An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.

Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.

Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.

Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

An Investigation into the Role of Polymeric Carriers on Crystal Growth within Amorphous Solid Dispersion Systems

Using phase diagrams derived from Flory–Huggins theory, we defined the thermodynamic state of amorphous felodipine within three different polymeric carriers. Variation in the solubility and miscibility of felodipine within different polymeric materials (using F–H theory) has been identified and used to select the most suitable polymeric carriers for the production of amorphous drug–polymer solid dispersions. With this information, amorphous felodipine solid dispersions were manufactured using three different polymeric materials (HPMCAS-HF, Soluplus, and PVPK15) at predefined drug loadings, and the crystal growth rates of felodipine from these solid dispersions were investigated. Crystallization of amorphous felodipine was studied using Raman spectral imaging and polarized light microscopy. Using this data, we examined the correlation among several characteristics of solid dispersions to the crystal growth rate of felodipine. An exponential relationship was found to exist between drug loading and crystal growth rate. Moreover, crystal growth within all selected amorphous drug–polymer solid dispersion systems were viscosity dependent (η–ξ). The exponent, ξ, was estimated to be 1.36 at a temperature of 80 °C. Values of ξ exceeding 1 may indicate strong viscosity dependent crystal growth in the amorphous drug–polymer solid dispersion systems. We argue that the elevated exponent value (ξ > 1) is a result of drug–polymer mixing which leads to a less fragile amorphous drug–polymer solid dispersion system. All systems investigated displayed an upper critical solution temperature, and the solid–liquid boundary was always higher than the spinodal decomposition curve. Furthermore, for PVP–FD amorphous dispersions at drug loadings exceeding 0.6 volume ratio, the mechanism of phase separation within the metastable zone was found to be driven by nucleation and growth rather than liquid–liquid separation.

The significance of bruising in the pre-mobile infant

The majority of children in our society are loved andcherished. The occasional cases of intentional injury to a childresulting in death or significant harm evoke powerful anduncomfortable feelings (Devaney et al, 2013), and the publicoutcry may result in health and social workers facing criticism.Identifying whether an infant is at risk of abuse is a challengefor practitioners, and can be a source of stress and anxiety(Brandon et al, 2011). Bruising is a strong indicator of childabuse involving intentional injury (Kemp et al, 2014). Theincidence of bruising correlates to developmental stage, withnon-mobile infants least likely to incur bruising. Therefore, itspresence in pre-mobile infants requires immediate assessment.A search of the literature around bruising in pre-mobile infantsrevealed themes of missed opportunities for early intervention,the role of the father in the family and the significance of childdevelopment. Sharing of knowledge and expertise within themultidisciplinary team is key to safeguarding infants.

Sparse multi-carrier index keying OFDM with index separation over correlated sub-carriers

In this paper, we propose a sparse multi-carrier index keying (MCIK) method for orthogonal frequency division multiplexing (OFDM) system, which uses the indices of sparse sub-carriers to transmit the data, and improve the performance
of signal detection in highly correlated sub-carriers. Although a receiver is able to exploit a power gain with precoding in OFDM, the sensitivity of the signal detection is usually high as the orthogonality is not retained in highly dispersive
environments. To overcome this, we focus on developing the trade-off between the sparsity of the MCIK, correlation, and performances, analyzing the average probability of the error propagation imposed by incorrect index detection over highly correlated sub-carriers. In asymptotic cases, we are able to see how sparsity of MCIK should be designed in order to perform superior to the classical OFDM system. Based on this feature, sparse MCIK based OFDM is a better choice for low detection errors in highly correlated sub-carriers.

Northern Ireland Infant Death Thematic Review 2015

Co-Sleeping and bed sharing are considered the social norm for approximately 90% of the world's population, with two-thirds of the world's cultures habitually practicing mother-infant co-sleeping on the same bed. Although international studies show that the practice of co-sleeping is common, it is controversial in the public health community, as many consider it a significant risk for Sudden Infant Death Syndrome (SIDS), accounting for 50% of SIDS deaths in the UK. The report offers an international review of the evidence and provides important debates and critical knowledge for both health professionals, parents and all those organisations working to support the safety of infants in their first perinatal year.

Utility of US Norms for the Bayley Scales of Infant Development (III) in UK and Irish Children

The aim of this paper is to explore the utility of the United States norms for United Kingdom and Republic of Ireland populations. The Bayley Scales of Infant Development (BSID III) is a globally used developmental assessment for typically developing and clinical samples of children aged 1 to 42 months. A UK norming exercise (REF) confirmed the suitability of US norms for UK based research and practice. However, debate has continued concerning the utility of the US norms in other countries. This paper further explores the utility of the US norms for the UK and ROI populations using BSID III developmental outcome data from two samples of over one thousand typically developing children.

Progress and the Lack of Progress in Addressing Infant Health and Infant Health Inequalities in Ireland during the 20th Century

There is a growing literature which documents the importance of early life environment for outcomes across the life cycle. Research, including studies based on Irish data, demonstrates that those who experience better childhood conditions go on to be wealthier and healthier adults. Therefore, inequalities at birth and in childhood shape inequality in wellbeing in later life, and the historical evolution of the mortality and morbidity of children born in Ireland is important for understanding the current status of the Irish population. In this paper, I describe these patterns by reviewing the existing literature on infant health in Ireland over the course of the 20th century. Up to the 1950s, infant mortality in Ireland (both North and South) was substantially higher than in other developed countries, with a large penalty for those born in urban areas. The subsequent reduction in this penalty, and the sustained decline in infant death rates, occurred later than would be expected from the experience in other contexts. Using records from the Rotunda Lying-in Hospital in Dublin, I discuss sources of disparities in stillbirth in the early 1900s. Despite impressive improvements in death rates since that time, a comparison with those born at the end of the century reveals that Irish children continue to be born unequal. Evidence from studies which track people across the life course, for example research on the returns to birthweight, suggests that the economic cost of this early life inequality is substantial.