Sulphate-controlled Diversity of Subterranean Microbial Communities over Depth in Deep Groundwater with Opposing Gradients of Sulphate and Methane

The groundwater system in Olkiluoto, Finland, is stratified with a mixing layer at a depth of approximately 300m between sulphate-rich, methane-poor and sulphate-poor, methane-rich groundwaters. New sequence library data obtained by 454 pyrotag sequencing of the v4v6 16S rDNA region indicated that sulphate-reducing bacteria (SRB) dominated the mixing layer while SRB could not be detected in the deep sulphate-poor groundwater samples. With the indispensable support of the sequence data, it could be demonstrated that sulphate was the only component needed to trigger a very large community transition in deep sulphate-poor, methane-rich groundwater from a non-sulphate-reducing community comprising Hydrogenophaga, Pseudomonas, Thiobacillus, Fusibacter, and Lutibacter to a sulphate-reducing community with Desulfobacula, Desulfovibrio, Desufobulbaceae, Desulfobacterium, Desulfosporosinus, and Desulfotignum. Experiments with biofilms and planktonic microorganisms in flow cells under in situ conditions confirmed that adding sulphate to the sulphate-poor groundwater generated growth of cultivable SRB and detectable SRB-related sequences. It was also found that the 16S rDNA diversity of the biofilms was conserved over 103 d and that there was great similarity in diversity between the microorganisms in the biofilms and in the flowing groundwater. This work demonstrates that the presence/absence of only one geochemical parameter, i.e., sulphate, in the groundwater significantly influenced the diversity of the investigated subterranean microbial community

Risk of adverse events in patients prescribed long‐term opioids: a cohort study in the UK Clinical Practice Research Datalink

Background Long‐term opioid prescribing for musculoskeletal pain is controversial due to uncertainty regarding effectiveness and safety. This study examined the risks of a range of adverse events in a large cohort of patients prescribed long‐term opioids using the UK Clinical Practice Research Datalink. Methods Patients with musculoskeletal conditions starting a new long‐term opioid episode (defined as ≥3 opioid prescriptions within 90 days) between 2002 and 2012 were included. Primary outcomes: major trauma and intentional overdose (any). Secondary outcomes: addiction (any), falls, accidental poisoning, attempted suicide/self‐harm, gastrointestinal pathology and bleeding, and iron deficiency anaemia. “Control” outcomes (unrelated to opioid use): incident eczema and psoriasis. Results A total of 98,140 new long‐term opioids users (median age 61, 41% male) were followed for (median) 3.4 years. Major trauma risk increased from 285 per 10,000 person‐years without long‐term opioids to 369/10,000 for a long‐term opioid episode (<20 mg MED), 382/10,000 (20–50 mg MED), and 424/10,000 (≥50 mg MED). Adjusted hazard ratios were 1.09 (95% CI; 1.04, 1.14 for <20 mg MED vs. not being in an episode of long‐term prescribing), 1.24 (95% CI; 1.16, 1.32: 20–50 mg MED) and 1.34 (95% CI; 1.20, 1.50: ≥50 mg MED). Significant dose‐dependent increases in the risk of overdose (any type), addiction, falls, accidental poisoning, gastrointestinal pathology, and iron deficiency anaemia were also found. Conclusions Patients prescribed long‐term opioids are vulnerable to dose‐dependent serious adverse events. Opioid prescribing should be reviewed before long‐term use becomes established, and periodically thereafter to ensure that patients are not being exposed to increased risk of harm, which is not balanced by therapeutic benefit. Significance Long‐term opioid use is associated with serious adverse events such as major trauma, addiction and overdose. The risk increases with higher opioid doses. Opioid prescribing should be reviewed before long‐term use becomes established, and periodically thereafter to assess ongoing effectiveness

Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways

Validation of full-wave simulations for mode conversion of waves in the ion cyclotron range of frequencies with phase contrast imaging in Alcator C-Mod

Mode conversion of fast waves in the ion cyclotron range of frequencies (ICRF) is known to result in current drive and flow drive under optimised conditions, which may be utilized to control plasma profiles and improve fusion plasma performance. To describe these processes accurately in a realistic toroidal geometry, numerical simulations are essential. Quantitative comparison of these simulations and the actual experimental measurements is important to validate their predictions and to evaluate their limitations. The phase contrast imaging (PCI) diagnostic has been used to directly detect the ICRF waves in the Alcator C-Mod tokamak. The measurements have been compared with full-wave simulations through a synthetic diagnostic technique. Recently, the frequency response of the PCI detector array on Alcator C-Mod was recalibrated, which greatly improved the comparison between the measurements and the simulations. In this study, mode converted waves for D-{superscript 3]He and D-H plasmas with various ion species compositions were re-analyzed with the new calibration. For the minority heating cases, self-consistent electric fields and a minority ion distribution function were simulated by iterating a full-wave code and a Fokker-Planck code. The simulated mode converted wave intensity was in quite reasonable agreement with the measurements close to the antenna, but discrepancies remain for comparison at larger distances.United States. Department of Energy (Grant DE-FG02- 94ER54235