Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS)

Background: Non-invasive ventilation is part of the standard of care for treatment of respiratory failure in patients with amyotrophic lateral sclerosis (ALS). The NeuRx RA/4 Diaphragm Pacing System has received Humanitarian Device Exemption approval from the US Food and Drug Administration for treatment of respiratory failure in patients with ALS. We aimed to establish the safety and efficacy of diaphragm pacing with this system in patients with respiratory muscle weakness due to ALS. Methods: We undertook a multicentre, open-label, randomised controlled trial at seven specialist ALS and respiratory centres in the UK. Eligible participants were aged 18 years or older with laboratory supported probable, clinically probable, or clinically definite ALS; stable riluzole treatment for at least 30 days; and respiratory insufficiency. We randomly assigned participants (1:1), via a centralised web-based randomisation system with minimisation that balanced patients for age, sex, forced vital capacity, and bulbar function, to receive either non-invasive ventilation plus pacing with the NeuRx RA/4 Diaphragm Pacing System or non-invasive ventilation alone. Patients, carers, and outcome assessors were not masked to treatment allocation. The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Analysis was by intention to treat. This trial is registered, ISRCTN number 53817913. Findings: Between Dec 5, 2011, and Dec 18, 2013, we randomly assigned 74 participants to receive either non-invasive ventilation alone (n=37) or non-invasive ventilation plus diaphragm pacing (n=37). On Dec 18, 2013, the Data Monitoring and Ethics Committee (DMEC) recommended suspension of recruitment on the basis of overall survival figures. Randomly assigned participants continued as per the study protocol until June 23, 2014, when the DMEC advised discontinuation of pacing in all patients. Follow-up assessments continued until the planned end of the study in December, 2014. Survival was shorter in the non-invasive ventilation plus pacing group than in the non-invasive ventilation alone group (median 11·0 months [95% CI 8·3-13·6] vs 22·5 months [13·6-not reached]; adjusted hazard ratio 2·27, 95% CI 1·22-4·25; p=0·009). 28 (76%) patients died in the pacing group and 19 (51%) patients died in the non-invasive ventilation alone group. We recorded 162 adverse events (5·9 events per person-year) in the pacing group, of which 46 events were serious, compared with 81 events (2·5 events per person-year) in the non-invasive ventilation alone group, of which 31 events were serious. Interpretation: Addition of diaphragm pacing to standard care with non-invasive ventilation was associated with decreased survival in patients with ALS. Our results suggest that diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure. Funding: The National Institute for Health Research Health Technology Assessment Programme; the Motor Neurone Disease Association of England, Wales, and Northern Ireland

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Computational Phlebology: The Simulation of a Vein Valve

We present a three-dimensional computer simulation of the dynamics of a vein valve. In particular, we couple the solid mechanics of the vein wall and valve leaflets with the fluid dynamics of the blood flow in the valve. Our model captures the unidirectional nature of blood flow in vein valves; blood is allowed to flow proximally back to the heart, while retrograde blood flow is prohibited through the occlusion of the vein by the valve cusps. Furthermore, we investigate the dynamics of the valve opening area and the blood flow rate through the valve, gaining new insights into the physics of vein valve operation. It is anticipated that through computer simulations we can help raise our understanding of venous hemodynamics and various forms of venous dysfunction

Treatment of primary varicose veins by endovenous obliteration with the VNUS closure system: Results of a prospective multicentre study

Background. Radio frequency obliteration of the saphenous veins has been introduced as a less invasive alternative to traditional surgery for varicose veins. Objective. To report the efficacy of obliteration and clinical outcomes following endovenous obliteration of the saphenous vein with limited follow-up to 3 years. Materials and methods. Radiofreq uency obliteration (Closure® system, VNUS Medical Technologies, San Jose, CA) was performed in 330 limbs of 294 patients in a prospective worldwide multicentre study with 31 participating sites. Follow-up duplex ultrasound and clinical examinations were performed at annual intervals. The main outcome measures were the completeness of occlusion of the treated vein segment, presence of reflux and presence of signs and symptoms of venous disease. Results. Before treatment 3.9% of limbs were categorised as CEAP clinical class zero or one. This improved to 82.9% at 1 year, 83.1% at 2 years and 86.8% at 3 years following treatment. Varicose vein free rates were 1 year: 90.1%, 2 years: 87.2%, 3 years: 88.2%. Duplex ultrasound demonstrated a reflux-free rate of about 88% over 3 years. Total occlusion (TO) of veins was 1 year: 81%, 2 years: 80.4% and 3 years: 75%. Partial occlusion (PO, 5 cm open segment) was 1 year: 12.7%, 2 years: 12.2% and 3 years: 7.4%. Partial occlusion did not result in any differences in the symptom severity score, the number of symptom free limbs, or the varicose vein absence rates at any follow-up time point when compared to the total occlusion group. The varicose vein absence rates were significantly lower in the IO group comparing to the TO and PO groups. Conclusions. Radiofrequency saphenous vein obliteration improves the symptoms of varicose veins. The reflux-free rates in the treated veins remain constant over a 3 year follow-up period. There is no difference in clinical outcomes between the TO and the PO limbs, suggesting clinical effectiveness of the PO category. Greater than a 5 cm open segment in treated veins poses a risk of recurrence. © 2004 Elsevier Ltd. All rights reserved

Moving management : theorizing struggles against the hegemony of management

How do groups resist the apparently all-encompassing discourse of management? Rejecting current theories of resistance as 're-appropriation' or 'micro-politics', we argue that resistance may be thought of as a hegemonic struggle undertaken by social movements. We identify four major resistance movements that engage with management: unions, organizational misbehaviour, civic movements and civic movement organizations. We argue that these forms of resistance differ in terms of location ( civil society or workplace) and strategy (political or infra-political). We chart out the possible interconnections between these different modes of resistance and detail how these interconnections are established. By doing this, the paper provides a framework for understanding the many forms of resistance movements that seek to disrupt the hegemonic discourse of management

Do Cities Have Broad Shoulders? Does Motown Need a Haircut? On Urban Branding and the Personification of Place

Once regarded as dens of iniquity, injurious to human health and social welfare, cities are increasingly seen as a savior for our species. The world is becoming ever more urban and the benefits of city living – ecological benefits, educational benefits, financial benefits, well-being benefits (Glaeser 2011) – are ever more widely recognized. Marketing too is embracing the urban imperative. Recent years have witnessed a surge in geo-branding and scape-based scholarship generally. This essay reflects on the proliferation of place marketing publications and draws macromarketers’ attention to a hitherto overlooked aspect of the literature. Namely, our propensity to personify places, to treat them as living things, as organic entities – as people, in effect – that grow, flourish and finally pass away. Metaphors also suffer from the ravages of time, as do ostensibly healthy academic disciplines like marketing