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Improving nutrient management in grazing system dairy farms requires determining nutrient flows through animals, the placement of cows within farms and potential for collection, and the re-use and loss of nutrients. We applied a model incorporating data collected at a range of temporal and spatial scales to quantify nutrient excretion in all locations that lactating herds visited on five days over a year on 43 conventional and organic grazing system dairy farms. The calculated nutrient loads excreted by cows in different places were highly skewed; while N, P and K deposited loads were consistent across the year, S, Ca and Mg loads varied between sampling times and seasons. The greatest mean and range in nutrient loads were deposited in paddocks, with the smallest amounts deposited in dairy sheds. All excreted nutrient loads increased with farm and herd sizes and milk production. Mean daily loads of 112, 15, 85, 11, 22 and 13 kg of N, P, K, S, Ca and Mg were deposited by the herds which, when standardised to a 305-day lactation, amounted to 24, 4, 20, 3, 5 and 3 t excreted annually, respectively. In addition to routine manure collection in dairy sheds, ensuring collection and recycling of nutrients excreted on feed pads and holding areas would decrease potential nutrient losses by 29% on average. Non-collected, recycled nutrients were disproportionately returned to paddocks in which cows spent time overnight, and except for S and Ca, nutrient loading rates were greater than rates applied as fertilisers. These data demonstrate the extent of excreted nutrients in grazing dairy systems and indicate the need to account for these nutrients in nutrient management plans for Australian dairy farms. We propose incorporating excretion data in current budgeting tools using data currently collected on most Australian grazing system dairy farms.

The $$\mathbb Z$$ Z -genus of a link L in $$S^3$$ S 3 is the minimal genus of a locally flat, embedded, connected surface in $$D^4$$ D 4 whose boundary is L and with the fundamental group of the complement infinite cyclic. We characterise the $$\mathbb Z$$ Z -genus of boundary links in terms of their single variable Blanchfield forms, and we present some applications. In particular, we show that a variant of the shake genus of a knot, the $$\mathbb Z$$ Z -shake genus, equals the $$\mathbb Z$$ Z -genus of the knot.

The emergence of multidrug resistant bacteria has driven the need for novel antibiotics. Our investigations have focussed on lichens as they naturally produce a wide range of unique and very effective defence chemicals. The aim of this study was to evaluate some of the antimicrobial properties of ten common British churchyard lichens. The lichen material was sampled from 10 species, namely Caloplaca flavescens, Diploicia canescens, Cladonia fimbriata, Psilolechia lucida, Lecanora campestris subsp. Campestris, Lecanora sulphurea, Pertusaria amara f.amara, Lepraria incana, Porpidia tuberculosa and Xanthoria calcicola. Crude acetone extracts of these lichens were tested against 6 bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonela typhimurium, Listeria monocytogenes and Lactobacillus acidophilus) and two fungi (Trichophyton interdigitale and Aspergillus flavus) by using the disc diffusion susceptibility test method. Extracts of Diploicia canescens, Psilolechia lucida, Lecanora sulphurea,Pertusaria amara and Lepraria incana showed clear inhibition of the Gram positive bacteria tested (S. aureus, L. monocytogenes, L. Plantarum). Diploicia canescens, Pertusaria amara and Lepraria incana extracts also inhibited the dermatophyte fungi tested. Lepraria incana’s extract was the only sample tested here that showed activity against any of the Gram negative bacteria tested and that was inhibition of Pseudomnas aeruginosa. Overall, our results showed that crude extracts of Diploicia canescens and Pertusaria amara had the most potent antimicrobial activity of all the extracts tested against the organisms in these studies. This finding is in agreement with published findings elsewhere. The activity of the Porpidia tuberculosa margin material being different from that of the main colony material was an interesting and new finding

We illustrate the rich landscape of 4-manifold topology through the lens of counterexamples. We consider several of the most commonly studied equivalence relations on 4-manifolds and how they are related to one another. We explain implications e.g. that $h$-cobordant manifolds are stably homeomorphic, and we provide examples illustrating the failure of other potential implications. The information is conveniently organised in a flowchart and a table., Comment: 37 pages, 4 figures, 1 table; in v2, we have made several changes in response to a referee report, including writing a more detailed introduction, adding more details about the surgery exact sequence, uniformising the structure of the subsections describing counterexamples, and adding Proposition 5.6. This is the version published in EMS Surveys

We study locally flat, compact, oriented surfaces in $4$-manifolds whose exteriors have infinite cyclic fundamental group. We give algebraic topological criteria for two such surfaces, with the same genus $g$, to be related by an ambient homeomorphism, and further criteria that imply they are ambiently isotopic. Along the way, we prove that certain pairs of topological $4$-manifolds with infinite cyclic fundamental group, homeomorphic boundaries, and equivalent equivariant intersection forms, are homeomorphic., Comment: 57 pages, 5 figures. v2 fixes an error in the proof of Theorem 1.3. The issue in the proof Theorem 5.10 (now Theorem 5.11) has been corrected. v3 improves the introduction. v4 reorganises the later sections of the paper; new figures and applications have been added. v5: Added report number. v6: Fixed the definition of a trivial 1-handle stabilisation. To appear in Geometry & Topology

Purpose Preeclampsia has been inconsistently associated with altered later life risk of cancer. This study utilizes the Nurses’ Health Study 2 (NHS2) to determine if the future risk of breast and non-breast cancers in women who experience preeclampsia is modified by carrying a protective variant of rs2016347, a functional insulin-like growth factor receptor-1 (IGF1R) single nucleotide polymorphism. Methods This retrospective cohort study completed within the NHS2 evaluated participants enrolled in 1989 and followed them through 2015, with a study population of 86,751 after exclusions. Cox proportional hazards models both with and without the impact of rs2016347 genotype were used to assess the risk of invasive breast cancer, hormone receptor-positive (HR+) breast cancer, and non-breast cancers. Results Women with preeclampsia had no change in risk of all breast, HR+ breast, or non-breast cancers when not considering genotype. However, women carrying at least one T allele of rs2016347 had a lower risk of HR+ breast cancer, HR 0.67, 95% CI: 0.47–0.97, P = 0.04, with interaction term P = 0.06. For non-breast cancers as a group, women carrying a T allele had an HR 0.76, 95% CI: 0.53–1.08, P = 0.12, with interaction term P = 0.26. Conclusions This retrospective cohort study found that women with preeclampsia who carry a T allele of IGF1R rs2016347 had a reduced future risk of developing HR+ breast cancer, and a reduced but not statistically significant decreased risk of non-breast cancers suggesting a possible role for the IGF-1 axis in the development of cancer in these women.

BackgroundNovel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in phase I studies in solid tumors.MethodsWe conducted a phase I multicenter study of intravenous enadenotucirev plus nivolumab in patients with advanced/metastatic epithelial cancer not responding to standard therapy. Co-primary objectives were safety/tolerability and maximum tolerated dose and/or maximum feasible dose (MTD/MFD) of enadenotucirev plus nivolumab. Additional endpoints included response rate, cytokine responses, and anti-tumor immune responses.ResultsOverall, 51 heavily pre-treated patients were treated, 45/51 (88%) of whom had colorectal cancer (35/35 patients with information available were microsatellite instability-low/microsatellite stable) and 6/51 (12%) had squamous cell carcinoma of the head and neck. The MTD/MFD of enadenotucirev plus nivolumab was not reached, with the highest dose level tested (1×1012 vp day 1; 6×1012 vp days 3 and 5) shown to be tolerable. Overall, 31/51 (61%) patients experienced a grade 3–4 treatment-emergent adverse event (TEAE), most frequently anemia (12%), infusion-related reaction (8%), hyponatremia (6%), and large intestinal obstruction (6%). Seven (14%) patients experienced serious TEAEs related to enadenotucirev; the only serious TEAE related to enadenotucirev occurring in >1 patient was infusion-related reaction (n=2). Among the 47 patients included in efficacy analyses, median progression-free survival was 1.6 months, objective response rate was 2% (one partial response for 10 months), and 45% of patients achieved stable disease. Median overall survival was 16.0 months; 69% of patients were alive at 12 months. Persistent increases in Th1 and related cytokines (IFNγ, IL-12p70, IL-17A) were seen from ~day 15 in two patients, one of whom had a partial response. Among the 14 patients with matching pre-tumor and post-tumor biopsies, 12 had an increase in intra-tumoral CD8+T-cell infiltration and 7 had increased markers of CD8 T-cell cytolytic activity.ConclusionsIntravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing.Trial registration numberNCT02636036.

The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported.To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia.Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505).46 U.S. and Canadian hospitals.Patients aged 50 years or older undergoing hip fracture surgery.Spinal or general anesthesia.Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care.A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups.Missing outcome data and multiple outcomes assessed.Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia.Patient-Centered Outcomes Research Institute

This paper brings together socio-technical transitions theory with strategic foresight and human centred design. The aim is to bring in new methods for analysing the business model element of sustainability transitions. We propose a process for doing business model innovation work. Business models have become a key area of focus, particularly in the energy sector. Recent work shows how the development of new business models co-evolves with elements of the energy system, either driving technological innovation, changing user practices or placing pressure on the institutional or policy regime. At the same time, there is no recognised process for business model research aimed at transition management. It is time therefore to propose a more formalised and theoretically grounded approach to business model innovation work. We use this contribution to synthesise the lessons of a four-year research project centred on energy utility business models with industrial, commercial and government stakeholders. We describe the process adopted, and insights this process generated. We seek to establish this process in the literature, invite others to utilise it, adapt it and critique it.

For every $k \geq 2$ and $n \geq 2$ we construct $n$ pairwise homotopically inequivalent simply-connected, closed $4k$-dimensional manifolds, all of which are stably diffeomorphic to one another. Each of these manifolds has hyperbolic intersection form and is stably parallelisable. In dimension $4$, we exhibit an analogous phenomenon for spin$^{c}$ structures on $S^2 \times S^2$. For $m\geq 1$, we also provide similar $(4m{-}1)$-connected $8m$-dimensional examples, where the number of homotopy types in a stable diffeomorphism class is related to the order of the image of the stable $J$-homomorphism $\pi_{4m-1}(SO) \to \pi^s_{4m-1}$., Comment: Minor revision: corrected a mistake in the proof of Theorem 4.11 and improved exposition in Section 4. 27 pages

Background: Previous studies of breast samples from cosmetic surgeries, benign biopsies associated with abnormal mammograms or cancer-adjacent tissue have identified at least two different transcriptional phenotypes of “normal” human breast tissue (Troester, 2009; Haakensen, 2011), including an “Active” phenotype linked to increased risk of later breast cancer mortality (Roman-Perez, 2012; Troester, 2016). This study compares breast histology and transcriptional phenotypes from healthy parous women with no prior history of breast disease who donated breast core biopsies for research and supplied reproductive histories enabling breast cancer risk calculation. Since the Active transcriptome phenotype was recently associated with increased mammary adipocyte content, we focused on the possibility that adipocyte activation contributes to the Active transcriptome and drives breast cancer risk. Methods: RNA from paraffin-embedded tissue sections sufficient for RNAseq analysis (~100ng) was extracted from 151/200 core biopsies donated to the Komen Tissue Bank by healthy, parous white women (age range: 27-66, median = 45) with no history of breast cancer. Questionnaire data enabled breast cancer risk (Gail) score calculation; and digitized H&E images were used for histologic analyses. A previously validated classifying signature was used in unsupervised hierarchical clustering to identify samples with Active (78/151) vs. Inactive (73/151) transcriptome phenotypes for comparison with donor risk factors, breast tissue composition, and expression of candidate genes and gene signatures. Results: Mean (+/-SD) BMI and Gail score values were 29.60 (+/-7.92) and 1.27 (+/- 1.34), respectively; BMI scores were not significantly different by phenotype, but Gail scores were significantly higher for donors with an Active phenotype (1.46 vs. 1.18; p=0.007, Wilcoxon rank-sum). Active normal breast tissue samples possessed significantly more (%) adipocyte nuclei (p=3.9e-11) and greater adipocyte size (p80% of this donor cohort would not qualify for breast cancer chemoprevention, those with Active transcriptomes had significantly higher Gail scores supporting their increased future risk for breast cancer development. The Active breast transcriptome is strongly associated with increased adipocyte content, size, and overexpression of signatures and genes (including those previously linked to breast cancer progression) indicating a differentially activated adipocyte population. This dysregulated mammary adipocyte microenvironment not only appears to underlie the Active transcriptome phenotype but also precedes and potentially predicts the future histologic development of breast cancer. Citation Format: Christopher C Benz, Taekyu Kang, Christina Yau, Chris Wong, Yulia Newton, Charlie Vaske, Stephen C Benz, Gregor Krings, Roman Camarda, Jill E Henry, Josh Stuart, Mark Powell. The normal breast Active transcriptome associated with future breast cancer risk is driven by a dysregulated adipocyte microenvironment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-20.

Plastic accumulation in the marine environment is a major concern given the harmful effects and longevity of plastics at sea. Although rivers are likely to significantly contribute to the flux of plastic to marine systems, the behaviour of plastic debris in fluvial systems remains poorly understood and estimates of riverine plastic flux derived from field measurements and modelling efforts are highly uncertain. This paper presents a new probabilistic model of plastic transport in rivers which describes the main processes controlling plastic displacement and which predicts the statistical distribution of travel distances for individual items of buoyant macroplastic debris. Macroplastic transport is controlled by retention in temporary stores (or traps) created by vegetation, bank roughness elements and other obstacles. The behaviour of these traps is represented in the model via a series of Bernoulli trials conducted in a Monte Carlo simulation framework. The model was applied to a tracer experiment in a small 1.1 km river reach. Three replicates were used for calibration and three for validation. For each replicate, 90 closed air-filled polyethylene terephthalate (PET) bottles were introduced at the upstream end of the reach and the location of each bottle was recorded after 24 h. Bottles were chosen as “model” macroplastic litter items given their high usage and littering rate. Travel distances were low. The average and maximum distances travelled over 24 h were 231 m and 1.1 km, respectively. They were also variable. The coefficient of variation of travel distances was 0.94. Spatial patterns were controlled by the location and characteristics of discrete traps. The model was able to describe the observed travel distance distributions reasonably well, suggesting that modelling plastic behaviour in longer reaches and even whole catchments using a stochastic travel distance approach is feasible. The approach has the potential to improve estimates of river plastic flux, although significant knowledge gaps remain (e.g., the rate and location of plastic supply to river systems, the transport behaviours of different types of plastic debris and trap effectiveness in different types of river system, season, and discharge).

‘Replicable Rooms and Boundary Shrinkable Skyscrapers’ points out precisely which properties of skyscrapers are required in the remainder of the proof of the disc embedding theorem. To achieve this, it introduces an abstraction of towers, known as buildings. The required properties for a generalized skyscraper include boundary shrinkability and replicability. The former allows the conclusion that the vertical boundary of a generalized skyscraper is a solid torus. Replicability ensures that any generalized skyscraper contains uncountably many other skyscrapers as subsets. Both of the above properties will be essential in the construction of the design in a subsequent chapter.

The disc embedding theorem provides a detailed proof of the eponymous theorem in 4-manifold topology. The theorem, due to Michael Freedman, underpins virtually all of our understanding of 4-manifolds in the topological category. Most famously, this includes the 4-dimensional topological Poincaré conjecture. Combined with the concurrent work of Simon Donaldson, the theorem reveals a remarkable disparity between the topological and smooth categories for 4-manifolds. A thorough exposition of Freedman’s proof of the disc embedding theorem is given, with many new details. A self-contained account of decomposition space theory, a beautiful but outmoded branch of topology that produces non-differentiable homeomorphisms between manifolds, is provided. Techniques from decomposition space theory are used to show that an object produced by an infinite, iterative process, which we call a skyscraper, is homeomorphic to a thickened disc, relative to its boundary. A stand-alone interlude explains the disc embedding theorem’s key role in smoothing theory, the existence of exotic smooth structures on Euclidean space, and all known homeomorphism classifications of 4-manifolds via surgery theory and the s-cobordism theorem. The book is written to be accessible to graduate students working on 4-manifolds, as well as researchers in related areas. It contains over a hundred professionally rendered figures.

The s-cobordism theorem, the sphere embedding theorem, and the Poincaré conjecture comprise three key consequences of the disc embedding theorem. The chapter begins by explaining in detail how to use the disc embedding theorem to prove the 5-dimensional s-cobordism theorem and the sphere embedding theorem. The sphere embedding theorem is the output from the disc embedding theorem that one wants in many situations. A version of the Poincaré conjecture is proven, specifically that every smooth homotopy 4-sphere is homeomorphic to the 4-sphere. All the results proved in this chapter are category losing; that is, they require smooth input but only produce homeomorphisms.

‘A Decomposition That Does Not Shrink’ gives a nontrivial example of a decomposition of the 3-sphere such that the corresponding quotient space is not homeomorphic to the 3-sphere. The decomposition in question is called the Bing-2 decomposition. Similar to the Bing decomposition from the previous chapter, it consists of the connected components of the intersection of an infinite sequence of nested solid tori. However, unlike the Bing decomposition, the Bing-2 decomposition does not shrink. This indicates the subtlety of the question of which decompositions shrink. The question of when certain decompositions of the 3-sphere shrink is central to the proof of the disc embedding theorem.

‘Intersection Numbers and the Statement of the Disc Embedding Theorem’ provides detailed definitions of some of the notions involved in the statement of the disc embedding theorem, focusing specifically on intersection numbers. The chapter begins with a detailed analysis of immersions, regular homotopies, finger moves, and Whitney moves. Then it defines intersection and self-intersection numbers for families of discs and spheres, taking values in the group ring of the fundamental group of the ambient space, with the correct relations. Then it enumerates certain properties of intersection numbers, in particular relating them to the existence of Whitney discs. This work enables the disc embedding theorem to be stated carefully.