Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10,337 cases and 11,174 controls (OR=1.10; p-value=3.79×10(-5)). Thus, it appears that rare and common variants in a single gene - FBN2 - can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

L'indicateur EU2020 de suivi de la pauvreté et de l'exclusion: une analyse critique

The reduction of poverty and social exclusion is one of the targets of the European Union's 2020 strategy. The appropriateness and success of such a policy require the choice of relevant indicators that not only highlight poverty gaps between countries but also identify the groups of individuals in each country that need particular attention from social policies. The target retained in the European strategy combines three criteria: people living in households below the monetary poverty threshold, poor people “in terms of standard of living” who live in a situation of severe material deprivation, and those who live in households with very low or zero work intensity. We first show that neither the combination nor the intersection of these three criteria produces an adequate measure of the fight against poverty, or an objective for it. We therefore propose an alternative concept, that of “consistent poverty”, which targets people who simultaneously live below the monetary poverty threshold and above a certain level of material deprivation. The special material deprivation module of the EU-SILC 2009 database allows us to examine two versions of this notion of deprivation: the measurement of “severe” deprivation currently used by the European Union, which adopts a threshold with four items, and an alternative measure of “elementary” material deprivation with a three-item threshold. The intersection between our three-item elementary deprivation criterion and the monetary poverty criterion produces more satisfactory results than those obtained by the European Union approach, in terms of both coherency and profile of the population identified.

Lead in rice: Analysis of baseline lead levels in market and field collected rice grains

In a large scale survey of rice grains from markets (13 countries) and fields (6 countries), a total of 1578 rice grain samples were analysed for lead. From the market collected samples, only 0.6% of the samples exceeded the Chinese and EU limit of 0.2 μg g− 1 lead in rice (when excluding samples collected from known contaminated/mine impacted regions). When evaluating the rice grain samples against the Food and Drug Administration's (FDA) provisional total tolerable intake (PTTI) values for children and pregnant women, it was found that only people consuming large quantities of rice were at risk of exceeding the PTTI from rice alone. Furthermore, 6 field experiments were conducted to evaluate the proportion of the variation in lead concentration in rice grains due to genetics. A total of 4 of the 6 field experiments had significant differences between genotypes, but when the genotypes common across all six field sites were assessed, only 4% of the variation was explained by genotype, with 9.5% and 11% of the variation explained by the environment and genotype by environment interaction respectively. Further work is needed to identify the sources of lead contamination in rice, with detailed information obtained on the locations and environments where the rice is sampled, so that specific risk assessments can be performed.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Geographical differences in first acquisition of Pseudomonas aeruginosa in cystic fibrosis

RATIONALE: Risk of infection with Pseudomonas aeruginosa in cystic fibrosis (CF) may be associated with environmental factors.

OBJECTIVES: To determine whether residential location is associated with risk of first acquisition of P. aeruginosa.

METHODS: We performed bronchoalveolar lavage and upper airway cultures in children newly diagnosed with CF to identify infection with P. aeruginosa during infancy and early childhood. Children were assessed according to their residence in a regional or metropolitan area. Multilocus sequence typing was used to determine P. aeruginosa genotype. An environmental questionnaire was also administered.

MEASUREMENTS AND MAIN RESULTS: A total of 105 of 120 (87.5%) infants diagnosed with CF were included in this study. Diagnosis in 65 infants (61.9%) followed newborn screening at mean age of 4.6 weeks. Sixty subjects (57.1%) were homozygous ΔF508, and 47 (44.8%) were female. Fifty-five (52.3%) infants were regional, of whom 26 (47.3%), compared with 9 of 50 (18.0%) metropolitan children, acquired infection with P. aeruginosa (odds ratio, 4.084; 95% confidence interval, 1.55-11.30). Age at acquisition was similar (regional: median, 2.31 yr; range, 0.27-5.96 yr; metropolitan: median, 3.10 yr, range, 0.89-3.70 yr). Strain typing identified P. aeruginosa genotypes often encountered in different ecological settings and little evidence of cross-infection. Ninety questionnaires (85.7%) were completed. Those who acquired P. aeruginosa were more likely to be living in a household that used water sprinkler systems (P = 0.032), but no differences were identified to explain increased risk of acquisition of P. aeruginosa in regional children.

CONCLUSIONS: Geographical difference in residence of children with CF was associated with increased risk of first acquisition of P. aeruginosa, usually with strains associated with the environment rather than with cross-infection.

Increased Exposure to Rigid Routines can Lead to Increased Challenging Behavior Following Changes to Those Routines

Several neurodevelopmental disorders are associated with preference for routine and challenging behavior following changes to routines. We examine individuals with Prader–Willi syndrome, who show elevated levels of this behavior, to better understand how previous experience of a routine can affect challenging behavior elicited by disruption to that routine. Play based challenges exposed 16 participants to routines, which were either adhered to or changed. Temper outburst behaviors, heart rate and movement were measured. As participants were exposed to routines for longer before a change (between 10 and 80 min; within participants), more temper outburst behaviors were elicited by changes. Increased emotional arousal was also elicited, which was indexed by heart rate increases not driven by movement. Further study will be important to understand whether current intervention approaches that limit exposure to changes, may benefit from the structured integration of flexibility to ensure that the opportunity for routine establishment is also limited.

Economic Stress and the Great Recession in Ireland: Polarization, Individualization or ‘Middle Class Squeeze’?

Following an unprecedented boom, since 2008 Ireland has experienced a severe economic crisis. Considerable debate persists as to where the heaviest burden of the recession has fallen. Conventional measures of income poverty and inequality have a limited capacity to answer this question. Our analysis, which focuses on economic stress and the mediating role of material deprivation, provides no evidence for individualization or class polarization. Instead we find that while economic stress level are highly stratified in income class and social class terms in both boom and bust periods, the changing impact of class is contingent on life course stage. The affluent income class remained largely insulated from the experience of economic stress. However, it saw its relative advantage overthe income poor class decline at the earlier stage of the life-course. At the other end of the hierarchy, the income poor experienced a relative improvement in their situation in the early life course phases. The precarious income class experienced some improvement in its situation at the earlier life course stages while the outcomes for the middle classes remain unchanged. In the mid-life course stages the precarious and lower middle classes experienced disproportionate increase in their stress levels while at the later life-cycle stage it is the combined middle classes that lost out. Additional effects over time relating to social class are restricted to the deteriorating situation of the petit bourgeoisie at the middle stage of the life-course. The pattern is clearly a good deal more complex that suggested by conventional notions of ‘middle class squeeze’ and points to the distinctive challenges relating to welfare and taxation policy faced by governments in the Great Recession.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - http://www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.

Real-time temperature estimation for power MOSFETs considering thermal aging effects

This paper presents a novel real-time power-device temperature estimation method that monitors the power MOSFET's junction temperature shift arising from thermal aging effects and incorporates the updated electrothermal models of power modules into digital controllers. Currently, the real-time estimator is emerging as an important tool for active control of device junction temperature as well as online health monitoring for power electronic systems, but its thermal model fails to address the device's ongoing degradation. Because of a mismatch of coefficients of thermal expansion between layers of power devices, repetitive thermal cycling will cause cracks, voids, and even delamination within the device components, particularly in the solder and thermal grease layers. Consequently, the thermal resistance of power devices will increase, making it possible to use thermal resistance (and junction temperature) as key indicators for condition monitoring and control purposes. In this paper, the predicted device temperature via threshold voltage measurements is compared with the real-time estimated ones, and the difference is attributed to the aging of the device. The thermal models in digital controllers are frequently updated to correct the shift caused by thermal aging effects. Experimental results on three power MOSFETs confirm that the proposed methodologies are effective to incorporate the thermal aging effects in the power-device temperature estimator with good accuracy. The developed adaptive technologies can be applied to other power devices such as IGBTs and SiC MOSFETs, and have significant economic implications. 

Family Economic Vulnerability & the Great Recession: An Analysis of the First two Waves of the Growing Up in Ireland Study

In this paper we make use of the first and second waves of the 2008 and 1998 cohorts of the Growing Up in Ireland study, to develop a multidimensional and dynamic approach to understanding the impact on families and children in Ireland of the Great Recession. Economic vulnerability is operationalised as involving a distinctive risk profile in relation to relative income, household joblessness and economic stress. We find that the recession was associated with a significant increase in levels of economic vulnerability and changing risk profiles involving a more prominent role for economic stress for both the 2008 and 1998 cohorts. The factors affecting vulnerability outcomes were broadly similar for both cohorts. Persistent economic vulnerability was significantly associated with lone parenthood, particularly for those with more than one child, lower levels of Primary Care Giver (PCG) education and to a lesser extent younger age of PCG at child’s birth, number of children and a parent leaving or dying. Similar factors were associated with transient vulnerability in the first wave but the magnitude of the effects was significantly weaker particularly in relation to lone parenthood and level of education of the PCG. For entry into vulnerability the impact of these factors was again substantially weaker than for persistent and transient vulnerability indicating a significantly greater degree of socio-economic heterogeneity among the group that became vulnerable during the recession. The findings raise policy and political problems that go beyond those associated with catering for groups that have tended to be characterized by high dependence on social welfare.

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

Despite significant advances in treatment strategies targeting the underlying defect in cystic fibrosis (CF), airway infection remains an important cause of lung disease. In this two-part series, we review recent evidence related to the complexity of CF airway infection, explore data suggesting the relevance of individual microbial species, and discuss current and future treatment options. In Part I, the evidence with respect to the spectrum of bacteria present in the CF airway, known as the lung microbiome is discussed. Subsequently, the current approach to treat methicillin-resistant Staphylococcus aureus, gram-negative bacteria, as well as multiple coinfections is reviewed. Newer molecular techniques have demonstrated that the airway microbiome consists of a large number of microbes, and the balance between microbes, rather than the mere presence of a single species, may be relevant for disease pathophysiology. A better understanding of this complex environment could help define optimal treatment regimens that target pathogens without affecting others. Although relevance of these organisms is unclear, the pathologic consequences of methicillin-resistant S. aureus infection in patients with CF have been recently determined. New strategies for eradication and treatment of both acute and chronic infections are discussed. Pseudomonas aeruginosa plays a prominent role in CF lung disease, butmany other nonfermenting gram-negative bacteria are also found in the CF airway. Many new inhaled antibiotics specifically targeting P. aeruginosa have become available with the hope that they will improve the quality of life for patients. Part I concludes with a discussion of how best to treat patients with multiple coinfections.

European Cystic Fibrosis Society Standards of Care: Quality Management in cystic fibrosis

Since the earliest days of cystic fibrosis (CF) treatment, patient data have been recorded and reviewed in order to identify the factors that lead to more favourable outcomes. Large data repositories, such as the US Cystic Fibrosis Registry, which was established in the 1960s, enabled successful treatments and patient outcomes to be recognized and improvement programmes to be implemented in specialist CF centres. Over the past decades, the greater volumes of data becoming available through Centre databases and patient registries led to the possibility of making comparisons between different therapies, approaches to care and indeed data recording. The quality of care for individuals with CF has become a focus at several levels: patient, centre, regional, national and international. This paper reviews the quality management and improvement issues at each of these levels with particular reference to indicators of health, the role of CF Centres, regional networks, national health policy, and international data registration and comparisons. 

Analysis of the early-time optical spectra of SN 2011fe in M101

The nearby Type Ia supernova SN 2011fe in M101 (cz=241 km s^-1) provides a unique opportunity to study the early evolution of a "normal" Type Ia supernova, its compositional structure, and its elusive progenitor system. We present 18 high signal-to-noise spectra of SN 2011fe during its first month beginning 1.2 days post-explosion and with an average cadence of 1.8 days. This gives a clear picture of how various line-forming species are distributed within the outer layers of the ejecta, including that of unburned material (C+O). We follow the evolution of C II absorption features until they diminish near maximum light, showing overlapping regions of burned and unburned material between ejection velocities of 10,000 and 16,000 km s^-1. This supports the notion that incomplete burning, in addition to progenitor scenarios, is a relevant source of spectroscopic diversity among SNe Ia. The observed evolution of the highly Doppler-shifted O I 7774 absorption features detected within five days post-explosion indicate the presence of O I with expansion velocities from 11,500 to 21,000 km s^-1. The fact that some O I is present above C II suggests that SN 2011fe may have had an appreciable amount of unburned oxygen within the outer layers of the ejecta.

Old Town Glasgow: Squalor, Agitation and City Improvements

In 1862, Glasgow Corporation initiated the first of a series of three legislative acts which would become known collectively as the City Improvements Acts. Despite having some influence on the nature of the built fabric on the expanding city as a whole, the most extensive consequences of these acts was reserved for one specific area of the city, the remnants of the medieval Old Town. As the city had expanded towards all points of the compass in a regular, grid-iron structure throughout the nineteenth century, the Old Town remained singularly as a densely wrought fabric of medieval wynds, vennels, oblique passageways and accelerated tenementalisation. Here, as the rest of the city began to assume the form of an ordered entity, visible and classifiable, one could still find and addresses such as ‘Bridgegate, No. 29, backland, stair first left, three up, right lobby, door facing’ (quoted in Pacione, 1995).

Unsurprisingly, this place, where proximity to the midden (dung-heap) was considered an enviable position, was seen by the authorities as a major health hazard and a source not only of cholera, but also of the more alarming typhoid epidemic of 1842. Accordingly, the demolitions which occurred in the backlands of the Old Town under the first of the acts, the Glasgow Police Act of 1862, were justified on health and medical grounds. But disease was not the only social problem thought to issue from this district. Reports from social reformers including Fredrick Engels suggested that the decay of the area’s physical fabric could be extended to the moral profile of its inhabitants. This was in such a state of degeneracy that there were calls for a nearby military barracks to be relocated to more salubrious climes because troops were routinely coming into contact ‘with the most dissolute and profligate portion of the population’ (Peter Clonston, Lord Provost, June 1861). Perhaps more worrying for the city fathers, however, was that the barracks’ arsenal was seen as a potential source of arms for the militant and often illegal cotton workers’ unions and organisations who inhabited the Old Town as well as the districts to the east. In fact, the Old Town and East End had been the site of numerous working class actions and riots since 1787, including a strike of 60,000 workers in 1820, 100,000 in 1838, and the so-called Bread Riots of 1848 where shouts of ‘Vive La Revolution’ were reported in the Gallowgate.

The events in Paris in 1848 precipitated Baron Hausmann’s interventions into that city. The boulevards were in turn visited by members of Glasgow Corporation and ultimately, it can be argued, provided an example for Old Town Glasgow. This paper suggests that the city improvement acts carried a similarly complex and pervasive agenda, one which embodied not only health, class conflict and sexual morality but also the more local condition of sectarianism. And, like in Paris, these were played out spatially in a extensive reconfiguration of the urban fabric of the Old Town which, through the creation of new streets and a railway yard, not only made it more amenable to large scale military manoeuvres but also, opened up the area to capitalist accumulation. By the end of the works, the medieval heritage of the Old Town had been almost completely razed, the working class and Catholic East End had, through the insertion of the railway yard, been isolated from the city centre and approximately 70,000 people had been made homeless.