Phase I, randomized, observer-blind, placebo-controlled studies to evaluate the safety, reactogenicity and immunogenicity of an investigational non-typeable Haemophilus influenzae (NTHi) protein vaccine in adults

Background: Non-typeable Haemophilus influenzae (NTHi) is a major cause of various respiratory diseases. The development of an effective vaccine against NTHi mandates new approaches beyond conjugated vaccines as this opportunistic bacterium is non-encapsulated. Here we report on the safety, reactogenicity and immunogenicity of a multi-component investigational vaccine based on three conserved surface proteins from NTHi (proteins D [PD],E [PE] and Pilin A [PilA]) in two observer-blind phase I studies. Methods: In the first study (NCT01657526), 48 healthy 18-40 year-olds received two vaccine formulations (10 or 30 mu g of each antigen [PD and a fusion protein PE-PilA]) or saline placebo at months 0 and 2. In the second study (NCT01678677), 270 50-70 year-olds, current or former smokers, received eight vaccine formulations (10 or 30 mu g antigen/dose non-adjuvanted or adjuvanted with alum, AS01(E) or ASO4(c)) or saline placebo at months 0,2 and 6 (plain and alum-adjuvanted groups) and at months 0 and 2 (AS-adjuvanted groups). Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days post-vaccination, respectively; potential immune-mediated diseases (pIMDs) and serious AEs (SAEs) throughout the studies. Humoral and antigen-specific T-cell immunity (in study 2 only) responses were assessed up to 12 months post-vaccination. Results: Observed reactogenicity was highest in the AS-adjuvanted groups but no safety concerns were identified with any of the NTHi vaccine formulations. One fatal SAE (cardiac arrest) not considered related to vaccination, and one pIMD (non-serious psoriasis) in the Placebo group, were reported post-dose 3 in Study 2. All formulations generated a robust antibody response while the AS01-adjuvanted formulations produced the highest humoral and cellular immune responses. Conclusion: This study confirms that the NTHi vaccine formulations had an acceptable reactogenicity and safety profile and were immunogenic in adults. These results justify further clinical development of this NTHi vaccine candidate

Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response

Background: Selective serotonin reuptake inhibitors take several weeks to achieve their full antidepressant effects. Post-synaptic 5-HT<sub>2A</sub> receptor activation is thought to be involved in this delayed therapeutic effect. Pipamperone acts as a highly selective 5-HT<sub>2A</sub>/D<sub>4</sub> antagonist when administered in low doses. The purpose of this study was to compare citalopram 40 mg once daily plus pipamperone 5 mg twice daily (PipCit) versus citalopram plus placebo twice daily for magnitude and onset of therapeutic effect. Method: An 8-week, randomized, double-blind study in patients with major depressive disorder was carried out. Results: The study population comprised 165 patients (citalopram and placebo, n=82; PipCit, n=83) with a mean baseline Montgomery–Asberg Depression Rating Scale (MADRS) score of 32.6 (S.D.=5.5). In the first 4 weeks, more citalopram and placebo than PipCit patients discontinued treatment (18% v. 4%, respectively, p=0.003). PipCit patients had significantly greater improvement in MADRS score at week 1 [observed cases (OC), p=0.021; last observation carried forward (LOCF), p=0.007] and week 4 (LOCF, p=0.025) but not at week 8 compared with citalopram and placebo patients. Significant differences in MADRS scores favoured PipCit in reduced sleep, reduced appetite, concentration difficulties and pessimistic thoughts. Mean Clinical Global Impression–Improvement scores were significantly improved after 1 week of PipCit compared with citalopram and placebo (OC and LOCF, p=0.002). Conclusions: Although the MADRS score from baseline to 8 weeks did not differ between groups, PipCit provided superior antidepressant effects and fewer discontinuations compared with citalopram and placebo during the first 4 weeks of treatment, especially in the first week

Recente ontwikkelingen: sterke verruiming van de tenuitvoerlegging van buitenlandse arbitrale vonnissen in New York [TvA 2017/37]

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20 Jaar Private Securities Litigation Reform Act – private rechtshandhaving in het Amerikaans financieel recht

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Laxatives or methylnaltrexone for the management of constipation in palliative care patients

Background: Constipation is common in palliative care; it can generate considerable suffering due to the unpleasant physical symptoms. In the first Cochrane Review on effectiveness of laxatives for the management of constipation in palliative care patients, published in 2006, no conclusions could be drawn because of the limited number of evaluations. This article describes the first update of this review. / Objectives: To determine the effectiveness of laxatives or methylnaltrexone for the management of constipation in palliative care patients. / Search methods: We searched databases including MEDLINE and CENTRAL (The Cochrane Library) in 2005 and in the update to August 2010. / Selection criteria: Randomised controlled trials (RCTs) evaluating laxatives for constipation in palliative care patients. In the update we also included RCTs on subcutaneous methylnaltrexone; an opioid-receptor antagonist that is now licensed for the treatment of opioid-induced constipation in palliative care when response to usual laxative therapy is insufficient. / Data collection and analysis: Two authors assessed trial quality and extracted data. The appropriateness of combining data from the studies depended upon clinical and outcome measure homogeneity. / Main results: We included seven studies involving 616 participants; all under-reported methodological features. In four studies the laxatives lactulose, senna, co-danthramer, misrakasneham, and magnesium hydroxide with liquid paraffin were evaluated. In three methylnaltrexone. In studies comparing the different laxatives evidence was inconclusive. Evidence on subcutaneous methylnaltrexone was clearer; in combined analysis (287 participants) methylnaltrexone, in comparison with a placebo, significantly induced laxation at 4 hours (odds ratio 6.95; 95% confidence interval 3.83 to 12.61). In combined analyses there was no difference in the proportion experiencing side effects, although participants on methylnaltrexone suffered more flatulence and dizziness. No evidence of opioid withdrawal was found. In one study severe adverse events, commonly abdominal pain, were reported that were possibly related to methylnaltrexone. A serious adverse event considered to be related to the methylnaltrexone also occurred; this involved a participant having severe diarrhoea, subsequent dehydration and cardiovascular collapse. / Authors' conclusions: The 2010 update found evidence on laxatives for management of constipation remains limited due to insufficient RCTs. However, the conclusions of this update have changed since the original review publication in that it now includes evidence on methylnaltrexone. Here it found that subcutaneous methylnaltrexone is effective in inducing laxation in palliative care patients with opioid-induced constipation and where conventional laxatives have failed. However, the safety of this product is not fully evaluated. Large, rigorous, independent trials are needed

Optimizing the Great Lakes-St. Lawrence Seaway Transportation System

This report presents an analysis of the major opportunities and barriers to container shipping on the Great Lakes-St. Lawrence Seaway Transportation System in North America against the background of recent global economic developments, and is drawn up in conjunction with an economic analysis of the system’s potentials by Verboon (2012). Despite plenty of transit capacity and access to major North American markets not a single container moves beyond the Welland Canal to be discharged at American Great Lakes port today. The opportunities identified encompass the fuel efficiency advantage of the marine mode over competing modes – in particular evaluated as an opportunity against the background of rising fuel prices, congestion relief on roads and railroads in and between the economic centers of the U.S. Midwest, the potential of the marine mode to reduce air pollution if a larger fraction of transportation needs is captured, and lower safety risks of marine mode activities compared to its surface transportation counterparts. Interviews with stakeholders in the Great Lakes area have led to the identification of several key barriers to enhanced system performance. To begin with, services in the system cannot be provided on a year-round basis, primarily because of maintenance requirements. Additionally, an ad-valorem tax levied on goods imported into the U.S. through U.S. ports creates a cost disadvantage and a mental barrier to use of the marine mode, which is particularly relevant for the Great Lakes area given its proximity to Canadian ports and railroads where no tax is levied. Furthermore, U.S. and Canadian cabotage regulation limits competition for maritime transport services and flexibility of the system, which leads to higher prices paid by shippers and consumers. Pilotage requirements in the system drive up prices further because of costly pilotage activities. Although there are options to get an exemption, for cross-Atlantic trade it generally holds that the payments are made. Finally, perception of the Great Lakes as suitable for recreation activities rather commercial activities causes authorities, shippers, and the financial sector to be insufficiently aware of the system’s potentials. Two sectors in the U.S. Midwest are identified as having the potential to reap the benefits from container movements on the Great Lakes in particular; the automotive sector and the chemicals sector. Both sectors are found to require transportation services for cargo volumes that are large enough for a new service to accommodate and are very well represented in the proximity of American Great Lakes ports. For these sectors, it holds that non-tariff barriers account for price increases that could be reduced significantly. To gain insights into the likelihood of a new service being successful, previous container shipping initiatives on the Great Lakes have been evaluated which has led to the conclusion that the timing aspect of launching a new service and appropriate government support are crucial factors contributing to the success of new services. Compared to these initiatives, new service providers are advised to consider operations over longer distances and with larger ships to fully exploit economies of scale. For the system to thrive a number of key system improvement opportunities are found. There seems to be significant potential for Canadian and American authorities to collaborate on efforts to improve the ease by which business can be done in the system. In this respect, evaluation of alternatives to current cost recovery practices of maintenance activities, integration of cabotage regulation, education of authorities and businesses domestically and overseas, and the implementation of intelligent technologies are key components of strategies that aim to explore the benefits of intensified use of the marine mode in the Great Lakes area. Based on these findings policy makers are recommended to take a proactive role in the development of container shipping in the Great Lakes-St. Lawrence Seaway Transportation System. In particular, the current structure of the ad-valorem tax needs to be redefined, the legal frameworks between Canada and the U.S. need to be streamlined, and promotional efforts should be installed to make stakeholders familiar with the commercial potentials of the system. A good start for the shipping industry would be to conduct a study in which potential cargo diversion as a result of the ad-valorem tax for the Great Lakes area specifically is researched. In addition, a North American common framework for cabotage regulation can be drawn up – perhaps based on the European Union model – and technologies can be installed to relieve the administrative burden to shipping in bi-national waters. Lastly, stakeholders can join forces to promote the system in the domestic setting as well as in Europe. Matching perception of the lakes with reality and transport needs with services available can provide the basis from which the Great Lakes-St. Lawrence Seaway Transportation System can contribute to the development of profitable and sustainable transport services

Spin-orbit torque in Pt/CoNiCo/Pt symmetric devices

Current induced magnetization switching by spin-orbit torques offers an energy-efficient means of writing information in heavy metal/ferromagnet (FM) multilayer systems. The relative contributions of field-like torques and damping-like torques to the magnetization switching induced by the electrical current are still under debate. Here, we describe a device based on a symmetric Pt/FM/Pt structure, in which we demonstrate a strong damping-like torque from the spin Hall effect and unmeasurable field-like torque from Rashba effect. The spin-orbit effective fields due to the spin Hall effect were investigated quantitatively and were found to be consistent with the switching effective fields after accounting for the switching current reduction due to thermal fluctuations from the current pulse. A non-linear dependence of deterministic switching of average Mzon the in-plane magnetic field was revealed, which could be explained and understood by micromagnetic simulation