Factorised spatial representation learning: application in semi-supervised myocardial segmentation

The success and generalisation of deep learning algorithms heavily depend on learning good feature representations. In medical imaging this entails representing anatomical information, as well as properties related to the specific imaging setting. Anatomical information is required to perform further analysis, whereas imaging information is key to disentangle scanner variability and potential artefacts. The ability to factorise these would allow for training algorithms only on the relevant information according to the task. To date, such factorisation has not been attempted. In this paper, we propose a methodology of latent space factorisation relying on the cycle-consistency principle. As an example application, we consider cardiac MR segmentation, where we separate information related to the myocardium from other features related to imaging and surrounding substructures. We demonstrate the proposed method's utility in a semi-supervised setting: we use very few labelled images together with many unlabelled images to train a myocardium segmentation neural network. Specifically, we achieve comparable performance to fully supervised networks using a fraction of labelled images in experiments on ACDC and a dataset from Edinburgh Imaging Facility QMRI. Code will be made available at https://github.com/agis85/spatial_factorisation.Comment: Accepted in MICCAI 201

Diagnosis of insulin autoimmune syndrome using polyethylene glycol precipitation and gel filtration chromatography with ex vivo insulin exchange.

CONTEXT: Insulin-binding antibodies may produce severe dysglycaemia in insulin-naïve patients ('insulin autoimmune syndrome' (IAS) or Hirata disease), while rendering routine insulin assays unreliable. OBJECTIVE: To assess the performance of clinically used insulin assays and an optimal analytical approach in the context of IAS. DESIGN: Observational biochemical study of selected patients with hyperinsulinaemic hypoglycaemia. PATIENTS: Three patients without diabetes with recurrent spontaneous hyperinsulinaemic hypoglycaemia and 'positive' insulin antibodies. MEASUREMENTS: A panel of clinically used insulin assays (Siemens ADVIA® Centaur, Siemens Immulite® 2000, DiaSorin LIAISON® XL, PE AutoDELFIA® and the Beckman Coulter Access® 2) were used before and after plasma dilution or polyethylene glycol (PEG) precipitation. Anti-insulin IgG antibodies were measured by Isletest™ -IAA ELISA. Gel filtration chromatography (GFC) was undertaken with and without preincubation of plasma with exogenous insulin. RESULTS: Dilution of IAS plasma with assay-specific buffer increased insulin recovery, supporting negative immunoassay interference by antibodies. PEG precipitation of IAS plasma decreased insulin recovery using all assays except the Immulite® 2000. GFC discriminated high molecular weight and monomeric insulin, while ex vivo addition of exogenous insulin to plasma increased insulin bound to antibody, thereby improving the sensitivity of detection of insulin immunocomplexes. CONCLUSIONS: Immunoprecipitation with PEG must be used with caution in screening for insulin-antibody complexes as results are assay dependent. GFC with addition of exogenous insulin can identify significant insulin immunocomplexes with enhanced sensitivity, with attendant greater clinical utility and avoidance of radiolabelled reagents.Diabetes Research & Wellness Foundation Sutherland-Earl Clinical Fellowship (Grant ID: RG68554), Wellcome Trust (Grant ID: WT098498), Medical Research Council (Grant ID: MRC_MC_UU_12012/5), National Institute for Health Research (NIHR), Cambridge Biomedical Research CentreThis is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/cen.1317

Random tree growth by vertex splitting

We study a model of growing planar tree graphs where in each time step we separate the tree into two components by splitting a vertex and then connect the two pieces by inserting a new link between the daughter vertices. This model generalises the preferential attachment model and Ford's $\alpha$-model for phylogenetic trees. We develop a mean field theory for the vertex degree distribution, prove that the mean field theory is exact in some special cases and check that it agrees with numerical simulations in general. We calculate various correlation functions and show that the intrinsic Hausdorff dimension can vary from one to infinity, depending on the parameters of the model.Comment: 47 page

Uremic cardiomyopathy is characterised by loss of the cardioprotective effects of insulin

Chronic kidney disease is associated with a unique cardiomyopathy, characterised by a combination of structural and cellular remodelling, and an enhanced susceptibility to ischaemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway, due to insulin resistance. Aims: The susceptibility of the uraemic heart to ischaemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Methods and Results: Uraemia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischaemia was investigated in vitro in control and uraemic hearts ±insulin ±rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by 13C NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immuno-precipitation. Insulin improved post-ischaemic rate pressure product in control but not uraemic hearts, (recovered rate pressure product (%), control 59.6±10.7 vs 88.9±8.5, p<0.05; uraemic 19.3±4.6 vs 28.5±10.4, p=ns). Rosiglitazone resensitised uraemic hearts to insulin-mediated cardio-protection (recovered rate pressure product (%) 12.7±7.0 vs. 61.8±15.9, p<0.05). Myocardial carbohydrate metabolism remained responsive to insulin in uraemic hearts. Uraemia was associated with increased phosphorylation of Akt (1.00±0.08 vs. 1.31±0.11, p<0.05) in normoxia, but no change in post-ischaemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased post-ischaemia in uraemic hearts (p<0.05). Conclusion: Uraemia is associated with enhanced susceptibility to ischaemia-reperfusion injury and a loss of insulin-mediated cardio-protection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uraemic hearts post ischaemia-reperfusion and impaired activation of reperfusion injury salvage kinase pathway may underlie these findings

Primary Paediatric Bronchial Airway Epithelial Cell in Vitro Responses to Environmental Exposures

Acknowledgments: The authors are grateful to the children who participated in this study and their parents. The authors would like to thank the following colleagues in the department of Ear Nose and Throat Surgery at NHS Grampian for allowing us to recruit their patients: Nicola Kryle, Derek Veitch, Kim Ah-See, Bhaskar Ram, Sangeeta Maini and Clive Brewis. We are also grateful to Tenovus Scotland whose funds enabled analysis of the samples (Grant reference G13_17) but did not include open access publishing fees.Peer reviewedPublisher PD

Truncation of POC1A associated with short stature and extreme insulin resistance

We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health

Chronic Household Air Pollution Exposure Is Associated with Impaired Alveolar Macrophage Function in Malawian Non-Smokers

Background Household air pollution in low income countries is an important cause of mortality from respiratory infection. We hypothesised that chronic smoke exposure is detrimental to alveolar macrophage function, causing failure of innate immunity. We report the relationship between macrophage function and prior smoke exposure in healthy Malawians. Methods Healthy subjects exposed daily to cooking smoke at home volunteered for bronchoalveolar lavage. Alveolar macrophage particulate content was measured as a known correlate of smoke exposure. Phagocytosis and intraphagosomal function (oxidative burst and proteolysis) were measured by a flow cytometric assay. Cytokine responses in macrophages were compared following re-exposure in vitro to wood smoke, before and after glutathione depletion. Results Volunteers had a range of alveolar macrophage particulate loading. The macrophage capacity for phagosomal oxidative burst was negatively associated with alveolar macrophage particulate content (n = 29, r2 = 0.16, p = 0.033), but phagocytosis per se and proteolytic function were unaffected. High particulate content was associated with lower baseline CXCL8 release (ratio 0.51, CI 0.29–0.89) and lower final concentrations on re-exposure to smoke in vitro (ratio 0.58, CI 0.34–0.97). Glutathione depletion augmented CXCL8 responses by 1.49x (CI 1.02–2.17) compared with wood smoke alone. This response was specific to smoke as macrophages response to LPS were not modulated by glutathione. Conclusion Chronic smoke exposure is associated with reduced human macrophage oxidative burst, and dampened inflammatory cytokine responses. These are critical processes in lung defence against infection and likely to underpin the relationship between air pollution and pneumonia

Truncation of POC1A associated with short stature and extreme insulin resistance.

We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health.This work was supported by the Wellcome Trust [grant numbers WT098498, WT098051,WT095515, and WT091310]; the Medical Research Council [MRC_MC_UU_12012/5]; the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Bioscientifica via http://dx.doi.org/10.1530/JME-15-009