Histone variants in archaea - An undiscovered country.

Exchanging core histones in the nucleosome for paralogous variants can have important functional ramifications. Many of these variants, and their physiological roles, have been characterized in exquisite detail in model eukaryotes, including humans. In comparison, our knowledge of histone biology in archaea remains rudimentary. This is true in particular for our knowledge of histone variants. Many archaea encode several histone genes that differ in sequence, but do these paralogs make distinct, adaptive contributions to genome organization and regulation in a manner comparable to eukaryotes? Below, we review what we know about histone variants in archaea at the level of structure, regulation, and evolution. In all areas, our knowledge pales when compared to the wealth of insight that has been gathered for eukaryotes. Recent findings, however, provide tantalizing glimpses into a rich and largely undiscovered country that is at times familiar and eukaryote-like and at times strange and uniquely archaeal. We sketch a preliminary roadmap for further exploration of this country; an undertaking that may ultimately shed light not only on chromatin biology in archaea but also on the origin of histone-based chromatin in eukaryotes.

Myositis and Its Mimics: Guideline Updates, MRI Characteristics, and New Horizons.

Myositis is defined as inflammation within skeletal muscle and is a subcategory of myopathy, which is more broadly defined as any disorder affecting skeletal muscle. Myositis may be encountered as a component of autoimmune and connective tissue disease, where it is described as idiopathic inflammatory myopathy. Myositis can also be caused by infections, as well as toxins and drugs, including newer classes of medications. MRI plays an important role in the diagnosis and evaluation of patients with suspected myositis, but many entities may have imaging features similar to myositis and can be considered myositis mimics. These include muscular dystrophies, denervation, deep venous thrombosis, diabetic myonecrosis, muscle injury, heterotopic ossification, and even neoplasms. In patients with suspected myositis, definitive diagnosis may require integrated analysis of imaging findings with clinical, laboratory, and pathology data. The objectives of this article are to review the fundamental features of myositis, including recent updates in terminology and consensus guidelines for idiopathic inflammatory myopathies, the most important MRI differential diagnostic considerations for myositis (i.e., myositis mimics), and new horizons, including the potential importance of artificial intelligence and multimodal integrated diagnostics in the evaluation of patients with muscle disorders.

Histone variants in archaea and the evolution of combinatorial chromatin complexity.

Nucleosomes in eukaryotes act as platforms for the dynamic integration of epigenetic information. Posttranslational modifications are reversibly added or removed and core histones exchanged for paralogous variants, in concert with changing demands on transcription and genome accessibility. Histones are also common in archaea. Their role in genome regulation, however, and the capacity of individual paralogs to assemble into histone-DNA complexes with distinct properties remain poorly understood. Here, we combine structural modeling with phylogenetic analysis to shed light on archaeal histone paralogs, their evolutionary history, and capacity to generate combinatorial chromatin states through hetero-oligomeric assembly. Focusing on the human commensal Methanosphaera stadtmanae as a model archaeal system, we show that the heteromeric complexes that can be assembled from its seven histone paralogs vary substantially in DNA binding affinity and tetramer stability. Using molecular dynamics simulations, we go on to identify unique paralogs in M. stadtmanae and Methanobrevibacter smithii that are characterized by unstable interfaces between dimers. We propose that these paralogs act as capstones that prevent stable tetramer formation and extension into longer oligomers characteristic of model archaeal histones. Importantly, we provide evidence from phylogeny and genome architecture that these capstones, as well as other paralogs in the Methanobacteriales, have been maintained for hundreds of millions of years following ancient duplication events. Taken together, our findings indicate that at least some archaeal histone paralogs have evolved to play distinct and conserved functional roles, reminiscent of eukaryotic histone variants. We conclude that combinatorially complex histone-based chromatin is not restricted to eukaryotes and likely predates their emergence.

Clinical utility of accelerated MAVRIC-SL with robust-PCA compared to conventional MAVRIC-SL in evaluation of total hip arthroplasties.

OBJECTIVE: To compare the diagnostic performance of a conventional metal artifact suppression sequence MAVRIC-SL (multi-acquisition variable-resonance image combination selective) and a novel 2.6-fold faster sequence employing robust principal component analysis (RPCA), in the MR evaluation of hip implants at 3 T. MATERIALS AND METHODS: Thirty-six total hip implants in 25 patients were scanned at 3 T using a conventional MAVRIC-SL proton density-weighted sequence and an RPCA MAVRIC-SL proton density-weighted sequence. Comparison was made of image quality, geometric distortion, visualization around acetabular and femoral components, and conspicuity of abnormal imaging findings using the Wilcoxon signed-rank test and a non-inferiority test. Abnormal findings were correlated with subsequent clinical management and intraoperative findings if the patient underwent subsequent surgery. RESULTS: Mean scores for conventional MAVRIC-SL were better than RPCA MAVRIC-SL for all qualitative parameters (p < 0.05), although the probability of RPCA MAVRIC-SL being clinically useful was non-inferior to conventional MAVRIC-SL (within our accepted 10% difference, p < 0.05), except for visualization around the acetabular component. Abnormal imaging findings were seen in 25 hips, and either equally visible or visible but less conspicuous on RPCA MAVRIC-SL in 21 out of 25 cases. In 4 cases, a small joint effusion was queried on MAVRIC-SL but not RPCA MAVRIC-SL, but the presence or absence of a small effusion did not affect subsequent clinical management and patient outcome. CONCLUSION: While the overall image quality is reduced, RPCA MAVRIC-SL allows for significantly reduced scan time and maintains almost equal diagnostic performance.

Automating Scoliosis Measurements in Radiographic Studies with Machine Learning: Comparing Artificial Intelligence and Clinical Reports.

Scoliosis is a condition of abnormal lateral spinal curvature affecting an estimated 2 to 3% of the US population, or seven million people. The Cobb angle is the standard measurement of spinal curvature in scoliosis but is known to have high interobserver and intraobserver variability. Thus, the objective of this study was to build and validate a system for automatic quantitative evaluation of the Cobb angle and to compare AI generated and human reports in the clinical setting. After IRB was obtained, we retrospectively collected 2150 frontal view scoliosis radiographs at a tertiary referral center (January 1, 2019, to January 1, 2021, ≥ 16 years old, no hardware). The dataset was partitioned into 1505 train (70%), 215 validation (10%), and 430 test images (20%). All thoracic and lumbar vertebral bodies were segmented with bounding boxes, generating approximately 36,550 object annotations that were used to train a Faster R-CNN Resnet-101 object detection model. A controller algorithm was written to localize vertebral centroid coordinates and derive the Cobb properties (angle and endplate) of dominant and secondary curves. AI-derived Cobb angle measurements were compared to the clinical report measurements, and the Spearman rank-order demonstrated significant correlation (0.89, p < 0.001). Mean difference between AI and clinical report angle measurements was 7.34° (95% CI: 5.90-8.78°), which is similar to published literature (up to 10°). We demonstrate the feasibility of an AI system to automate measurement of level-by-level spinal angulation with performance comparable to radiologists.

Non-contrast MRI of synovitis in the knee using quantitative DESS.

OBJECTIVES: To determine whether synovitis graded by radiologists using hybrid quantitative double-echo in steady-state (qDESS) images can be utilized as a non-contrast approach to assess synovitis in the knee, compared against the reference standard of contrast-enhanced MRI (CE-MRI). METHODS: Twenty-two knees (11 subjects) with moderate to severe osteoarthritis (OA) were scanned using CE-MRI, qDESS with a high diffusion weighting (qDESSHigh), and qDESS with a low diffusion weighting (qDESSLow). Four radiologists graded the overall impression of synovitis, their diagnostic confidence, and regional grading of synovitis severity at four sites (suprapatellar pouch, intercondylar notch, and medial and lateral peripatellar recesses) in the knee using a 4-point scale. Agreement between CE-MRI and qDESS, inter-rater agreement, and intra-rater agreement were assessed using a linearly weighted Gwet's AC2. RESULTS: Good agreement was seen between CE-MRI and both qDESSLow (AC2 = 0.74) and qDESSHigh (AC2 = 0.66) for the overall impression of synovitis, but both qDESS sequences tended to underestimate the severity of synovitis compared to CE-MRI. Good inter-rater agreement was seen for both qDESS sequences (AC2 = 0.74 for qDESSLow, AC2 = 0.64 for qDESSHigh), and good intra-rater agreement was seen for both sequences as well (qDESSLow AC2 = 0.78, qDESSHigh AC2 = 0.80). Diagnostic confidence was moderate to high for qDESSLow (mean = 2.36) and slightly less than moderate for qDESSHigh (mean = 1.86), compared to mostly high confidence for CE-MRI (mean = 2.73). CONCLUSIONS: qDESS shows potential as an alternative MRI technique for assessing the severity of synovitis without the use of a gadolinium-based contrast agent. KEY POINTS: The use of the quantitative double-echo in steady-state (qDESS) sequence for synovitis assessment does not require the use of a gadolinium-based contrast agent. Preliminary results found that low diffusion-weighted qDESS (qDESSLow) shows good agreement to contrast-enhanced MRI for characterization of the severity of synovitis, with a relative bias towards underestimation of severity. Preliminary results also found that qDESSLow shows good inter- and intra-rater agreement for the depiction of synovitis, particularly for readers experienced with the sequence.

Diagnostic Accuracy of Quantitative Multicontrast 5-Minute Knee MRI Using Prospective Artificial Intelligence Image Quality Enhancement.

BACKGROUND. Potential approaches for abbreviated knee MRI, including prospective acceleration with deep learning, have achieved limited clinical implementation. OBJECTIVE. The objective of this study was to evaluate the interreader agreement between conventional knee MRI and a 5-minute 3D quantitative double-echo steady-state (qDESS) sequence with automatic T2 mapping and deep learning super-resolutionaugmentation and to compare the diagnostic performance of the two methods regarding findings from arthroscopic surgery. METHODS. Fifty-one patients with knee pain underwent knee MRI that included an additional 3D qDESS sequence with automatic T2 mapping. Fourier interpolation was followed by prospective deep learning super resolution to enhance qDESS slice resolution twofold. A musculoskeletal radiologist and a radiology resident performed independent retrospective evaluations of articular cartilage, menisci, ligaments, bones, extensor mechanism, and synovium using conventional MRI. Following a 2-month washout period, readers reviewed qDESS images alone followed by qDESS with the automatic T2 maps. Interreader agreement between conventional MRI and qDESS was computed using percentage agreement and Cohen kappa. The sensitivity and specificity of conventional MRI, qDESS alone, and qDESS plus T2 mapping were compared with arthroscopic findings using exact McNemar tests. RESULTS. Conventional MRI and qDESS showed 92% agreement in evaluating all tissues. Kappa was 0.79 (95% CI, 0.76-0.81) across all imaging findings. In 43 patients who underwent arthroscopy, sensitivity and specificity were not significantly different (p = .23 to > .99) between conventional MRI (sensitivity, 58-93%; specificity, 27-87%) and qDESS alone (sensitivity, 54-90%; specificity, 23-91%) for cartilage, menisci, ligaments, and synovium. For grade 1 cartilage lesions, sensitivity and specificity were 33% and 56%, respectively, for conventional MRI; 23% and 53% for qDESS (p = .81); and 46% and 39% for qDESS with T2 mapping (p = .80). For grade 2A lesions, values were 27% and 53% for conventional MRI, 26% and 52% for qDESS (p = .02), and 58% and 40% for qDESS with T2 mapping (p < .001). CONCLUSION. The qDESS method prospectively augmented with deep learning showed strong interreader agreement with conventional knee MRI and near-equivalent diagnostic performance regarding arthroscopy. The ability of qDESS to automatically generate T2 maps increases sensitivity for cartilage abnormalities. CLINICAL IMPACT. Using prospective artificial intelligence to enhance qDESS image quality may facilitate an abbreviated knee MRI protocol while generating quantitative T2 maps.

Elbow Imaging: Variants and Asymptomatic Findings.

One of the key principles in the interpretation of radiology images is the ability to differentiate between normal and abnormal findings. This article provides a comprehensive overview of normal structures and anatomical variants occurring around the elbow including potential diagnostic pitfalls. We discuss frequently observed anatomical variants found in routine clinical practice associated with osseous, ligamentous, musculotendinous, and neurovascular structures at the elbow that may simulate pathology or predispose to symptoms under specific circumstances.

The Stieda fracture revisited.

OBJECTIVE: This study aimed to evaluate injury patterns associated with Stieda avulsion fractures of the medial femoral condyle at the attachment of the proximal MCL. MATERIALS AND METHODS: Knee radiographs and MRI scans of 11 patients with Stieda fractures were evaluated by two fellowship-trained MSK radiologists for fracture origin, integrity of the deep and superficial components of the MCL, medial retinacular structures, posterior oblique ligament, other ligamentous injuries, meniscal tears, and osteochondral injuries. The mechanism of injury and subsequent clinical management were recorded. RESULTS: Eight Stieda fractures only involved the meniscofemoral fibers of the deep MCL, two larger Stieda fractures related to both superficial and deep layers, and one fracture only involved the superficial layer. Posteromedial retinacular structures and posterior oblique ligament were injured in all cases. Eight had high-grade ACL injuries, but none had high-grade PCL nor FCL injuries. The proximal anterolateral ligament was injured in seven, including two with associated Segond fractures. Other injuries included posterolateral corner injuries in six, meniscal injuries in seven, and additional fractures in nine, most commonly ACL-associated impaction fractures in the lateral tibiofemoral compartment. None had high-grade chondral injury. None of the Stieda fractures were treated surgically, but four underwent subsequent ACL reconstruction. CONCLUSION: Stieda fractures most commonly involved the deep fibers of the MCL and were accompanied by moderate-to-high-grade injury of other MCL components. There was a high association with other ligamentous injuries, particularly the posterior medial retinacular structures, posterior oblique ligament, and ACL, and many were associated with additional fractures.

Utility of deep learning super-resolution in the context of osteoarthritis MRI biomarkers.

BACKGROUND: Super-resolution is an emerging method for enhancing MRI resolution; however, its impact on image quality is still unknown. PURPOSE: To evaluate MRI super-resolution using quantitative and qualitative metrics of cartilage morphometry, osteophyte detection, and global image blurring. STUDY TYPE: Retrospective. POPULATION: In all, 176 MRI studies of subjects at varying stages of osteoarthritis. FIELD STRENGTH/SEQUENCE: Original-resolution 3D double-echo steady-state (DESS) and DESS with 3× thicker slices retrospectively enhanced using super-resolution and tricubic interpolation (TCI) at 3T. ASSESSMENT: A quantitative comparison of femoral cartilage morphometry was performed for the original-resolution DESS, the super-resolution, and the TCI scans in 17 subjects. A reader study by three musculoskeletal radiologists assessed cartilage image quality, overall image sharpness, and osteophytes incidence in all three sets of scans. A referenceless blurring metric evaluated blurring in all three image dimensions for the three sets of scans. STATISTICAL TESTS: Mann-Whitney U-tests compared Dice coefficients (DC) of segmentation accuracy for the DESS, super-resolution, and TCI images, along with the image quality readings and blurring metrics. Sensitivity, specificity, and diagnostic odds ratio (DOR) with 95% confidence intervals compared osteophyte detection for the super-resolution and TCI images, with the original-resolution as a reference. RESULTS: DC for the original-resolution (90.2 ± 1.7%) and super-resolution (89.6 ± 2.0%) were significantly higher (P < 0.001) than TCI (86.3 ± 5.6%). Segmentation overlap of super-resolution with the original-resolution (DC = 97.6 ± 0.7%) was significantly higher (P < 0.0001) than TCI overlap (DC = 95.0 ± 1.1%). Cartilage image quality for sharpness and contrast levels, and the through-plane quantitative blur factor for super-resolution images, was significantly (P < 0.001) better than TCI. Super-resolution osteophyte detection sensitivity of 80% (76-82%), specificity of 93% (92-94%), and DOR of 32 (22-46) was significantly higher (P < 0.001) than TCI sensitivity of 73% (69-76%), specificity of 90% (89-91%), and DOR of 17 (13-22). DATA CONCLUSION: Super-resolution appears to consistently outperform naïve interpolation and may improve image quality without biasing quantitative biomarkers. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:768-779.

Combined 5-minute double-echo in steady-state with separated echoes and 2-minute proton-density-weighted 2D FSE sequence for comprehensive whole-joint knee MRI assessment.

BACKGROUND: Clinical knee MRI protocols require upwards of 15 minutes of scan time. PURPOSE/HYPOTHESIS: To compare the imaging appearance of knee abnormalities depicted with a 5-minute 3D double-echo in steady-state (DESS) sequence with separate echo images, with that of a routine clinical knee MRI protocol. A secondary goal was to compare the imaging appearance of knee abnormalities depicted with 5-minute DESS paired with a 2-minute coronal proton-density fat-saturated (PDFS) sequence. STUDY TYPE: Prospective. SUBJECTS: Thirty-six consecutive patients (19 male) referred for a routine knee MRI. FIELD STRENGTH/SEQUENCES: DESS and PDFS at 3T. ASSESSMENT: Five musculoskeletal radiologists evaluated all images for the presence of internal knee derangement using DESS, DESS+PDFS, and the conventional imaging protocol, and their associated diagnostic confidence of the reading. STATISTICAL TESTS: Differences in positive and negative percent agreement (PPA and NPA, respectively) and 95% confidence intervals (CIs) for DESS and DESS+PDFS compared with the conventional protocol were calculated and tested using exact McNemar tests. The percentage of observations where DESS or DESS+PDFS had equivalent confidence ratings to DESS+Conv were tested with exact symmetry tests. Interreader agreement was calculated using Krippendorff's alpha. RESULTS: DESS had a PPA of 90% (88-92% CI) and NPA of 99% (99-99% CI). DESS+PDFS had increased PPA of 99% (95-99% CI) and NPA of 100% (99-100% CI) compared with DESS (both P < 0.001). DESS had equivalent diagnostic confidence to DESS+Conv in 94% of findings, whereas DESS+PDFS had equivalent diagnostic confidence in 99% of findings (both P < 0.001). All readers had moderate concordance for all three protocols (Krippendorff's alpha 47-48%). DATA CONCLUSION: Both 1) 5-minute 3D-DESS with separated echoes and 2) 5-minute 3D-DESS paired with a 2-minute coronal PDFS sequence depicted knee abnormalities similarly to a routine clinical knee MRI protocol, which may be a promising technique for abbreviated knee MRI. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Nephrology and Public Policy Committee propositions to stimulate research collaboration in adults and children in Europe.

The strengths and the limitations of research activities currently present in Europe are explored in order to outline how to proceed in the near future. Epidemiological and clinical research and public policy in Europe are generally considered to be comprehensive and successful, and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) is playing a key role in the field of nephrology research. The Nephrology and Public Policy Committee (NPPC) aims to improve the current situation and translation into public policy by planning eight research topics to be supported in the coming 5 years by ERA-EDTA.

Accelerated three-dimensional multispectral MRI with robust principal component analysis for separation of on- and off-resonance signals.

PURPOSE: To enable highly accelerated distortion-free MRI near metal by separating on- and off-resonance to exploit the redundancy of slice-phase encoding for the dominant on-resonance component. METHODS: Multispectral MRI techniques resolve off-resonance distortions by a combination of limited excitation bins and additional encoding. Inspired by robust principal component analysis, a novel compact representation of multispectral images as a sum of rank-one and sparse matrices corresponding to on- and off-resonance respectively is described. This representation is used in a calibration-free and model-free reconstruction for data with an undersampling pattern that varies between bins. Retrospective undersampling was used to compare the proposed reconstruction and bin-by-bin compressed sensing. Hip images were acquired in eight patients with standard and prospectively undersampled three-dimensional multispectral imaging, and image quality was evaluated by two radiologists on a 5-point scale. RESULTS: Experiments with retrospective undersampling showed that the enhanced sparsity afforded by the separation greatly reduces reconstruction errors and artifacts. Images from prospectively undersampled multispectral imaging offered 2.6-3.4-fold (18-24-fold overall) acceleration compared to standard multispectral imaging with parallel imaging and partial-Fourier acceleration with equivalence in all qualitative assessments within a tolerance of one point (P < 0.004). CONCLUSION: Three-dimensional multispectral imaging can be highly accelerated by varying undersampling between bins and separating on- and off-resonance. Magn Reson Med 79:1495-1505, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Super-resolution musculoskeletal MRI using deep learning.

PURPOSE: To develop a super-resolution technique using convolutional neural networks for generating thin-slice knee MR images from thicker input slices, and compare this method with alternative through-plane interpolation methods. METHODS: We implemented a 3D convolutional neural network entitled DeepResolve to learn residual-based transformations between high-resolution thin-slice images and lower-resolution thick-slice images at the same center locations. DeepResolve was trained using 124 double echo in steady-state (DESS) data sets with 0.7-mm slice thickness and tested on 17 patients. Ground-truth images were compared with DeepResolve, clinically used tricubic interpolation, and Fourier interpolation methods, along with state-of-the-art single-image sparse-coding super-resolution. Comparisons were performed using structural similarity, peak SNR, and RMS error image quality metrics for a multitude of thin-slice downsampling factors. Two musculoskeletal radiologists ranked the 3 data sets and reviewed the diagnostic quality of the DeepResolve, tricubic interpolation, and ground-truth images for sharpness, contrast, artifacts, SNR, and overall diagnostic quality. Mann-Whitney U tests evaluated differences among the quantitative image metrics, reader scores, and rankings. Cohen's Kappa (κ) evaluated interreader reliability. RESULTS: DeepResolve had significantly better structural similarity, peak SNR, and RMS error than tricubic interpolation, Fourier interpolation, and sparse-coding super-resolution for all downsampling factors (p < .05, except 4 × and 8 × sparse-coding super-resolution downsampling factors). In the reader study, DeepResolve significantly outperformed (p < .01) tricubic interpolation in all image quality categories and overall image ranking. Both readers had substantial scoring agreement (κ = 0.73). CONCLUSION: DeepResolve was capable of resolving high-resolution thin-slice knee MRI from lower-resolution thicker slices, achieving superior quantitative and qualitative diagnostic performance to both conventionally used and state-of-the-art methods.

Dynamic evaluation of a trilobal capillary-channeled polymer fiber shape for reversed phase protein separations and comparison to the eight-channeled form.

A new, trilobal-shaped capillary-channeled polymer fiber is under development to address the issues of poor A-term performance of the previous eight-channeled form. The trilobal geometry should provide better packing homogeneity due to the fewer potential orientations of the symmetric fiber geometry. Comparisons of separation efficiency and peak shape were made between the two fiber shapes through several dynamic parameters. Column hydrodynamics were investigated with two marker compounds, uracil and bovine serum albumin, with van Deemter plots of those two compounds revealing differences in the packing qualities between the different fiber shapes. Parametric fitting to the van Deemter, Knox, and Giddings equations provides insights into the column physical structures. Separation quality for both shapes was evaluated across differences in fiber packing density, gradient rate, and mobile phase linear velocity for the reversed phase separation of a four protein mixture, containing ribonuclease A, cytochrome c, lysozyme, and myoglobin. The results of this study lay the ground work for future efforts in the use of trilobal fibers for the separation of biomacromolecules.

Deleterious effects of phosphate on vascular and endothelial function via disruption to the nitric oxide pathway.

BACKGROUND: Hyperphosphataemia is an independent risk factor for accelerated cardiovascular disease in chronic kidney disease (CKD), although the mechanism for this is poorly understood. We investigated the effects of sustained exposure to a high-phosphate environment on endothelial function in cellular and preclinical models, as well as in human subjects. METHODS: Resistance vessels from rats and humans (± CKD) were incubated in a normal (1.18 mM) or high (2.5 mM) phosphate concentration solution and cells were cultured in normal- (0.5 mM) or high-phosphate (3 mM) concentration media. A single-blind crossover study was performed in healthy volunteers, receiving phosphate supplements or a phosphate binder (lanthanum), and endothelial function measured was by flow-mediated dilatation. RESULTS: Endothelium-dependent vasodilatation was impaired when resistance vessels were exposed to high phosphate; this could be reversed in the presence of a phosphodiesterase-5-inhibitor. Vessels from patients with CKD relaxed normally when incubated in normal-phosphate conditions, suggesting that the detrimental effects of phosphate may be reversible. Exposure to high-phosphate disrupted the whole nitric oxide pathway with reduced nitric oxide and cyclic guanosine monophosphate production and total and phospho endothelial nitric oxide synthase expression. In humans, endothelial function was reduced by chronic phosphate loading independent of serum phosphate, but was associated with higher urinary phosphate excretion and serum fibroblast growth factor 23. CONCLUSIONS: These directly detrimental effects of phosphate, independent of other factors in the uraemic environment, may explain the increased cardiovascular risk associated with phosphate in CKD.

Phosphate as a cardiovascular risk factor: effects on vascular and endothelial function.

BACKGROUND: Hyperphosphataemia is a risk factor for accelerated cardiovascular disease in chronic kidney disease. The mechanism is poorly understood; it is unclear whether phosphate has direct effects or effects mediated via calcification or FGF23. We investigated direct effects of phosphate on endothelial function using myography to study rat and human blood vessels. In addition we assessed the effects of phosphate loading on endothelial function in a clinical study. METHODS: Resistance vessels from patients with (n=12) and without (n=13) chronic kidney disease were incubated in normal or high phosphate. Vasoconstrictor and vasorelaxation responses were measured. Concentration-response curves were constructed and comparisons made. Identical experiments were performed in rat mesenteric vessels with and without phosphodiesterase type 5 inhibitor. A cross-over study was done in 19 healthy volunteers receiving phosphate supplements or binders and endothelial function measured by flow mediated dilatation (FMD). Primary outcome was percent change in FMD from baseline. FINDINGS: Nine to 13 vessels were used in each group. Endothelium-dependent vasodilatation was impaired in high compared with normal phosphate in rat (mean maximum vasodilatation 64% [SE 9] vs 95 [1], p<0·001) and human vessels with (25·3 [11·1] vs 75·7 [13·6], p<0·001) and without chronic kidney disease (42·9 [12] vs 79·4 [8·2], p=0·003). In rat vessels, these effects were reversed by a phosphodiesterase type 5 inhibitor. In vivo in volunteers, endothelial function was reduced by phosphate loading (median maximum vasodilatation 3·38% [IQR 2·57-5·26] vs 8·4 [6·2-11·6], p<0·001); this effect was independent of serum phosphate concentration but associated with urinary phosphate excretion and serum FGF23 concentrations. INTERPRETATION: Prolonged exposure to phosphate is associated with endothelial dysfunction, a direct effect of phosphate, which might contribute to cardiovascular risk in chronic kidney disease. In a high phosphate environment, endothelial and vascular dysfunction is evident in blood vessels and in man exposed to prolonged oral phosphate loading. These effects might be mediated by disruption of the NO pathway. FUNDING: British Heart Foundation, Darlinda's Charity for Renal Research.

Elbow Imaging in Sport: Sports Imaging Series.

Elbow pain is a frequent presenting symptom in athletes, particularly athletes who throw. The elbow can be injured as a result of acute trauma, such as a direct blow or a fall onto an outstretched hand or from chronic microtrauma. In particular, valgus extension overload during the throwing motion can precipitate a cascade of chronic injuries that can be debilitating for both casual and high-performance athletes. Prompt imaging evaluation facilitates accurate diagnosis and appropriate targeted interventions.

Risk factors and outcome of stroke in renal transplant recipients.

Stroke incidence is high in end-stage renal disease, and risk factors differ between the dialysis and general populations. However, risk factors and outcomes following renal transplantation remain unclear. We analyzed all adult patients with a functioning renal transplant from 01/01/2007 to 12/31/2012. Data were extracted from the electronic patient record. Variables associated with stroke were identified by survival analyses; demographic, clinical, and imaging and laboratory variables were assessed and case fatality determined. Follow-up was until 05/12/2013. A total of 956 patients were identified (median age 40.1 years, 59.9% male). Atrial fibrillation (AF) prevalence was 9.2%, and 38.2% received a transplant during follow-up. A total of 26 (2.7%) experienced a stroke during 4409 patient-years of follow-up (84.6% ischemic). Stroke incidence was 5.96/1000 patient-years. Factors associated with stroke on regression analysis were prior stroke, diabetes, age, systolic hypertension, and hemoglobin. Atrial fibrillation was associated with time to stroke (P<0.001). Warfarin did not associate with ischemic stroke risk in those with AF. Fatality was 19.2% at 7, 23.1% at 28, and 42.3% at 365 days after stroke. Patients with a functioning renal transplant have a high stroke incidence and case fatality. Unlike those on hemodialysis, risk factors are similar to the general population. We did not demonstrate benefit from warfarin use in those with AF.