The role of cranial and thoracic EMG within diagnostic criteria for ALS.

INTRODUCTION: The contribution of cranial and thoracic region electromyography (EMG) to diagnostic criteria for amyotrophic lateral sclerosis (ALS) has not been evaluated. METHODS: Clinical and EMG data from each craniospinal region were retrospectively assessed in 470 patients; 214 had ALS. Changes to diagnostic classification in Awaji-Shima and revised El Escorial criteria following withdrawal of cranial/thoracic EMG data were ascertained. RESULTS: Sensitivity for lower motor neuron involvement in ALS was highest in cervical/lumbar regions; specificity was highest in cranial/thoracic regions. Cranial EMG contributed to definite/probable Awaji-Shima categorization in 1.4% of patients. Thoracic EMG made no contribution. For revised El Escorial criteria, cranial and thoracic data reclassified 1% and 5% of patients, respectively. CONCLUSION: Cranial EMG data make small contributions to both criteria, thoracic data contribute only to the revised El Escorial criteria. However, cranial and thoracic region abnormalities are specific in ALS. Consideration should be given to allowing greater diagnostic contribution from thoracic EMG

Individual surgeon mortality rates: can outliers be detected? A national utility analysis

Objectives: There is controversy on the proposed benefits of publishing mortality rates for individual surgeons. In some procedures, analysis at the level of an individual surgeon may lack statistical power. The aim was to determine the likelihood that variation in surgeon performance will be detected using published outcome data. Design: A national analysis surgeon-level mortality rates to calculate the level of power for the reported mortality rate across multiple surgical procedures. Setting: The UK from 2010 to 2014. Participants: Surgeons who performed colon cancer resection, oesophagectomy or gastrectomy, elective aortic aneurysm repair, hip replacement, bariatric surgery or thyroidectomy. Outcomes: The likelihood of detecting an individual with a 30-day, 90-day or in-patient mortality rate of up to 5 times the national mean or median (as available). This was represented using a novel heat-map approach. Results: Overall mortality rates for the procedures ranged from 0.07% to 4.5% and mean/median surgeon volume was between 23 and 75 cases. The national median case volume for colorectal (n=55) and upper gastrointestinal (n=23) cancer resections provides around 20% power to detect a mortality rate of 3 times the national median, while, for hip replacement, this is a rate 5 times the national average. At the mortality rates reported for thyroid (0.08%) and bariatric (0.07%) procedures, it is unlikely a surgeon would perform a sufficient number of procedures in his/her entire career to stand a good chance of detecting a mortality rate 5 times the national average. Conclusions: At present, surgeons with increased mortality rates are unlikely to be detected. Performance within an expected mortality rate range cannot be considered reliable evidence of acceptable performance. Alternative approaches should focus on commonly occurring meaningful outcome measures, with infrequent events analysed predominately at the hospital level

Further support for thermal ecosystem engineering by wandering albatross

On sub-Antarctic Marion Island, wandering albatross (Diomedea exulans) nests support high abundances of tineid moth, Pringleophaga marioni, caterpillars. Previous work proposed that the birds serve as thermal ecosystem engineers by elevating nest temperatures relative to ambient, thereby promoting growth and survival of the caterpillars. However, only 17 days of temperature data were presented previously, despite year-long nest occupation by birds. Previous sampling was also restricted to old and recently failed nests, though nests from which chicks have recently fledged are key to understanding how the engineering effect is realized. Here we build on previous work by providing nest temperature data for a full year and by sampling all three nest types. For the full duration of nest occupancy, temperatures within occupied nests are significantly higher, consistently by c. 7°C, than those in surrounding soils and abandoned nests, declining noticeably when chicks fledge. Caterpillar abundance is significantly higher in new nests compared to nests from which chicks have fledged, which in turn have higher caterpillar abundances than old nests. Combined with recent information on the life history of P. marioni, our data suggest that caterpillars are incidentally added to the nests during nest construction, and subsequently benefit from an engineering effect

A self-optimised approach to synthesising DEHiBA for advanced nuclear reprocessing, exploiting the power of machine-learning

In an effort to advance the development of hydrometallurgical reprocessing of used nuclear fuel across the globe, this work sets out to explore and identify an optimised, cost effective pathway to synthesise the ligand DEHiBA (N,N-di-(2-ethylhexyl)isobutyramide). Currently, very few chemical suppliers stock and distribute this specialist ligand, designed for selective uranium chelation and extraction from nuclear fuel. The current high cost of DEHiBA therefore restricts access to essential large-scale testing of this promising ligand designed to advance nuclear reprocessing. This work utilises an automated flow reactor platform for the efficient optimisation of four synthetic routes to DEHiBA. These optimisations focus on optimising cost, reagent efficiency, yield, and productivity target functions by exploiting the power of machine-learning algorithms for rapid process development. Ultimately, we have identified an efficient and cost-effective solvent-free route to DEHiBA from isobutyric anhydride and di-2-ethylhexylamine for 99%, at a purity of 76%, and a process mass intensity of 1.29 g g−1, whilst alternative conditions demonstrated productivities >75 kg L−1 h−1, all whilst maintaining a high level of process control with outlet temperatures not exceeding 35 °C

The utility of exhaled nitric oxide in patients with suspected asthma

The value of FENO measurements in patients with symptoms suggestive of asthma is unclear. We performed an observational study to assess the ability of FENO to diagnose asthma and to predict response to inhaled corticosteroids (ICS). Our findings suggest FENO is not useful for asthma diagnosis but is accurate at predicting ICS response

Longitudinal multi-modal muscle-based biomarker assessment in motor neuron disease

Background Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression. Materials and methods A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months. Results MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7–29%, p < 0.01), maximal in leg muscles (left tibialis anterior 71% (95% CI 33–122%, p < 0.01). Clinical and electrophysiological associations were evident. By 12 months, 16 patients had died or could not continue. In the remainder, relative T2-signal increased over 12 months by 14–29% in right tibialis anterior, right quadriceps, bilateral hamstrings and gastrocnemius/soleus (p < 0.01), independent of onset-site, and paralleled progressive weakness and electrophysiological loss of motor units. Highest clinical, electrophysiological and radiological SRMs were found for revised ALS-functional rating scale scores (1.22), tibialis anterior MUNIX (1.59), and relative T2-weighted leg muscle MR (right hamstrings: 0.98), respectively. Diffusion MR detected minimal changes. Conclusion MUNIX and relative T2-weighted MR represent objective surrogate markers of progressive denervation in MND. Radiological changes were maximal in leg muscles, irrespective of clinical onset-site

Metric properties of discrete time exclusion type processes in continuum

A new class of exclusion type processes acting in continuum with synchronous updating is introduced and studied. Ergodic averages of particle velocities are obtained and their connections to other statistical quantities, in particular to the particle density (the so called Fundamental Diagram) is analyzed rigorously. The main technical tool is a "dynamical" coupling applied in a nonstandard fashion: we do not prove the existence of the successful coupling (which even might not hold) but instead use its presence/absence as an important diagnostic tool. Despite that this approach cannot be applied to lattice systems directly, it allows to obtain new results for the lattice systems embedding them to the systems in continuum. Applications to the traffic flows modelling are discussed as well.Comment: 27 pages, 4 figures; minor errors corrected; details added to proofs of Theorems 4.1 and 5.

Analysis of brain and spinal MRI measures in a common domain to investigate directional neurodegeneration in motor neuron disease

Background Magnetic resonance imaging (MRI) of the brain and cervical spinal cord is often performed in diagnostic evaluation of suspected motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). Analysis of MRI-derived tissue damage metrics in a common domain facilitates group-level inferences on pathophysiology. This approach was applied to address competing hypotheses of directionality of neurodegeneration, whether anterograde, cranio-caudal dying-forward from precentral gyrus or retrograde, dying-back. Methods In this cross-sectional study, MRI was performed on 75 MND patients and 13 healthy controls. Precentral gyral thickness was estimated from volumetric T1-weighted images using FreeSurfer, corticospinal tract fractional anisotropy (FA) from diffusion tensor imaging using FSL, and cross-sectional cervical cord area between C1-C8 levels using Spinal Cord Toolbox. To analyse these multimodal data within a common domain, individual parameter estimates representing tissue damage at each corticospinal tract level were first converted to z-scores, referenced to healthy control norms. Mixed-effects linear regression models were then fitted to these z-scores, with gradients hypothesised to represent directionality of neurodegeneration. Results At group-level, z-scores did not differ significantly between precentral gyral and intracranial corticospinal tract tissue damage estimates (regression coefficient − 0.24, [95% CI − 0.62, 0.14], p = 0.222), but step-changes were evident between intracranial corticospinal tract and C1 (1.14, [95% CI 0.74, 1.53], p < 0.001), and between C5 and C6 cord levels (0.98, [95% CI 0.58, 1.38], p < 0.001). Discussion Analysis of brain and cervical spinal MRI data in a common domain enabled investigation of pathophysiological hypotheses in vivo. A cranio-caudal step-change in MND patients was observed, and requires further investigation in larger cohorts

Early interneuron dysfunction in ALS: Insights from a mutant sod1 zebrafish model

Objective: To determine, when, how, and which neurons initiate the onset of pathophysiology in amyotrophic lateral sclerosis (ALS) using a transgenic mutant sod1 zebrafish model and identify neuroprotective drugs. Methods: Proteinopathies such as ALS involve mutant proteins that misfold and activate the heat shock stress response (HSR). The HSR is indicative of neuronal stress, and we used a fluorescent hsp70-DsRed reporter in our transgenic zebrafish to track neuronal stress and to measure functional changes in neurons and muscle over the course of the disease. Results: We show that mutant sod1 fish first exhibited the HSR in glycinergic interneurons at 24 hours postfertilization (hpf). By 96 hpf, we observed a significant reduction in spontaneous glycinergic currents induced in spinal motor neurons. The loss of inhibition was followed by increased stress in the motor neurons of symptomatic adults and concurrent morphological changes at the neuromuscular junction (NMJ) indicative of denervation. Riluzole, the only approved ALS drug and apomorphine, an NRF2 activator, reduced the observed early neuronal stress response. Interpretation: The earliest event in the pathophysiology of ALS in the mutant sod1 zebrafish model involves neuronal stress in inhibitory interneurons, resulting from mutant Sod1 expression. This is followed by a reduction in inhibitory input to motor neurons. The loss of inhibitory input may contribute to the later development of neuronal stress in motor neurons and concurrent inability to maintain the NMJ. Riluzole, the approved drug for use in ALS, modulates neuronal stress in interneurons, indicating a novel mechanism of riluzole action

Using confirmatory factor analysis to evaluate construct validity of the Brief Pain Inventory (BPI)

Context: The Brief Pain Inventory (BPI) is a frequently used instrument designed to assess the patient-reported outcome of pain. The majority of factor analytic studies have found a two-factor (i.e., pain intensity and pain interference) structure for this instrument; however, because the BPI was developed with an a priori hypothesis of the relationship among its items, it follows that construct validity investigations should use confirmatory factor analysis (CFA). Objectives: The purpose of this work was to establish the construct validity of the BPI using a CFA framework and demonstrate factorial invariance using a range of demographic variables. Methods: A retrospective CFA was completed in a sample of individuals diagnosed with HIV/AIDS and cancer (n = 364; 63% male; age 21-92 years, M = 51.80). A baseline one-factor model was compared against two-factor and three-factor models (i.e., pain intensity, activity interference, and affective interference) that were developed based on the hypothetical design of the instrument. Results: Fit indices for the three-factor model were statistically superior when compared with the one-factor model and marginally better when compared with the two-factor model. This three-factor structure was found to be invariant across disease, age, and ethnicity groups. Conclusion: The results of this study provide evidence to support a three-factor representation of the BPI, and the originally hypothesized two-factor structure. Such findings will begin to provide clinical trialists, pharmaceutical sponsors, and regulators with confidence in the psychometric properties of this instrument when considering its inclusion in clinical research