Dual contribution of the gut microbiome to immunotherapy efficacy and toxicity: supportive care implications and recommendations.

The efficacy of immune checkpoint inhibitors (immunotherapy) is increasingly recognized to be linked to the composition the gut microbiome. Given the high rates of resistance, interventions targeting the gut microbiome are now being investigated for its ability to improve the efficacy of immunotherapy. In light of recently published data demonstrating a strong correlation between the efficacy and toxicity of immunotherapy, there is a risk that efforts to enhance immunotherapy efficacy may be undermined by increases in immune-related adverse events (IrAEs) This is particularly important for microbial interventions aimed at increasing immunotherapy efficacy, with many microbes implicated in tumour response also linked to IrAEs, especially colitis. IrAEs have a profound impact on patient quality of life, causing physical, psychosocial, and financial distress. Here, we outline strategies at the discovery, translational, and clinical research phases to ensure the impact of augmenting immunotherapy efficacy is approached in a manner that considers adverse implications. Adopting these strategies will ensure that our ongoing efforts to overcome immunotherapy resistance are not impacted by unacceptable toxicity

Learning Convex Partitions and Computing Game-theoretic Equilibria from Best Response Queries

Suppose that an $m$-simplex is partitioned into $n$ convex regions having disjoint interiors and distinct labels, and we may learn the label of any point by querying it. The learning objective is to know, for any point in the simplex, a label that occurs within some distance $\epsilon$ from that point. We present two algorithms for this task: Constant-Dimension Generalised Binary Search (CD-GBS), which for constant $m$ uses $poly(n, \log \left( \frac{1}{\epsilon} \right))$ queries, and Constant-Region Generalised Binary Search (CR-GBS), which uses CD-GBS as a subroutine and for constant $n$ uses $poly(m, \log \left( \frac{1}{\epsilon} \right))$ queries. We show via Kakutani's fixed-point theorem that these algorithms provide bounds on the best-response query complexity of computing approximate well-supported equilibria of bimatrix games in which one of the players has a constant number of pure strategies. We also partially extend our results to games with multiple players, establishing further query complexity bounds for computing approximate well-supported equilibria in this setting.Comment: 38 pages, 7 figures, second version strengthens lower bound in Theorem 6, adds footnotes with additional comments and fixes typo

Building the plane while it's flying: implementation lessons from integrating a co-located exercise clinic into oncology care.

BACKGROUND: Despite its therapeutic role during cancer treatment, exercise is not routinely integrated into care and implementation efforts are largely absent from the literature. The aim of this study was to evaluate a strategy to integrate the workflow of a co-located exercise clinic into routine care within a private oncology setting in two clinics in the metropolitan region of Western Australia. METHODS: This prospective evaluation utilised a mixed methods approach to summarise lessons learned during the implementation of an integrated exercise workflow and supporting implementation plan. Data collection was informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Reports detailing utilisation of the exercise service and its referral pathways, as well as patient surveys and meeting minutes documenting the implementation process informed the evaluation. RESULTS: The co-located exercise service achieved integration into routine care within the clinical oncology setting. Patient utilisation was near capacity (reach) and 100% of clinicians referred to the service during the 13-month evaluation period (adoption). Moreover, ongoing adaptations were made to improve the program (implementation) and workflows were integrated into standard operating practices at the clinic (maintenance). The workflow performed as intended for ~70% of exercise participants (effectiveness); however, gaps were identified in utilisation of the workflow by both patients and clinicians. CONCLUSION: Integration of exercise into standard oncology care is possible, but it requires the ongoing commitment of multiple stakeholders across an organisation. The integrated workflow and supporting implementation plan greatly improved utilisation of the co-located exercise service, demonstrating the importance of targeted implementation planning. However, challenges regarding workflow fidelity within and across sites limited its success highlighting the complexities inherent in integrating exercise into clinical oncology care in a real-world setting

Can exercise delay transition to active therapy in men with low-grade prostate cancer? A multicentre randomised controlled trial

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Introduction Active surveillance is a strategy for managing low-risk, localised prostate cancer, where men are observed with serial prostate-specific antigen assessments to identify signs of disease progression. Currently, there are no strategies to support active surveillance compliance nor are there interventions that can prevent or slow disease progression, ultimately delaying transition to active treatment before it is clinically required. Recently, we proposed that exercise may have a therapeutic potential in delaying the need for active treatment in men on active surveillance. Methods and analysis A single-blinded, two arm, multicentre randomised controlled trial will be undertaken with 168 patients randomly allocated in a ratio of 1:1 to exercise or usual care. Exercise will consist of supervised resistance and aerobic exercise performed three times per week for the first 6 months in an exercise clinical setting, and during months 7-12, a progressive stepped down approach will be used with men transitioning to once a week supervised training. Thereafter, for months 13 to 36, the men will self-manage their exercise programme. The primary endpoint will be the time until the patients begin active therapy. Secondary endpoints include disease progression (prostate specific antigen), body composition and muscle density, quality of life, distress and anxiety and an economic analysis will be performed. Measurements will be undertaken at 6 and 12 months (postintervention) and at 24 and 36 months follow-up. The primary outcome (time to initiation of curative therapy) will be analysed using Cox proportional hazards regression. Outcomes measured repeatedly will be analysed using mixed effects models to examine between-group differences. Data will be analysed using an intention-to-treat approach. Ethics and dissemination Outcomes from the study will be published in peer-reviewed academic journals and presented in scientific, consumer and clinical meetings. Trial registration number ACTRN12618000225213

Please Don't Move—Evaluating Motion Artifact From Peripheral Quantitative Computed Tomography Scans Using Textural Features

Most imaging methods, including peripheral quantitative computed tomography (pQCT), are susceptible to motion artifacts particularly in fidgety pediatric populations. Methods currently used to address motion artifact include manual screening (visual inspection) and objective assessments of the scans. However, previously reported objective methods either cannot be applied on the reconstructed image or have not been tested for distal bone sites. Therefore, the purpose of the present study was to develop and validate motion artifact classifiers to quantify motion artifact in pQCT scans. Whether textural features could provide adequate motion artifact classification performance in 2 adolescent datasets with pQCT scans from tibial and radial diaphyses and epiphyses was tested. The first dataset was split into training (66% of sample) and validation (33% of sample) datasets. Visual classification was used as the ground truth. Moderate to substantial classification performance (J48 classifier, kappa coefficients from 0.57 to 0.80) was observed in the validation dataset with the novel texture-based classifier. In applying the same classifier to the second cross-sectional dataset, a slight-to-fair (κ = 0.01–0.39) classification performance was observed. Overall, this novel textural analysis-based classifier provided a moderate-to-substantial classification of motion artifact when the classifier was specifically trained for the measurement device and population. Classification based on textural features may be used to prescreen obviously acceptable and unacceptable scans, with a subsequent human-operated visual classification of any remaining scans

Interdependent Utilities: How Social Ranking Affects Choice Behavior

Organization in hierarchical dominance structures is prevalent in animal societies, so a strong preference for higher positions in social ranking is likely to be an important motivation of human social and economic behavior. This preference is also likely to influence the way in which we evaluate our outcome and the outcome of others, and finally the way we choose. In our experiment participants choose among lotteries with different levels of risk, and can observe the choice that others have made. Results show that the relative weight of gains and losses is the opposite in the private and social domain. For private outcomes, experience and anticipation of losses loom larger than gains, whereas in the social domain, gains loom larger than losses, as indexed by subjective emotional evaluations and physiological responses. We propose a theoretical model (interdependent utilities), predicting the implication of this effect for choice behavior. The relatively larger weight assigned to social gains strongly affects choices, inducing complementary behavior: faced with a weaker competitor, participants adopt a more risky and dominant behavior

Bridging reproductive and microbial ecology: a case study in arbuscular mycorrhizal fungi

Offspring size is a key trait for understanding the reproductive ecology of species, yet studies addressing the ecological meaning of offspring size have so far been limited to macro-organisms. We consider this a missed opportunity in microbial ecology and provide what we believe is the first formal study of offspring-size variation in microbes using reproductive models developed for macro-organisms. We mapped the entire distribution of fungal spore size in the arbuscular mycorrhizal (AM) fungi (subphylum Glomeromycotina) and tested allometric expectations of this trait to offspring (spore) output and body size. Our results reveal a potential paradox in the reproductive ecology of AM fungi: while large spore-size variation is maintained through evolutionary time (independent of body size), increases in spore size trade off with spore output. That is, parental mycelia of large-spored species produce fewer spores and thus may have a fitness disadvantage compared to small-spored species. The persistence of the large-spore strategy, despite this apparent fitness disadvantage, suggests the existence of advantages to large-spored species that could manifest later in fungal life history. Thus, we consider that solving this paradox opens the door to fruitful future research establishing the relationship between offspring size and other AM life history traits

O-Glycosylation of snails

The glycosylation abilities of snails deserve attention, because snail species serve as intermediate hosts in the developmental cycles of some human and cattle parasites. In analogy to many other host-pathogen relations, the glycosylation of snail proteins may likewise contribute to these host-parasite interactions. Here we present an overview on the O-glycan structures of 8 different snails (land and water snails, with or without shell): Arion lusitanicus, Achatina fulica, Biomphalaria glabrata, Cepaea hortensis, Clea helena, Helix pomatia, Limax maximus and Planorbarius corneus. The O-glycans were released from the purified snail proteins by β-elimination. Further analysis was carried out by liquid chromatography coupled to electrospray ionization mass spectrometry and – for the main structures – by gas chromatography/mass spectrometry. Snail O-glycans are built from the four monosaccharide constituents: N-acetylgalactosamine, galactose, mannose and fucose. An additional modification is a methylation of the hexoses. The common trisaccharide core structure was determined in Arion lusitanicus to be N-acetylgalactosamine linked to the protein elongated by two 4-O-methylated galactose residues. Further elongations by methylated and unmethylated galactose and mannose residues and/or fucose are present. The typical snail O-glycan structures are different to those so far described. Similar to snail N-glycan structures they display methylated hexose residues

Isolation of chick retina cones and study of their diversity based on oil droplet colour and nucleus position

The chick retina has four morphological cone types that differ not only in shape, but also in the visual pigment in the outer segment, in the colour of the oil droplet in the inner segment and in synaptic connectivity. Neither the type of droplet nor the visual pigment has been definitively established for the four cone types. The main aim of the present work has been the isolation of entire live photoreceptors in order to study the oil droplet colour in each cone type and to quantify each type. We have improved an earlier retinal cell isolation method and obtained large numbers of entire cones. Principal cones (27% of the cones) possess a yellow or colourless droplet. Accessory cones (27% of the cones) all contain a small pale green droplet. Straight cones (44% of the cones) have a red, orange, yellow, or colourless droplet. Oblique cones (1.66% of the cones) all have a colourless droplet. We have found that straight cones with a red, orange, or yellow droplet differ in terms of the position of the nucleus and their percentage and conclude that they are distributed in three rows in the outer nuclear layer (ONL) of the central retina. Our study of 4,6-diamidino-2-phenylindole-stained retinal sections has revealed three rows of nuclei instead of the two currently thought to form the ONL. Together, our results show a larger cone diversity than previously known, suggest a larger functional diversity and provide an efficient method for isolating entire chick photoreceptors