Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States

Objective: To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences.

Design: Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US.

Setting: General population.

Participants: 26 018 men and women aged 50-79 years

Main outcome measures: All-cause, cardiovascular, and cancer mortality.

Results: 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses.

Conclusions: Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

A unique and robust single slice FPGA identification generator

In this paper, a new field-programmable gate array (FPGA) identification generator circuit is introduced based on physically unclonable function (PUF) technology. The new identification generator is able to convert flip-flop delay path variations to unique n-bit digital identifiers (IDs), while requiring only a single slice per ID bit by using 1-bit ID cells formed as hard-macros. An exemplary 128-bit identification generator is implemented on ten Xilinx Spartan-6 FPGA devices. Experimental results show an uniqueness of 48.52%, and reliability of 92.41% over a 25°C to 70°C temperature range and 10% fluctuation in supply voltage

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.

First comprehensive peat depositional records for tin, lead and copper associated with the antiquity of Europe's largest cassiterite deposits

Tin, as a constituent of bronze, was central to the technological development of early societies, but cassiterite (SnO2) deposits were scarce and located distantly from the centres of Mediterranean civilizations. As Britain had the largest workable ore deposits in the ancient Western world, this has led to much historical speculation and myth regarding the long-distance trading of tin from the Bronze Age onwards. Here we establish the first detailed chronology for tin, along with lead and copper deposition, into undisturbed ombrotrophic (rain-fed) peat bogs located at Bodmin Moor and Dartmoor in the centre of the British tin ore fields. Sustained elevated tin deposition is demonstrated clearly, with peaks occurring at 100-400 and 700-1000 calendar years AD - contemporaneous with the Roman and Anglo-Saxon periods respectively. While pre-Roman Iron Age tin exploitation undoubtedly took place, it was on a scale that did not result in convincingly enhanced deposition of the metal. The deposition of lead in the peat record provides evidence of a pre-Roman metal-based economy in southwest Britain. Emerging in the 4th century BC, this was centred on copper and lead ore processing that expanded exponentially and then collapsed upon Roman colonization during the 1st century AD. (C) 2011 Elsevier Ltd. All rights reserved.

Frame:for soprano sax, bass clarinet and tape

written for and first performed by Julian Siegel (sax) and Simon Atkinson (bass clarinet)

A small predatory core genome in the divergent marine Bacteriovorax marinus SJ and the terrestrial Bdellovibrio bacteriovorus

Bacteriovorax marinus SJ is a predatory delta-proteobacterium isolated from a marine environment. The genome sequence of this strain provides an interesting contrast to that of the terrestrial predatory bacterium Bdellovibrio bacteriovorus HD100. Based on their predatory lifestyle, Bacteriovorax were originally designated as members of the genus Bdellovibrio but subsequently were re-assigned to a new genus and family based on genetic and phenotypic differences. B. marinus attaches to gram-negative bacteria, penetrates through the cell wall to form a bdelloplast, in which it replicates, as shown using microscopy. Bacteriovorax is distinct, as it shares only 30% of its gene products with its closest sequenced relatives. Remarkably, 34% of predicted genes over 500 nt in length were completely unique with no significant matches in the databases. As expected, Bacteriovorax shares several characteristic loci with the other delta-proteobacteria. A geneset shared between Bacteriovorax and Bdellovibrio that is not conserved among other delta-proteobacteria such as Myxobacteria (which destroy prey bacteria externally via lysis), or the non-predatory Desulfo-bacteria and Geobacter species was identified. These 291 gene orthologues common to both Bacteriovorax and Bdellovibrio may be the key indicators of host-interaction predatory-specific processes required for prey entry. The locus from Bdellovibrio bacteriovorus is implicated in the switch from predatory to prey/host-independent growth. Although the locus is conserved in B. marinus, the sequence has only limited similarity. The results of this study advance understanding of both the similarities and differences between Bdellovibrio and Bacteriovorax and confirm the distant relationship between the two and their separation into different families.

Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia

Burkholderia cenocepacia and other members of the Burkholderia cepacia complex (Bcc) are highly multidrug-resistant bacteria that cause severe pulmonary infections in patients with cystic fibrosis. A screen of 2686 compounds derived from marine organisms identified molecules that could synergize with polymyxin B to inhibit growth of B. cenocepacia. At 1 μg/ml, five compounds synergized with polymyxin B and inhibited the growth of B. cenocepacia by more than 70% compared to growth in polymyxin B alone. Follow-up testing revealed that one compound from the screen, the aminocoumarin antibiotic novobiocin, synergized with polymyxin B and colistin against tobramycin-resistant clinical isolates of B. cenocepacia and Burkholderia multivorans. In parallel, we show that novobiocin sensitivity is common among Bcc species and these bacteria are even more susceptible to an alternative aminocoumarin, clorobiocin, which also had an additive effect with polymyxin B against B. cenocepacia. These studies support using aminocoumarin antibiotics to treat Bcc infections and show that synergizers can be found to increase the efficacy of antimicrobial peptides and polymyxins against Bcc bacteria.

Faith-based Non-Governmental Organizations in the Public Square

This chapter has both a methodological and a substantive aim. First, I suggest, using the role and function of NGOs in religiously related legal disputes as a paradigm example, the distinction between institutional, doctrinal, and theoretical approaches to the study of the relationship between religion and law is sometimes unhelpful, creating a barrier preventing us from understanding the phenomenon that we are examining. Instead, I suggest, a more integrated understanding, drawing on each of these approaches and seeing how they relate to each other, may well be more illuminating. The second aim of this chapter is to suggest, in a preliminary way, that the phenomenon of faith-based organizations should be more integrated than in the past into doctrinal and theoretical debates in the area of law and religion, in particular the problem of how liberal society is to engage with organized religion where there is a fundamental dispute as to who represents that religion, or as to what the basic tenets of that religion are.

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Temporal and spatial patterns in α- and γ-hexachlorocyclohexane concentrations in industrially contaminated rivers

Fluxes of HCH isomers α- and γ-HCH dynamics were determined in four industrial U.K. rivers feeding the North Sea. Sampling was conducted weekly basis over a 2-year period. This was complemented by discrete studies of events where two hourly sampling periods were used to investigate the fine time scale dynamics of fluxes. Two intensively industrialized rivers had average isomer concentrations of ~20 ng L^-1 for both isomers, while average concentrations in the two less industrialized rivers ranged between 1.5 and 5.0 ng L^-1. α-HCH concentrations showed no strong temporal patterns on any river, which contrasts with γ-HCH levels that increased considerably during late summer/early autumn following sustained periods of low river flow. Sampling during high river flow events on rivers with differing HCH pollution histories both showed the same dynamics in HCH isomer concentrations. γ-HCH concentrations decreased 4-fold during events while α-HCH-concentrations stayed constant. The increases in γ-HCH concentrations under low flow conditions and the rapid dilution of this isomer during events indicate that γ-HCH has current inputs to these river systems. It was calculated that these four rivers export 30.8 kg yr^-1 of γ-HCH and 14.8 kg yr^-1 of α-HCH to the North Sea.

Toxicity of chlorobenzenes to a lux-marked terrestrial bacterium, Pseudomonas fluorescens

Insertion of lux genes, encoding for bioluminescence in naturally bioluminescent marine bacteria, into the genome of Pseudomonas fluorescens resulted in a bioluminescent strain of this terrestrial bacterium. The lux- marked bacterium was used to toxicity test the chlorobenzene series. By correlating chlorobenzenes 50% effective concentration (EC50) values against physiochemical parameters, the physiochemical properties of chlorobenzenes that elicit toxic responses were investigated. The results showed that the more chlorinated the compounds, the more toxic they were to lux-marked P. fluorescens. Furthermore, it was shown that the more symmetrical the compound, the greater its toxicity to P. fluorescens. In general, the toxicity of a chlorobenzene was inversely proportional to its solubility (S) and directly proportional to its lipophilicity (K(ow). By correlating lux- marked P. fluorescens EC50 values, determined for chlorobenzenes, with toxicity values determined using Pimephales promelas (fathead minnow), Cyclotella meneghiniana (diatom), and Vibrio fischeri (marine bacterium), it was apparent that lux-marked P. fluorescens correlated well with freshwater species such as the diatoms and fathead minnow but not with the bioluminescent marine bacterium V. fischeri. The implications of these findings are that a terrestrial bacterium such as P. fluorescens should be used for toxicity testing of soils and freshwaters rather than the marine bacterium V. fischeri.