Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine. A post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial

Background: The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore®) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication. Methods: Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation. Results: A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60 min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008). When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037). Conclusions: This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events. Trial registration: ClinicalTrials.gov identifier: NCT02686034

Integrated results from the COPERNICUS and GALILEO studies.

OBJECTIVES: To report on the efficacy and safety of intravitreal aflibercept in patients with macular edema secondary to central retinal vein occlusion (CRVO) in an integrated analysis of COPERNICUS and GALILEO. PATIENTS AND METHODS: Patients were randomized to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until week 24. From week 24 to week 52, all intravitreal aflibercept-treated patients in both studies and sham-treated patients in COPERNICUS were eligible to receive intravitreal aflibercept based on prespecified criteria. In GALILEO, sham-treated patients continued to receive sham treatment through week 52. RESULTS: At week 24, mean gain in best-corrected visual acuity and mean reduction in central retinal thickness were greater for intravitreal aflibercept-treated patients compared with sham, consistent with individual trial results. At week 52, after 6 months of intravitreal aflibercept as-needed treatment in COPERNICUS, patients originally randomized to sham group experienced visual and anatomic improvements but did not improve to the extent of those initially treated with intravitreal aflibercept, while the sham group in GALILEO did not improve over week 24 mean best-corrected visual acuity scores. Ocular serious adverse events occurred in CONCLUSION: This analysis of integrated data from COPERNICUS and GALILEO confirmed that intravitreal aflibercept is an effective treatment for macular edema following CRVO

Single-Particle Properties from Kohn-Sham Green's Functions

An effective action approach to Kohn-Sham density functional theory is used to illustrate how the exact Green's function can be calculated in terms of the Kohn-Sham Green's function. An example based on Skyrme energy functionals shows that single-particle Kohn-Sham spectra can be improved by adding sources used to construct the energy functional.Comment: 9 pages, 3 figure

The Galaxy Clustering Crisis in Abundance Matching

Galaxy clustering on small scales is significantly under-predicted by sub-halo abundance matching (SHAM) models that populate (sub-)haloes with galaxies based on peak halo mass, $M_{\rm peak}$. SHAM models based on the peak maximum circular velocity, $V_{\rm peak}$, have had much better success. The primary reason $M_{\rm peak}$ based models fail is the relatively low abundance of satellite galaxies produced in these models compared to those based on $V_{\rm peak}$. Despite success in predicting clustering, a simple $V_{\rm peak}$ based SHAM model results in predictions for galaxy growth that are at odds with observations. We evaluate three possible remedies that could "save" mass-based SHAM: (1) SHAM models require a significant population of "orphan" galaxies as a result of artificial disruption/merging of sub-haloes in modern high resolution dark matter simulations; (2) satellites must grow significantly after their accretion; and (3) stellar mass is significantly affected by halo assembly history. No solution is entirely satisfactory. However, regardless of the particulars, we show that popular SHAM models based on $M_{\rm peak}$ cannot be complete physical models as presented. Either $V_{\rm peak}$ truly is a better predictor of stellar mass at $z\sim 0$ and it remains to be seen how the correlation between stellar mass and $V_{\rm peak}$ comes about, or SHAM models are missing vital component(s) that significantly affect galaxy clustering.Comment: 25 pages, 22 figures, submitted to MNRAS, comments welcom

Fraudulent Contracting of Work: Sham Companies (Austria, Estonia and Italy)

[Excerpt] Among the fraudulent contracting of work practices, one of the most difficult to identify is the creation of sham companies (usually, in another country). Sham companies are essentially new entities created to disguise the real employer. Creating a company, even abroad, is – of course – legal and may well be institutionally and economically advisable. However, when the only purpose of its creation is to benefit from more favourable regulations relating to labour and tax (and not to develop an activity in the country), then questions should be asked about the ‘genuine’ nature of the company. The Eurofound study Exploring the fraudulent contracting of work in the European Union emphasises that the term ‘sham contracting’ or ‘sham companies’ embraces a diversity of fraudulent practices, embedded in different institutional contexts (Eurofound, 2016a).1 Fraudulent practices are perpetrated for different purposes, the most important of which are to avoid paying, or to save, employment-related taxes and social security contributions, and to evade employers’ liability towards employees. Beyond some recent analysis of ‘letter-box’ companies,2 there is not much research into sham contracting or sham companies. In addition, EU legislation has not played any role in this respect. Sham companies share the common goal of disguising the real employer. This can be achieved through different mechanisms such as: the creation of companies without assets, generally within subcontracting chains commercial or civil law contracts between companies where employees are misrepresented as contractors or company owners workers’ cooperatives, where workers lack actual control over the organisation’s decisions

Two Weeks of Ischemic Conditioning Improves Walking Speed and Reduces Neuromuscular Fatigability in Chronic Stroke Survivors

This pilot study examined whether ischemic conditioning (IC), a noninvasive, cost-effective, and easy-to-administer intervention, could improve gait speed and paretic leg muscle function in stroke survivors. We hypothesized that 2 wk of IC training would increase self-selected walking speed, increase paretic muscle strength, and reduce neuromuscular fatigability in chronic stroke survivors. Twenty-two chronic stroke survivors received either IC or IC Sham on their paretic leg every other day for 2 wk (7 total sessions). IC involved 5-min bouts of ischemia, repeated five times, using a cuff inflated to 225 mmHg on the paretic thigh. For IC Sham, the cuff inflation pressure was 10 mmHg. Self-selected walking speed was assessed using the 10-m walk test, and paretic leg knee extensor strength and fatigability were assessed using a Biodex dynamometer. Self-selected walking speed increased in the IC group (0.86 ± 0.21 m/s pretest vs. 1.04 ± 0.22 m/s posttest, means ± SD; P\u3c 0.001) but not in the IC Sham group (0.92 ± 0.47 m/s pretest vs. 0.96 ± 0.46 m/s posttest; P= 0.25). Paretic leg maximum voluntary contractions were unchanged in both groups (103 ± 57 N·m pre-IC vs. 109 ± 65 N·m post-IC; 103 ± 59 N·m pre-IC Sham vs. 108 ± 67 N·m post-IC Sham; P = 0.81); however, participants in the IC group maintained a submaximal isometric contraction longer than participants in the IC Sham group (278 ± 163 s pre-IC vs. 496 ± 313 s post-IC, P = 0.004; 397 ± 203 s pre-IC Sham vs. 355 ± 195 s post-IC Sham; P = 0.46). The results from this pilot study thus indicate that IC training has the potential to improve walking speed and paretic muscle fatigue resistance poststroke

Revisiting the Polyak step size

This paper revisits the Polyak step size schedule for convex optimization problems, proving that a simple variant of it simultaneously attains near optimal convergence rates for the gradient descent algorithm, for all ranges of strong convexity, smoothness, and Lipschitz parameters, without a-priory knowledge of these parameters