Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency MAF >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with ...large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with
< 0.05 and
<
In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 C, MAF 0.5%) within the first intron of
with an effect size comparable with those of common variants in the
and
loci (combined from the discovery and replication cohorts estimate of odds ratio OR
1.97, 95% CI 1.58-2.47,
= 2.9 × 10
). Pharmacological inhibition of
activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.
To determine whether reformatted computed tomography (CT) scans would increase surgeons' confidence in placing a trans sacral (TS) screw in the first sacral segment.
Level 1 trauma center.
A ...retrospective cohort study.
There were 50 patients with uninjured pelvises who were reviewed by 9 orthopaedic trauma fellowship-trained surgeons and 5 orthopaedic residents.
The overall percentage of surgeons who believe it was safe to place a TS screw in the first sacral segment with standard (axial cuts perpendicular to the scanner gantry) versus reformatted (parallel to the S1 end plate) CT scans.
Overall, 58% of patients were believed to have a safe corridor in traditional cut axial CT scans, whereas 68% were believed to have a safe corridor on reformatted CT scans ( P < 0.001). When grouped by dysplasia, those without sacral dysplasia (n = 28) had a safe corridor 93% of the time on traditional scans and 93% of the time with reformatted CT scans ( P = 0.87). However, of those who had dysplasia (n = 22), only 12% were believed to have a safe corridor on original scans compared with 35% on reformatted scans ( P < 0.001).
CT scan reformatting parallel to the S1 superior end plate increases the likelihood of identifying a safe corridor for a TS screw, especially in patients with evidence of sacral dysplasia. The authors would recommend the routine use of reformatting CT scans in this manner to provide a better understanding of the upper sacral segment osseous fixation pathways.
The goal of this article is to aid the orthopedic surgeon in determining whether an intra-medullary (IM) device for fixation of a distal tibia fracture is feasible. Using Computed Tomography (CT) ...scans of the fracture, this review demonstrates a simple way to determine whether two or even three distal interlocking screws are achievable in stable bone. Additionally, this paper offers a summary chart of commonly used tibial nails which can be used for planning purposes. Finally, a clinical summary of very distal tibial shaft fractures treated with IM fixation is provided.
Multipotential stem cells can be selected from the bone marrow by plastic adhesion, expanded, and cultured. They are able to differentiate not only into multiple cell types, including cartilage, ...bone, adipose and fibrous tissues, and myelosupportive stroma, but also into mesodermal (endothelium), neuroectodermal, or endodermal (hepatocytes) lineages. Our goal was to characterize the multipotential capacities of human mesenchymal stem cells (hMSCs) and to evaluate their ability to differentiate into insulin-secreting cells in vitro. hMSCs were obtained from healthy donors, selected by plastic adhesion, and phenotyped by fluorescence-activated cell sorter and reverse transcription-polymerase chain reaction analysis before and after infection with adenoviruses coding for mouse IPF1, HLXB9, and FOXA2 transcription factors involved early in the endocrine developmental pathway. We found that native hMSCs have a pluripotent phenotype (OCT4 expression and high telomere length) and constitutively express NKX6-1 at a low level but lack all other transcription factors implicated in beta-cell differentiation. In all hMSCs, we detected mRNA of cytokeratin 18 and 19, epithelial markers present in pancreatic ductal cells, whereas proconvertase 1/3 mRNA expression was detected only in some hMSCs. Ectopic expression of IPF1, HLXB9, and FOXA2 with or without islet coculture or islet-conditioned medium results in insulin gene expression. In conclusion, our results demonstrated that in vitro human bone marrow stem cells are able to differentiate into insulin-expressing cells by a mechanism involving several transcription factors of the beta-cell developmental pathway when cultured in an appropriate microenvironment.
In New Caledonia, one third of the Island is composed of ultramafic rocks, and lateritic soils enriched in Fe, Ni and Cr. Open-cast mining occurs all around the Island, and processes of erosion and ...sedimentation, which occur naturally along the coastline, are strongly amplified by mining activities. Due to their position, at the interface between land and sea, mangroves receive extensive amounts of particles emanating from rivers through estuaries. The purpose of this study is to understand the distribution and partitioning of some transitional metals (Fe, Mn, Ni, Cr) in sediments and pore-waters in a mangrove swamp, which is situated downstream of a catchment characterized by lateritic soils that were exploited a century ago. Quantitative analyses on bulk and after selective extraction, were carried out on cores collected along a transect within the intertidal zone, i.e. beneath a Rhizophora stylosa stand, an Avicennia marina stand, and within a salt flat. Mean metal concentrations were (μmolg−1): Fe (1997)>Ni (44.2)>Cr (31.9)>Mn (8.8). Thus, Ni, Cr and Fe concentrations in this study are substantially higher than mangrove world average. In addition, Ni concentrations are 10 to 100 times higher than in other New Caledonian mangrove developing downstream of a catchment not composed of ultramafic rocks. The studied mangrove is characterized by gradients of water and organic contents with depth and along the intertidal zone, which induced different redox conditions, and thus different metals partitioning. Transitional metals are deposited in the mangrove mainly as oxides and/or oxy-hydroxides, that are subsequently dissolved by bacteria for the decomposition of organic matter, and which leads to a strong increase of metals in the dissolved phase. Then, dissolved metals were precipitated with organic and sulfide compounds. To conclude, organic diagenesis in mangrove sediments leads to the transfer of transitional metals from oxide form to organic and sulfide forms.
► Erosion of ferralsols induces high concentrations of Fe, Ni, Cr in mangrove soils. ► Lateral and depth stratification of redox processes linked to organic content. ► Metals are deposited in the mangrove mainly as oxides and/or oxy-hydroxides. ► Within mangrove soils, Fe, Ni, Cr are mainly as organic and sulfide forms.
Abstract
Background
Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of ...TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.
Methods
We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.
Results
The multi-allelic 5p15.33 instrument explained 1.49–2.00% of TL variation in our data (p = 2.6 × 10–9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20–1.65 and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51–2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83–1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70–1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95–1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.
Conclusions
Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.
Coelenterazine is a luciferin found in many marine bioluminescent organisms. This luciferin also possesses high antioxidant properties and an exceptional ability to protect cells exposed to oxidative ...stress. It has been suggested that coelenterazine's antioxidative mechanisms include the formation of an oxidation product, coelenteramine, also endowed with chain-breaking properties. In this work, coelenterazine analogs were shown to delay the onset of lipid peroxidation in a linoleate micellar solution exposed to free radical initiators. Their consumption was accompanied by the concomitant formation of coelenteramine. This was followed by a reduction in the peroxidation rate coinciding with the consumption of coelenterazine's oxidation product coelenteramine. The addition of coelenteramine to micelles reduced the propagation rate of the oxidative process. When coelenterazine analogs oxidizing into an inactive analog of coelenteramine were applied, the delaying effect but not the reduced peroxidation rate nor the consumption of the aminopyrazine was observed. These results demonstrate the role of the oxidation product coelenteramine in the chain-breaking properties of coelenterazine and analogs.
A search for the Standard Model Higgs boson in proton–proton collisions with the ATLAS detector at the LHC is presented. The datasets used correspond to integrated luminosities of approximately 4.8 ...fb−1 collected at s=7 TeV in 2011 and 5.8 fb−1 at s=8 TeV in 2012. Individual searches in the channels H→ZZ(⁎)→4ℓ, H→γγ and H→WW(⁎)→eνμν in the 8 TeV data are combined with previously published results of searches for H→ZZ(⁎), WW(⁎), bb¯ and τ+τ− in the 7 TeV data and results from improved analyses of the H→ZZ(⁎)→4ℓ and H→γγ channels in the 7 TeV data. Clear evidence for the production of a neutral boson with a measured mass of 126.0±0.4(stat)±0.4(sys) GeV is presented. This observation, which has a significance of 5.9 standard deviations, corresponding to a background fluctuation probability of 1.7×10−9, is compatible with the production and decay of the Standard Model Higgs boson.
Background:
The time frame in which patients can expect functional improvement after open reduction internal fixation (ORIF) of pilon fractures is unclear. The purpose of this study was to determine ...the trajectory and rate at which patients’ physical function improves up to 2 years postinjury.
Methods:
The patients studied sustained a unilateral, isolated pilon fractures (AO/OTA 43B/C) and followed at a level 1 trauma center over a 5-year period (2015-2020). Patient-Reported Outcomes Measurement Information Systems (PROMIS) Physical Function (PF) scores from these patients at defined follow-up times of immediately, 6 weeks, 3 months, 6 months, 1 year, and 2 years after surgery defined the cohorts and were retrospectively studied.
Results:
There were 160 patients with PROMIS scores immediately postoperatively, 143 patients at 6 weeks, 146 patients at 12 weeks, 97 at 24 weeks, 84 at 1 year, and 45 at 2 years postoperatively. The average PROMIS PF score was 28 immediately postoperatively, 30 at 6 weeks, 36 at 3 months, 40 at 6 months, 41 at 1 year, and 39 at 2 years. There was a significant difference between PROMIS PF scores between 6 weeks and 3 months (P < .001), and between 3 and 6 months (P < .001). Otherwise, no significant differences were detected between consecutive time points.
Conclusion:
Patients with isolated pilon fractures demonstrate the majority of their improvement in terms of physical function between 6 weeks and 6 months postoperatively. No significant difference was detected in PF scores after 6 months postoperatively up to 2 years. Furthermore, the mean PROMIS PF score of patients 2 years after recovery was approximately 1 SD below the population average. This information is helpful in counseling patients and setting expectations for recovery after pilon fractures.
Level of Evidence:
Level III, prognostic.
Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association ...study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.
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