcity, particularly relating to spatio-temporal trends in catch and effort, compounds wider issues of governance capacity. This can hinder the implementation and effectiveness of spatial tools for fisheries management or conservation. This issue is acute in developing and low income regions with many small-scale inshore fisheries and high marine biodiversity, such as Southeast Asia. As a result, fleets often operate unmonitored with implications for target and non-target species populations and the wider marine ecosystem. Novel and cost-effective approaches to obtain fisheries data are required to monitor these activities and help inform sustainable fishery and marine ecosystem management. One such example is the detection and numeration of fishing vessels that use artificial light to attract catch with nighttime satellite imagery. Here we test the efficiency and application value of nighttime satellite imagery, in combination with landings data and GPS tracked vessels, to estimate the footprint and biomass removal of an inshore purse seine fishery operating within a region of high biodiversity in Myanmar. By quantifying the number of remotely sensed vessel detections per month, adjusted for error by the GPS tracked vessels, we can extrapolate data from fisher logbooks to provide fine-scale spatiotemporal estimates of the fishery’s effort, value and biomass removal. Estimates reveal local landings of nearly 9,000 mt worth close to $4 million USD annually. This approach details how remote sensed and in situ collected data can be applied to other fleets using artificial light to attract catch, notably inshore fisheries of Southeast Asia, whilst also providing a much-needed baseline understanding of a data-poor fishery’s spatiotemporal activity, biomass removal, catch composition and landing of vulnerable species.Wildlife Conservation Societ

Molecular imaging of glycan chains couples cell-wall polysaccharide architecture to bacterial cell

Biopolymer composite cell walls maintain cell shape and resist forces in plants, fungi and bacteria. Peptidoglycan, a crucial antibiotic target and immunomodulator, performs this role in bacteria. The textbook structural model of peptidoglycan is a highly ordered, crystalline material. Here we use atomic force microscopy (AFM) to image individual glycan chains in peptidoglycan from Escherichia coli in unprecedented detail. We quantify and map the extent to which chains are oriented in a similar direction (orientational order), showing it is much less ordered than previously depicted. Combining AFM with size exclusion chromatography, we reveal glycan chains up to 200 nm long. We show that altered cell shape is associated with substantial changes in peptidoglycan biophysical properties. Glycans from E. coli in its normal rod shape are long and circumferentially oriented, but when a spheroid shape is induced (chemically or genetically) glycans become short and disordered