Minkowski functionals: An MRI texture analysis tool for determination of the aggressiveness of breast cancer

Purpose: This work aims to see whether Minkowski Functionals can be used to distinguish between cancer types before chemotherapy treatment has begun, and whether a response to treatment can be predicted by an initial scan alone. Methods: Fat-nulled T1w 3T DCE-MRI scans were taken of 100 cases of biopsy confirmed breast cancer and a series of binary images created on lesion containing slices. Minkowski Functionals were calculated for each binary image and the change in these values as the binary threshold was raised was described using 6th order polynomials. These polynomials were used to compare between patient sub-groups, for triple negative breast cancer (TNBC) status, chemotherapy response, biopsy grade, nodal status, and lymphovascular invasion status. Results: When using Minkowski Functionals statistically significant (p<0.05) differences were found between TNBC status, biopsy grade, and lymphovascular invasion status sub-groups for all methodologies. The analysis performance did not appear to be affected by the number of threshold steps used. Most notably, very strong differences (p≤0.01) were found between TNBC and other intrinsic subtype patients. When analysed with a binary logistic regression model, an AUC value of 0.917 (0.846 – 0.987, 95% CI) for TNBC classification was found. Conclusion: The method of texture analysis presented here provides a novel way to characterise tumours, and demonstrates clear differences between cancer groups which are detectable before treatment begins, and can help with treatment planning as a valuable prognosis tool

Frequency of infant stroking reported by mothers moderates the effect of prenatal depression on infant behavioural and physiological outcomes

Animal studies find that prenatal stress is associated with increased physiological and emotional reactivity later in life, mediated via fetal programming of the HPA axis through decreased glucocorticoid receptor (GR) gene expression. Post-natal behaviours, notably licking and grooming in rats, cause decreased behavioural indices of fear and reduced HPA axis reactivity mediated via increased GR gene expression. Post-natal maternal behaviours may therefore be expected to modify prenatal effects, but this has not previously been examined in humans. We examined whether, according to self-report, maternal stroking over the first weeks of life modified associations between prenatal depression and physiological and behavioral outcomes in infancy, hence mimicking effects of rodent licking and grooming. From a general population sample of 1233 first time mothers recruited at 20 weeks gestation we drew a stratified random sample of 316 for assessment at 32 weeks based on reported inter-partner psychological abuse, a risk to child development. Of these 271 provided data at 5, 9 and 29 weeks post delivery. Mothers reported how often they stroked their babies at 5 and 9 weeks. At 29 weeks vagal withdrawal to a stressor, a measure of physiological adaptability, and maternal reported negative emotionality were assessed. There was a significant interaction between prenatal depression and maternal stroking in the prediction of vagal reactivity to a stressor (p = .01), and maternal reports of infant anger proneness (p = .007) and fear (p = .043). Increasing maternal depression was associated with decreasing physiological adaptability, and with increasing negative emotionality, only in the presence of low maternal stroking. These initial findings in humans indicate that maternal stroking in infancy, as reported by mothers, has effects strongly resembling the effects of observed maternal behaviours in animals, pointing to future studies of the epigenetic, physiological and behavioral effects of maternal stroking

Cost-effectiveness of home versus hospital management of children at onset of Type 1 Diabetes: The DECIDE randomised controlled trial

Objective The aim of this economic evaluation was to assess whether home management could represent a cost-effective strategy in the patient pathway of Type 1 diabetes (T1D). This is based on the DECIDE trial (ISRCTN78114042), which compared home versus hospital management from diagnosis in childhood diabetes and found no statistically significant difference in glycaemic control at 24 months. Design Cost-effectiveness analysis alongside a randomised controlled trial. Setting Eight paediatric diabetes centres in England, Wales and Northern Ireland. Participants 203 clinically well children aged under 17 years, with newly diagnosed type 1 diabetes and their carers. Outcome measures The base case analysis adopted an NHS perspective. A scenario analysis assessed costs from a broader societal perspective. The incremental cost-effectiveness ratio (ICER) expressed as cost per mmol/mol reduction in HbA1c, was based on the mean difference in costs between the home and hospital groups, divided by mean differences in effectiveness (HbA1c). Uncertainty was considered in terms of the probability of cost-effectiveness. Results At 24 months post-intervention, the base case analysis showed a difference in costs between home and hospital, in favour of home management (mean difference -£2,217; 95% CI -£2,825 to -£1,609; p<0.001). Home care dominated, with an ICER of £7,434 (saved) per mmol/mol reduction of HbA1c. The results of the scenario analysis also favoured home management. The greatest driver of cost differences was hospitalisation during the initiation period. Conclusions Home management from diagnosis of children with T1D who are medically stable represents a less costly approach for the NHS in the UK, without impacting clinical effectiveness

Infection of human mucosal tissue by Pseudomonas aeruginosa requires sequential and mutually dependent virulence factors and a novel pilus-associated adhesin

Tissue damage predisposes humans to life-threatening disseminating infection by the opportunistic pathogen Pseudomonas aeruginosa. Bacterial adherence to host tissue is a critical first step in this infection process. It is well established that P. aeruginosa attachment to host cells involves type IV pili (TFP), which are retractile surface fibers. The molecular details of attachment and the identity of the bacterial adhesin and host receptor remain controversial. Using a mucosal epithelium model system derived from primary human tissue, we show that the pilus-associated protein PilY1 is required for bacterial adherence. We establish that P. aeruginosa preferentially binds to exposed basolateral host cell surfaces, providing a mechanistic explanation for opportunistic infection of damaged tissue. Further, we demonstrate that invasion and fulminant infection of intact host tissue requires the coordinated and mutually dependent action of multiple bacterial factors, including pilus fiber retraction and the host cell intoxication system, termed type III secretion. Our findings offer new and important insights into the complex interactions between a pathogen and its human host and provide compelling evidence that PilY1 serves as the principal P. aeruginosa adhesin for human tissue and that it specifically recognizes a host receptor localized or enriched on basolateral epithelial cell surfaces

Light hadron spectroscopy with O(a) improved dynamical fermions

We present the first results for the static quark potential and the light hadron spectrum using dynamical fermions at $\beta=5.2$ using an O(a) improved Wilson fermion action together with the standard Wilson plaquette action for the gauge part. Sea quark masses were chosen such that the pseudoscalar-vector mass ratio, m_PS/m_V$, varies from 0.86 to 0.67. Finite-size effects are studied by using three different volumes, 8^3\cdot 24, 12^3\cdot 24 and 16^3\cdot 24. Comparing our results to previous ones obtained using the quenched approximation, we find evidence for sea quark effects in quantities like the static quark potential and the vector-pseudoscalar hyperfine splitting.Comment: 38 pages, 14 Postscript figure, LaTe

The costs of scaling up HIV prevention for high risk groups: lessons learned from the Avahan Programme in India.

OBJECTIVE: The study objective is to measure, analyse costs of scaling up HIV prevention for high-risk groups in India, in order to assist the design of future HIV prevention programmes in South Asia and beyond. DESIGN: Prospective costing study. METHODS: This study is one of the most comprehensive studies of the costs of HIV prevention for high-risk groups to date in both its scope and size. HIV prevention included outreach, sexually transmitted infections (STI) services, condom provision, expertise enhancement, community mobilisation and enabling environment activities. Economic costs were collected from 138 non-government organisations (NGOs) in 64 districts, four state level lead implementing partners (SLPs), and the national programme level (Bill and Melinda Gates Foundation (BMGF)) office over four years using a top down costing approach, presented in US$2011. RESULTS: Mean total unit costs (2004-08) per person reached at least once a year and per monthly contact were US$ 235(56-1864) and US$82(12-969) respectively. 35$ 477 per person reached in 2004 to US$145 per person reached in 2008). At the service level also unit costs decreased slightly over time from US$ 68 to US$ 64 per person reached. CONCLUSIONS: Scaling up HIV prevention for high risk groups requires significant investment in expertise enhancement and programme administration. However, unit costs decreased with programme expansion in spite of an increase in the scope of activities

KRAS mutation and Consensus Molecular Subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer

Abstract Purpose: KRAS mutation is a common canonical mutation in colorectal cancer, found at differing frequencies in all consensus molecular subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum. Experimental Design: Expression analysis of immune genes/signatures was performed using The Cancer Genome Atlas (TCGA) RNA-seq and the KFSYSCC microarray datasets. Multivariate analysis included KRAS status, CMS, tumor location, MSI status, and neoantigen load. Protein expression of STAT1, HLA-class II, and CXCL10 was analyzed by digital IHC. Results: The Th1-centric co-ordinate immune response cluster (CIRC) was significantly, albeit modestly, reduced in KRAS-mutant colorectal cancer in both datasets. Cytotoxic T cells, neutrophils, and the IFNγ pathway were suppressed in KRAS-mutant samples. The expressions of STAT1 and CXCL10 were reduced at the mRNA and protein levels. In multivariate analysis, KRAS mutation, CMS2, and CMS3 were independently predictive of reduced CIRC expression. Immune response was heterogeneous across KRAS-mutant colorectal cancer: KRAS-mutant CMS2 samples have the lowest CIRC expression, reduced expression of the IFNγ pathway, STAT1 and CXCL10, and reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to KRAS wild-type CMS2 samples in the TCGA. These trends held in the KFSYSCC dataset. Conclusions: KRAS mutation is associated with suppressed Th1/cytotoxic immunity in colorectal cancer, the extent of the effect being modulated by CMS subtype. These results add a novel immunobiological dimension to the biological heterogeneity of colorectal cancer. Clin Cancer Res; 24(1); 224–33. ©2017 AACR.</jats:p