An Evaluation of passive recumbent quantitative fluoroscopy to measure mid-lumber intervertebral motion in patients with chronic non-specific low back pain and healthy volunteers.

Introduction: The biomechanical model of back pain has failed to find distinct relationships between intervertebral movement and pain due to limitations and variation in methods, and errors in measurement. Quantitative fluoroscopy (QF) reduces variation and error and measures dynamic intervertebral motion in vivo. This thesis used recumbent QF to examine continuous mid-lumbar intervertebral motion (L2 to L5) in patients with assumed mechanical chronic non-specific low back pain (CNSLBP) that had been clinically diagnosed. It aimed to develop kinematic parameters from the continuous data and determine whether these could detect subtle mechanical differences by comparing this to data obtained from healthy volunteers. Methods: This was a prospective cross sectional study. Forty patients with CNSLBP (age 21 to 51 years), and 40 healthy volunteers matched for gender, age and body mass index underwent passive recumbent QF in the coronal and sagittal planes. The patient group completed questionnaires for pain and disability. Four kinematic parameters were developed and compared for differences and diagnostic accuracy. Reference intervals were developed for three of the parameters and reproducibility of two were assessed. The radiation dose was compared to lumbar spine radiographs and diagnostic reference levels were established. Finally, relationships between patient’s pain and disability and one of the kinematic parameters (continuous proportional motion CPM) were explored. Results: Reproducibility was high. There were some differences in the coronal plane and flexion for each kinematic parameter, but no consistency across segments and none had high diagnostic accuracy. Radiation dose for QF is of the same magnitude as radiographs, and there were no associations between patient characteristics of pain and disability and CPM. Conclusion: Although the kinematic differences were weak, they indicate that biomechanics may be partly responsible for clinically diagnosed mechanical CNSLBP, but this is not detectable by any one kinematic parameter. It is likely that other factors such as loading, central sensitisation and motor control may also be responsible for back pain that is considered mechanical. QF is easily adapted to clinical practice and is recommended to replace functional radiography, but further work is needed to determine which kinematic parameters are clinically useful

Aberrant intervertebral motion in patients with treatment‑resistant nonspecific low back pain: a retrospective cohort study and control comparison

Purpose Intervertebral kinematic assessments have been used to investigate mechanical causes when back pain is resistant to treatment, and recent studies have identified intervertebral motion markers that discriminate patients from controls. However, such patients are a heterogeneous group, some of whom have structural disruption, but the effects of this on intervertebral kinematics are unknown.Methods Thirty-seven patients with treatment-resistant back pain referred for quantitative fluoroscopy were matched to an equal number of pain-free controls for age and sex. All received passive recumbent flexion assessments for intervertebral motion sharing inequality (MSI), variability (MSV), laxity and translation. Comparisons were made between patient sub-groups, between patients and controls and against normative levels from a separate group of controls.Results Eleven patients had had surgical or interventional procedures, and ten had spondylolisthesis or pars defects. Sixteen had no disruption. Patients had significantly higher median MSI values (0.30) than controls (0.27, p = 0.010), but not MSV (patients 0.08 vs controls 0.08, p = 0.791). Patients who received invasive procedures had higher median MSI values (0.37) than those with bony defects (0.30, p = 0.018) or no disruption (0.28, p = 0.0007). Laxity and translation above reference limits were not more prevalent in patients.Conclusion Patients with treatment-resistant nonspecific back pain have greater MSI values than controls, especially if the former have received spinal surgery. However, excessive laxity, translation and MSV are not more prevalent in these patients. Thus, MSI should be investigated as a pain mechanism and for its possible value as a prognostic factor and/or target for treatment in larger patient populations

Measurement of Intervertebral Motion Using Quantitative Fluoroscopy: Report of an International Forum and Proposal for Use in the Assessment of Degenerative Disc Disease in the Lumbar Spine

Quantitative fluoroscopy (QF) is an emerging technology for measuring intervertebral motion patterns to investigate problem back pain and degenerative disc disease. This International Forum was a networking event of three research groups (UK, US, Hong Kong), over three days in San Francisco in August 2009. Its aim was to reach a consensus on how best to record, analyse, and communicate QF information for research and clinical purposes. The Forum recommended that images should be acquired during regular trunk motion that is controlled for velocity and range, in order to minimise externally imposed variability as well as to correlate intervertebral motion with trunk motion. This should be done in both the recumbent passive and weight bearing active patient configurations. The main recommended outputs from QF were the true ranges of intervertebral rotation and translation, neutral zone laxity and the consistency of shape of the motion patterns. The main clinical research priority should initially be to investigate the possibility of mechanical subgroups of patients with chronic, nonspecific low back pain by comparing their intervertebral motion patterns with those of matched healthy controls

Repressive and non-repressive chromatin at native telomeres in Saccharomyces cerevisiae

<p>Abstract</p> <p>Background</p> <p>In <it>Saccharomyces cerevisiae </it>genes that are located close to a telomere can become transcriptionally repressed by an epigenetic process known as telomere position effect. There is large variation in the level of the telomere position effect among telomeres, with many native ends exhibiting little repression.</p> <p>Results</p> <p>Chromatin analysis, using microccocal nuclease and indirect end labelling, reveals distinct patterns for ends with different silencing states. Differences were observed in the promoter accessibility of a subtelomeric reporter gene and a characteristic array of phased nucleosomes was observed on the centromere proximal side of core X at a repressive end. The silent information regulator proteins 2 - 4, the yKu heterodimer and the subtelomeric core X element are all required for the maintenance of the chromatin structure of repressive ends. However, gene deletions of particular histone modification proteins can eliminate the silencing without the disruption of this chromatin structure.</p> <p>Conclusion</p> <p>Our data identifies chromatin features that correlate with the silencing state and indicate that an array of phased nucleosomes is not sufficient for full repression.</p

Proportional lumbar spine inter-vertebral motion patterns: a comparison of patients with chronic, non-specific low back pain and healthy controls

Introduction: Identifying biomechanical subgroups in chronic, non-specific low back pain (CNSLBP) populations from inter-vertebral displacements has proven elusive. Quantitative fluoroscopy (QF) has excellent repeatability and provides continuous standardised inter-vertebral kinematic data from fluoroscopic sequences allowing assessment of mid-range motion. The aim of this study was to determine whether proportional continuous IV rotational patterns were different in patients and controls. A secondary aim was to update the repeatability of QF measurement of range of motion (RoM) for inter-vertebral (IV) rotation

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

An objective spinal motion imaging assessment (OSMIA): reliability, accuracy and exposure data

BACKGROUND: Minimally-invasive measurement of continuous inter-vertebral motion in clinical settings is difficult to achieve. This paper describes the reliability, validity and radiation exposure levels in a new Objective Spinal Motion Imaging Assessment system (OSMIA) based on low-dose fluoroscopy and image processing. METHODS: Fluoroscopic sequences in coronal and sagittal planes were obtained from 2 calibration models using dry lumbar vertebrae, plus the lumbar spines of 30 asymptomatic volunteers. Calibration model 1 (mobile) was screened upright, in 7 inter-vertebral positions. The volunteers and calibration model 2 (fixed) were screened on a motorised table comprising 2 horizontal sections, one of which moved through 80 degrees. Model 2 was screened during motion 5 times and the L2-S1 levels of the volunteers twice. Images were digitised at 5fps. Inter-vertebral motion from model 1 was compared to its pre-settings to investigate accuracy. For volunteers and model 2, the first digitised image in each sequence was marked with templates. Vertebrae were tracked throughout the motion using automated frame-to-frame registration. For each frame, vertebral angles were subtracted giving inter-vertebral motion graphs. Volunteer data were acquired twice on the same day and analysed by two blinded observers. The root-mean-square (RMS) differences between paired data were used as the measure of reliability. RESULTS: RMS difference between reference and computed inter-vertebral angles in model 1 was 0.32 degrees for side-bending and 0.52 degrees for flexion-extension. For model 2, X-ray positioning contributed more to the variance of range measurement than did automated registration. For volunteer image sequences, RMS inter-observer variation in intervertebral motion range in the coronal plane was 1.86 degreesand intra-subject biological variation was between 2.75 degrees and 2.91 degrees. RMS inter-observer variation in the sagittal plane was 1.94 degrees. Radiation dosages in each view were below the levels recommended for a plain film. CONCLUSION: OSMIA can measure inter-vertebral angular motion patterns in routine clinical settings if modern image intensifier systems are used. It requires skilful radiography to achieve optimal positioning and dose limitation. Reliability in individual subjects can be judged from the variance of their averaged inter-vertebral angles and by observing automated image registration

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice