Knee adduction moments are not increased in obese knee osteoarthritis patients during stair negotiation

Background: Negotiating stairs is an important activity of daily living that is also associated with large loads on the knee joint. In medial compartment knee osteoarthritis, the knee adduction moment during level walking is considered a marker for disease severity. It could be argued that the discriminative capability of this parameter is even better if tested in a strenuous stair negotiation task. Research question: What is the relation with knee osteoarthritis on the knee adduction moment during the stance phase of both stair ascent and descent in patients with and without obesity? Methods: This case control study included 22 lean controls, 16 lean knee osteoarthritis patients, and 14 obese knee osteoarthritis patients. All subjects ascended and descended a two-step staircase at a self-selected, comfortable speed. Three-dimensional motion analysis was performed to evaluate the knee adduction moment during stair negotiation. Results: Obese knee osteoarthritis patients show a prolonged stance time together with a more flattened knee adduction moment curve during stair ascent. Normalized knee adduction moment impulse, as well as the first and second peaks were not different between groups. During stair descent, a similar increase in stance time was found for both osteoarthritis groups. Significance: The absence of a significant effect of groups on the normalized knee adduction moment during stair negotiation may be explained by a lower ambulatory speed in the obese knee osteoarthritis group, that effectively lowers vertical ground reaction force. Decreasing ambulatory speed may be an effective strategy to lower knee adduction moment during stair negotiation

Diagnosis of diffuse idiopathic skeletal hyperostosis with chest computed tomography:inter-observer agreement

To evaluate and improve the interobserver agreement for the CT-based diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Six hundred participants of the CT arm of a lung cancer screening trial were randomly divided into two groups. The first 300 CTs were scored by five observers for the presence of DISH based on the original Resnick criteria for radiographs. After analysis of the data a consensus meeting was organised and the criteria were slightly modified regarding the definition of 'contiguous', the definition of 'flowing ossifications' and the viewing plane and window level. Subsequently, the second set of 300 CTs was scored by the same observers. kappa >= 0.61 was considered good agreement. The 600 male participants were on average 63.5 (SD 5.3) years old and had smoked on average 38.0 pack-years. In the first round kappa values ranged from 0.32 to 0.74 and 7 out of 10 values were below 0.61. After the consensus meeting the interobserver agreement ranged from 0.51 to 0.86 and 3 out of 10 values were below 0.61. The agreement improved significantly. This is the first study that reports interobserver agreement for the diagnosis of DISH on chest CT, showing mostly good agreement for modified Resnick criteria. . DISH is diagnosed on fluoroscopic and radiographic examinations using Resnick criteria . Evaluation of DISH on chest CT was modestly reproducible with the Resnick criteria . A consensus meeting and Resnick criteria modification improved inter-rater reliability for DISH . Reproducible CT criteria for DISH aids research into this poorly understood entity

Transcription-coupled nucleotide excision repair is coordinated by ubiquitin and SUMO in response to ultraviolet irradiation

Cockayne Syndrome (CS) is a severe neurodegenerative and premature aging autosomal-recessive disease, caused by inherited defects in the CSA and CSB genes, leading to defects in transcription-coupled nucleotide excision repair (TC-NER) and consequently hypersensitivity to ultraviolet (UV) irradiation. TC-NER is initiated by lesion-stalled RNA polymerase II, which stabilizes the interaction with the SNF2/SWI2 ATPase CSB to facilitate recruitment of the CSA E3 Cullin ubiquitin ligase complex. However, the precise biochemical connections between CSA and CSB are unknown. The small ubiquitin-like modifier SUMO is important in the DNA damage response. We found that CSB, among an extensive set of other target proteins, is the most dynamically SUMOylated substrate in response to UV irradiation. Inhibiting SUMOylation reduced the accumulation of CSB at local sites of UV irradiation and reduced recovery of RNA synthesis. Interestingly, CSA is required for the efficient clearance of SUMOylated CSB. However, subsequent proteomic analysis of CSA-dependent ubiquitinated substrates revealed that CSA does not ubiquitinate CSB in a UV-dependent manner. Surprisingly, we found that CSA is required for the ubiquitination of the largest subunit of RNA polymerase II, RPB1. Combined, our results indicate that the CSA, CSB, RNA polymerase II triad is coordinated by ubiquitin and SUMO in response to UV irradiation. Furthermore, our work provides a resource of SUMO targets regulated in response to UV or ionizing radiation

Using genomic repeats for phylogenomics: A case study in wild tomatoes (Solanum section Lycopersicon: Solanaceae)

High-throughput sequencing data have transformed molecular phylogenetics and a plethora of phylogenomic approaches are now readily available. Shotgun sequencing at low genome coverage is a common approach for isolating high-copy DNA, such as the plastid or mitochondrial genomes, and ribosomal DNA. These sequence data, however, are also rich in repetitive elements that are often discarded. Such data include a variety of repeats present throughout the nuclear genome in high copy number. It has recently been shown that the abundance of repetitive elements has phylogenetic signal and can be used as a continuous character to infer tree topologies. In the present study, we evaluate repetitive DNA data in tomatoes (Solanum section Lycopersicon) to explore how they perform at the inter- and intraspecific levels, utilizing the available data from the 100 Tomato Genome Sequencing Consortium. The results add to previous examples from angiosperms where genomic repeats have been used to resolve phylogenetic relationships at varying taxonomic levels. Future prospects now include the use of genomic repeats for population-level analyses and phylogeography, as well as potentially for DNA barcoding

Quantitative analysis of the anterolateral ossification mass in diffuse idiopathic skeletal hyperostosis of the thoracic spine

Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic condition leading to ossification of spinal ligaments and has been shown to behave similarly to ankylosing spondylitis (AS) often leading to unstable hyperextension fractures. Currently, no quantitative data are available on the spatial relationship between the bridging anterolateral ossification mass (ALOM) and the vertebral body/intervertebral disc to explain the propensity in DISH to fracture through the vertebral body instead of through the intervertebral disc as more often seen in AS. Furthermore, no reasonable explanation is available for the typical flowing wax morphology observed in DISH. In the current study, a quantitative analysis of computed tomography (CT) data from human cadaveric specimens with DISH was performed to better understand the newly formed osseous structures and fracture biomechanics. Additionally, the results were verified using computed tomography angiography data from ten patients with DISH and ten controls. Transverse CT images were analyzed to obtain ALOM area and centroid angle relative to the anteroposterior axis; intervertebral disc and adjacent cranial and caudal levels. The ALOM area at the mid-vertebral body level averaged 57.9 ± 50.0 mm2; at the mid-intervertebral disc space level it averaged 246.4 ± 95.9 mm2. The mean ALOM area at the adjacent level caudal to the mid-vertebral body level was 169.6 ± 81.3 mm2; at the adjacent cranial level, it was 161.7 ± 78.2 mm2. The main finding was the significant difference between mean ALOM area at the mid-vertebral body level and other three levels (p < 0.0001). The subsequent verification study showed the presence of vertebral segmental arteries at the mid-vertebral body level in nearly all images irrespective of the presence of DISH. A larger area of ALOM seemed associated with increased counter-clockwise rotation (away from the aorta) of the centroid relative to the anteroposterior axis. The results from the present study suggest a predisposition for fractures through the vertebral body and a role for the arterial system in the inhibition of soft tissue ossification

Costs Associated With Timely and Delayed Surgical Treatment of Spinal Metastases

Study Design: Retrospective cohort study. Objectives: Symptoms caused by spinal metastases are often difficult to distinguish from symptoms caused by non-malignant spinal disease, complicating timely diagnosis, referral and treatment. The ensuing delays may promote the risk of neurological deficits or severe mechanical instability and consequent emergency surgery, leading to poorer prognosis. Presumably, treatment delay may subsequently lead to more health-care consumption and therefore increased average costs of treatment. Methods: All patients surgically treated for spinal metastases were included in the current study. Based on the presence of alarming symptoms and urgency of the required intervention, patients were categorized as having received timely or delayed treatment. Pre-surgical, in-hospital, aftercare and total costs were analyzed and compared between the 2 groups. Results: In total, 299 patients were included, of which 205 underwent timely and 94 delayed treatment. There was no significant difference in pre-surigcal costs (€3.229,13 in the timely treated group vs. €2.528,70 in the delayed treatment group, p = 0.849). The in-hospital costs (€16.738,49 vs. €13.108,81, p < 0.001) and the aftercare costs (€13.950,37 vs. 3.981,93, p < 0.001) were significantly higher for delayed treatment vs. timely treatment, respectively. The total costs were €33.741,71 for delayed treatment and €20.318,52 for timely treatment (p < 0.001). Conclusions: The total costs for timely treated patients with spinal metastases are significantly lower compared with patients receiving delayed treatment. Investing in the optimization of referral patterns may therefore reduce the overall pretreatment delay and subsequently increase patient outcome, leading to better clinical outcomes at lower costs

DDA1, a novel factor in transcription-coupled repair, modulates CRL4CSA dynamics at DNA damage-stalled RNA polymerase II

Transcription-blocking DNA lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which removes a broad spectrum of DNA lesions to preserve transcriptional output and thereby cellular homeostasis to counteract aging. TC-NER is initiated by the stalling of RNA polymerase II at DNA lesions, which triggers the assembly of the TC-NER-specific proteins CSA, CSB and UVSSA. CSA, a WD40-repeat containing protein, is the substrate receptor subunit of a cullin-RING ubiquitin ligase complex composed of DDB1, CUL4A/B and RBX1 (CRL4CSA). Although ubiquitination of several TC-NER proteins by CRL4CSA has been reported, it is still unknown how this complex is regulated. To unravel the dynamic molecular interactions and the regulation of this complex, we applied a single-step protein-complex isolation coupled to mass spectrometry analysis and identified DDA1 as a CSA interacting protein. Cryo-EM analysis showed that DDA1 is an integral component of the CRL4CSA complex. Functional analysis revealed that DDA1 coordinates ubiquitination dynamics during TC-NER and is required for efficient turnover and progression of this process.<br/

Feasibility and reliability of PRISMA-Medical for specialty-based incident analysis

Aims and objectives: In this study, the feasibility and reliability of the Prevention Recovery Information System for Monitoring and Analysis (PRISMA)-Medical method for systematic, specialty-based analysis and classification of incidents in the neonatal intensive care unit (NICU) were determined. Methods: After the introduction of a Neonatology System for Analysis and Feedback on Medical Events (NEOSAFE) in eight tertiary care NICUs and one paediatric surgical ICU, PRISMA-Medical was started to be used to identify root causes of voluntary reported incidents by multidisciplinary unit patient safety committees. Committee members were PRISMA-trained and familiar with the department and its processes. In this study, the results of PRISMA-analysis of incidents reported during the first year are described. At t¿=¿3 months and t¿=¿12 months after introduction, test cases were performed to measure agreement at three levels of root cause classification using PRISMA-Medical. Inter-rater reliability was determined by calculating generalised ¿ values for each level of classification. Results: During the study period, 981 out of 1786 eligible incidents (55%) were analysed for underlying root causes. In total, 2313 root causes were identified and classified, giving an average of 2.4 root causes for every incident. Although substantial agreement (¿ 0.70–0.81) was reached at the main level of root cause classification of the test cases (discrimination between technical, organisational and human failure) and agreement among the committees at the second level (discrimination between skill-based, rule-based and knowledge-based errors) was acceptable (¿ 0.53–0.59), discrimination between rule-based errors (the third level of classification) was more difficult to assess (¿ 0.40–0.47). Conclusion: With some restraints, PRISMA-Medical proves to be both feasible and acceptably reliable to identify and classify multiple causes of medical events in the NICU