Colchicine promotes atherosclerotic plaque stability independently of inflammation.

Atherosclerosis is a chronic inflammatory disease which is driven in part by the aberrant trans -differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects. Using SMC fate mapping in an advanced atherosclerotic lesion model, colchicine induced plaque regression by converting pathogenic SMC-derived macrophage-like and osteoblast-like cells into protective myofibroblast-like cells which thickened, and thereby stabilized, the fibrous cap. This was dependent on Notch3 signaling in SMC-derived plaque cells. These findings may help explain the success of colchicine in clinical trials relative to other anti-inflammatory drugs. Thus, we demonstrate the potential of regulating SMC phenotype in advanced plaque regression through Notch3 signaling, in addition to the canonical anti-inflammatory actions of drugs to treat atherosclerosis.

New Targets in Atherosclerosis: Vascular Smooth Muscle Cell Plasticity and Macrophage Polarity.

PURPOSE: Despite an increase in treatment options, and substantial reductions in cardiovascular mortality over the past half-century, atherosclerosis remains the most prevalent cause of premature mortality worldwide. The development of innovative new therapies is crucial to further minimize atherosclerosis-related deaths. The diverse array of cell phenotypes derived from vascular smooth muscle cells (SMCs) and macrophages within atherosclerotic plaques are increasingly becoming recognized for their beneficial and detrimental roles in plaque stability and disease burden. This review explores how contemporary transcriptomics and fate-mapping studies have revealed vascular cell plasticity as a relatively unexplored target for therapeutic intervention. METHODS: Recent literature for this narrative review was obtained by searching electronic databases (ie, Google Scholar, PubMed). Additional studies were sourced from reference lists and the authors' personal databases. FINDINGS: The lipid-rich and inflammatory plaque milieu induces SMC phenotypic switching to both beneficial and detrimental phenotypes. Likewise, macrophage heterogeneity increases with disease burden to a variety of pro-inflammatory and anti-inflammatory activation states. These vascular cell phenotypes are determinants of plaque structure stability, and it is therefore highly likely that they influence clinical outcomes. Development of clinical treatments targeting deleterious phenotypes or promoting pro-healing phenotypes remains in its infancy. However, existing treatments (statins) have shown beneficial effects toward macrophage polarization, providing a rationale for more targeted approaches. In contrast, beneficial SMC phenotypic modulation with these pharmacologic agents has yet to be achieved. The range of modulated vascular cell phenotypes provides a multitude of novel targets and the potential to reduce future adverse events. IMPLICATIONS: Vascular cell phenotypic heterogeneity must continue to be explored to lower cardiovascular events in the future. The rapidly increasing weight of evidence surrounding the role of SMC plasticity and macrophage polarity in plaque vulnerability provides a strong foundation upon which development of new therapeutics must follow. This approach may prove to be crucial in reducing cardiovascular events and improving patient benefit in the future.

Predictors of poor outcome following lumbar spinal fusion surgery: a prospective observational study to derive two clinical prediction rules using British Spine Registry data.

PURPOSE: Lumbar spinal fusion surgery (LSFS) is common for lumbar degenerative disorders. The objective was to develop clinical prediction rules to identify which patients are likely to have a favourable outcome to inform decisions regarding surgery and rehabilitation. METHODS: A prospective observational study recruited 600 (derivation) and 600 (internal validation) consecutive adult patients undergoing LSFS for degenerative lumbar disorder through the British Spine Registry. Definition of good outcome (6 weeks, 12 months) was reduction in pain intensity (Numerical Rating Scale, 0-10) and disability (Oswestry Disability Index, ODI 0-50) > 1.7 and 14.3, respectively. Linear and logistic regression models were fitted and regression coefficients, Odds ratios and 95% CIs reported. RESULTS: Lower BMI, higher ODI and higher leg pain pre-operatively were predictive of good disability outcome, higher back pain was predictive of good back pain outcome, and no previous surgery and higher leg pain were predictive of good leg pain outcome; all at 6 weeks. Working and higher leg pain were predictive of good ODI and leg pain outcomes, higher back pain was predictive of good back pain outcome, and higher leg pain was predictive of good leg pain outcome at 12 months. Model performance demonstrated reasonable to good calibration and adequate/very good discrimination. CONCLUSIONS: BMI, ODI, leg and back pain and previous surgery are important considerations pre-operatively to inform decisions for surgery. Pre-operative leg and back pain and work status are important considerations to inform decisions for management following surgery. Findings may inform clinical decision making regarding LSFS and associated rehabilitation.

Identification of Intervention Opportunities through Assessment of the Appropriateness of Antibiotic Prescribing in Surgical Patients in a UK Hospital Using a National Audit Tool: A Single Centre Retrospective Audit.

Identifying opportunities to safely reduce antibiotic prescribing is necessary for prescribers and antibiotic stewardship teams to minimise unwarranted antibiotic use. We aimed to quantify excess antibiotic use in General Surgery. We retrospectively audited the antibiotic prescribing for patients discharged from the General Surgery specialty in an acute hospital in the south-west of England for one month using an audit tool developed by Public Health England. The appropriateness of prescribing was determined for each patient at three antibiotic decision time-points: at initiation, the pre-72-hour antibiotic review, and treatment duration. Two infection specialists and a general surgeon reviewed each patient. Indication and excess days of therapy (DOTs) were calculated at each decision time-point and expressed as a proportion of total DOTs. Eighty-six patients were prescribed 1162 DOTs; 192 (16.5%) excess DOTs were prescribed in 38 patients (44%), with zero excess days identified in the remaining 48 patients (56%). Seventy-five of 192 (39%) excess DOTs occurred at initiation; 55/192 (29%) after the pre-72-hour antibiotic review; and 62/192 (32%) due to protracted antibiotic courses. There was concordance between the general surgeon and infection specialist for most apportioned excess DOTs. However, the surgeon apportioned fewer excess DOTs 160/1162 (13.8%). Overall IV antibiotics accounted for 53.4% of total DOTs. Seventy-two of 86 (83.7%) patients received 620 intravenous DOTs; of these, 79 (12.7%) IV DOTS were unnecessary. We have identified excess antibiotic prescribing in General surgery with comparable excess DOTs at all three time-points.

Metabotropic Glutamate Receptors Modulate Exocytotic Tau Release and Propagation.

Using synaptosomes purified from the brains of two transgenic mouse models overexpressing mutated human tau (TgP301S and Tg4510) and brains of patients with sporadic Alzheimer's disease, we showed that aggregated and hyperphosphorylated tau was both present in purified synaptosomes and released in a calcium- and synaptosome-associated protein of 25 kDa (SNAP25)-dependent manner. In all mouse and human synaptosomal preparations, tau release was inhibited by the selective metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268, an effect prevented by the selective mGlu2/3 antagonist LY341495. LY379268 was also able to block pathologic tau propagation between primary neurons in an in vitro microfluidic cellular model. These novel results are transformational for our understanding of the molecular mechanisms mediating tau release and propagation at synaptic terminals in Alzheimer's disease and suggest that these processes could be inhibited therapeutically by the selective activation of presynaptic G protein-coupled receptors. SIGNIFICANCE STATEMENT: Pathological tau release and propagation are key neuropathological events underlying cognitive decline in Alzheimer's disease patients. This paper describes the role of regulated exocytosis, and the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) protein SNAP25, in mediating tau release from rodent and human synaptosomes. This paper also shows that a selective mGluR2/3 agonist is highly effective in blocking tau release from synaptosomes and tau propagation between neurons, opening the way to the discovery of novel therapeutic approaches to this devastating disease.

Dynamic Radiographs in Assessing Stability of Cervical Spine Fractures: A Multicentre Study.

BACKGROUND: In the management of a trauma patient with cervical spine injury, the need for accurate diagnostic imaging is key to ensure correct management. Different classification systems have been developed including the Subaxial Injury Classification (SLIC) system and AO cervical spine fracture classification. Through a multicentre study, we have identified a group of cases where the use of CT alone to classify fractures by either SLIC or AO score may be deficient and the use of dynamic cervical spine radiographs could help identify instability. METHODS: Three level 1 trauma centers retrospectively reviewed patients with cervical spine injuries. Cervical spine radiographs (AP and lateral) were undertaken in collar, in all patients with suspected cervical spine injury within 2 weeks, followed by reanalysis of scoring systems. RESULTS: Eleven cases were identified in total, and 72% were male with a mean age of 65 years, with approximately 54% being older than 70 years. All patients reported their pain as severe using the Visual Analogue Scale scale. The predynamic radiograph mean SLIC score was 0.73, which is in contrast to the postdynamic radiograph mean SLIC score of 6. The statistical significance (P = 0.004) was found using the Wilcoxon signed-rank test. CONCLUSION: Supine imaging eliminates the gravitational loads normally exerted on the c-spine. The cases show assumed cervical stability based on CT, but dynamic c-spine radiographs subsequently demonstrated instability. Therefore, we suggest a combination of SLIC and AO classification using radiologic imaging to classify fracture and correlate clinical symptoms with persistent neck pain, which warrants a Miami-J collar and dynamic c-spine radiograph to assess stability with re-evaluation of scoring.

A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G>T at the intron 9/exon 10 of the MAPT gene.

We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3' splice site.

Developing electronic learning to deliver MR safety training in a radiotherapy department.

INTRODUCTION/BACKGROUND: Magnetic Resonance Imaging (MRI) is used in radiotherapy planning, and increasingly in on-treatment guidance. The potential for the MR environment to be hazardous, without stringent safe working practices, is real. Guidance suggests all workers in MRI undergo annual safety training. To facilitate a tangible MR safety program, an electronic learning module was created and evaluated. METHODS: An existing presentation, normally delivered face-to-face, was modified and questions added to test knowledge. The module was delivered and feedback collected, together with answers to the questions, over three phases to ensure deliverability, clarity, and robustness. These comprised an initial pilot phase for non-MR personnel, an evaluation phase for staff renewing annual MR safety training, and finally for new therapeutic radiographer graduates, a test-retest methodology. RESULTS: Seven participants took part in the initial pilot phase, followed by thirty-one in the evaluation phase. Participants included radiographers (therapeutic and diagnostic), play specialists, clinical oncologists and anaesthetists, physicists and nursing staff. Within the evaluation group, 74.2% achieved a score >80%. Incorrect responses were principally related to questions regarding expected levels of responsibility and working practices, rather than the physics of high magnetic field strengths. The test-retest phase (n = 5) followed. Mean scores prior to learning were 59%, improving to 79% following learning, with the weakest sections mirroring those highlighted within the evaluation phase. DISCUSSION: Transferring MR safety training into an electronic format has provided a standardised, tangible tool that provides evidence of compliance with recommended guidance. CONCLUSIONS: This work illustrates the transition of MR safety learning for radiotherapy staff from passive presentation, to an interactive teaching methodology. The e-learning module has now been implemented within the department.

Magnet Fracture within a Magnetically Controlled Growing Rod: A Case Report of a New Mechanism of Failure.

INTRODUCTION: Magnetically controlled growing rods (MCGRs) have been widely adopted in the management of early-onset scoliosis since they were first described in 2012. Recent reports have highlighted concerns around their safety. To date, little is understood about the risk factors and modes of failure in these devices. CASE REPORT: We report a novel mechanism of device failure in a 14-year-old patient following multiple revisions of MCGRs.Clinically, there was no evidence of device failure and the MCGRs appeared radiologically intact. Explantation analysis revealed multiple compromised/non-functional components. A previously undocumented phenomenon of complete magnet fracture was also seen. CONCLUSION: The absence of clinical or radiological features of device failure in this case makes the findings of great concern. Given the relative paucity of high-quality evidence surrounding the use of MCGRs, we support calls for urgent comparative studies and further investigation of risk factors for device failure.

Quantitative propagation of assembled human Tau from Alzheimer's disease brain in microfluidic neuronal cultures.

Tau aggregation and hyperphosphorylation is a key neuropathological hallmark of Alzheimer's disease (AD), and the temporospatial spread of Tau observed during clinical manifestation suggests that Tau pathology may spread along the axonal network and propagate between synaptically connected neurons. Here, we have developed a cellular model that allows the study of human AD-derived Tau propagation from neuron to neuron using microfluidic devices. We show by using high-content imaging techniques and an in-house developed interactive computer program that human AD-derived Tau seeds rodent Tau that propagates trans-neuronally in a quantifiable manner in a microfluidic culture model. Moreover, we were able to convert this model to a medium-throughput format allowing the user to handle 16 two-chamber devices simultaneously in the footprint of a standard 96-well plate. Furthermore, we show that a small molecule inhibitor of aggregation can block the trans-neuronal transfer of Tau aggregates, suggesting that the system can be used to evaluate mechanisms of Tau transfer and find therapeutic interventions.

Imbalance in the response of pre- and post-synaptic components to amyloidopathy.

Alzheimer's disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid ß (Aß) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aß plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aß plaques grow faster in the earlier stages of the disease and if their initial area is >500 µm2; this may be due to deposition occurring in the outer regions of the plaque, the plaque cloud. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre- but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.

Development and validation of two clinical prediction models to inform clinical decision-making for lumbar spinal fusion surgery for degenerative disorders and rehabilitation following surgery: protocol for a prospective observational study.

INTRODUCTION: Potential predictors of poor outcome will be measured at baseline: (1) preoperatively to develop a clinical prediction model to predict which patients are likely to have favourable outcome following lumbar spinal fusion surgery (LSFS) and (2) postoperatively to predict which patients are likely to have favourable long-term outcomes (to inform rehabilitation). METHODS AND ANALYSIS: Prospective observational study with a defined episode inception of the point of surgery. Electronic data will be collected through the British Spine Registry and will include patient-reported outcome measures (eg, Fear-Avoidance Beliefs Questionnaire) and data items (eg, smoking status). Consecutive patients (≥18 years) undergoing LSFS for back and/or leg pain of degenerative cause will be recruited. EXCLUSION CRITERIA: LSFS for spinal fracture, inflammatory disease, malignancy, infection, deformity and revision surgery. 1000 participants will be recruited (n=600 prediction model development, n=400 internal validation derived model; planning 10 events per candidate prognostic factor). The outcome being predicted is an individual's absolute risk of poor outcome (disability and pain) at 6 weeks (objective 1) and 12 months postsurgery (objective 2). Disability and pain will be measured using the Oswestry Disability Index (ODI), and severity of pain in the previous week with a Numerical Rating Scale (NRS 0-10), respectively. Good outcome is defined as a change of 1.7 on the NRS for pain, and a change of 14.3 on the ODI. Both linear and logistic (to dichotomise outcome into low and high risk) multivariable regression models will be fitted and mean differences or ORs for each candidate predictive factor reported. Internal validation of the derived model will use a further set of British Spine Registry data. External validation will be geographical using two spinal registries in The Netherlands and Switzerland. ETHICS AND DISSEMINATION: Ethical approval (University of Birmingham ERN_17-0446A). Dissemination through peer-reviewed journals and conferences.

Alzheimer's Disease-Related Dementias Summit 2016: National research priorities.

Goal 1 of the National Plan to Address Alzheimer's Disease is to prevent and effectively treat Alzheimer disease and Alzheimer disease-related dementias by 2025. To help inform the research agenda toward achieving this goal, the NIH hosts periodic summits that set and refine relevant research priorities for the subsequent 5 to 10 years. This proceedings article summarizes the 2016 Alzheimer's Disease-Related Dementias Summit, including discussion of scientific progress, challenges, and opportunities in major areas of dementia research, including mixed-etiology dementias, Lewy body dementia, frontotemporal degeneration, vascular contributions to cognitive impairment and dementia, dementia disparities, and dementia nomenclature.

Incomplete cauda equina syndrome secondary to haemorrhage within a Tarlov cyst.

Sacral perineural (Tarlov) cysts are benign, cerebrospinal fluid containing lesions of the spinal nerve root sheath. They are usually asymptomatic; however, a small proportion have the potential to cause compression of nerve roots and/or the cauda equina.We report a case of a 61-year-old man who presented with acute onset back pain associated with bilateral radiculopathy. Between referral and consultation, the patient developed urinary dysfunction which resolved spontaneously.MRI revealed haemorrhage within a Tarlov cyst, resulting in compression of the cauda equina. Due to the considerable clinical improvement at the time of consultation, surgical decompression of the cyst was not considered to be indicated.An interval MRI scan 8 weeks later demonstrated that the haemorrhage within the perineural cyst had spontaneously resolved and the patient remained asymptomatic at 5-year follow-up.

Altered Synapse Stability in the Early Stages of Tauopathy.

Synapse loss is a key feature of dementia, but it is unclear whether synaptic dysfunction precedes degenerative phases of the disease. Here, we show that even before any decrease in synapse density, there is abnormal turnover of cortical axonal boutons and dendritic spines in a mouse model of tauopathy-associated dementia. Strikingly, tauopathy drives a mismatch in synapse turnover; postsynaptic spines turn over more rapidly, whereas presynaptic boutons are stabilized. This imbalance between pre- and post-synaptic stability coincides with reduced synaptically driven neuronal activity in pre-degenerative stages of the disease.

Recommendations for Lengthening of Magnetically Controlled Growing Rods in Children With Pacemakers.

PURPOSE OF THE STUDY: Pacemakers are currently identified as a contraindication for the use of magnetic growth rods (MGRs). This arises from concern that magnetic fields generated by the MGR external remote controller (ERC) during lengthening procedures may induce pacemaker dysfunction. We investigated (1) whether MGR lengthening affects pacemaker function, and (2) if the magnetic field of a pacemaker affects MGR lengthening. METHODS: MGRs were tested in conjunction with an magnetic resonance imaging-compatible pacemaker, which was connected to a virtual patient under continuous cardiac monitoring. To determine whether pacemaker function was affected during MGR lengthening, the electrocardiogram trace was monitored for arrhythmias, whereas an ERC was applied to lengthen the MGRs at varying distances from the pacemaker. To investigate if MGR lengthening was affected by the presence of a pacemaker, at the start and end of the experiment, the ability of the rods to fully elongate and shorten was tested to check for conservation of function. RESULTS: When the pacemaker was in normal mode, <16 cm away from the activated ERC during MGR lengthening, pacemaker function was affected by the ERC's magnetic forces. At this distance, prophylactically switching the pacemaker to tonic mode before lengthening prevented occurrence of inappropriate pacing discharges. No deleterious effect of the pacemaker's magnetic field on the MGR lengthening mechanism was identified. CONCLUSIONS: Magnetic resonance imaging-compatible pacemakers appear safe for concomitant use with MGRs, provided a pacemaker technician prophylactically switches the pacemaker to tonic function before outpatient lengthening procedures. CLINICAL RELEVANCE: This experiment was designed to provide the first safety information on MGR lengthening in children with pacemakers. Although currently a rare clinical scenario, with increasing use of MGRs, this clinical scenario may arise more frequently in the future.

Structure guided design of a series of selective pyrrolopyrimidinone MARK inhibitors.

The initial structure activity relationships around an isoindoline uHTS hit will be described. Information gleaned from ligand co-crystal structures allowed for rapid refinements in both MARK potency and kinase selectivity. These efforts allowed for the identification of a compound with properties suitable for use as an in vitro tool compound for validation studies on MARK as a viable target for Alzheimer's disease.

MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation.

Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.

Influence of Chronic Heat Acclimatization on Occupational Thermal Strain in Tropical Field Conditions.

OBJECTIVE: To examine whether non-heat acclimatized (NHA) emergency responders endure greater physiological and perceptual strain than heat acclimatized (HA) counterparts in tropical field settings. METHODS: Eight HA and eight NHA men urban search and rescue personnel had physiological and perceptual responses compared during the initial 4 hours shift of a simulated disaster in tropical conditions (ambient temperature 34.0 °C, 48% relative humidity, wet bulb globe temperature [WBGT] 31.4 °C). RESULTS: From the 90th minute through to end of shift, HA (38.5 °C) sustained a significantly higher gastrointestinal temperature than NHA (38.1 °C) (mean difference 0.4 ±â€Š0.2 °C, 95% confidence interval [CI] 0.2 to 0.7 °C, P = 0.005) despite comparable heart rate (P = 0.30), respiratory rate (P = 0.88), and axilla skin temperature (P = 0.47). Overall, perception of body temperature was similar between cohorts (P = 0.87). CONCLUSIONS: The apparent tolerance of greater physiological strain by HA responders occurred in the absence of perceptual differences.