Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Modelling the Demand for Sea Transport on the Baltic Sea

The paper includes a brief presentation of the relevant background theory for the empirical work presented. It also gives an overview of some basic characteristics of the international transport flows in the Baltic Sea region. The main purpose of the paper is, however, to describe the development of a new forecasting model for sea transports in the region. Specifically, it can be used for analysis of international transport generation, its distribution or both. Effects on generation and distribution can be summarised by two elasticity measures, which are simultaneously estimable in the model. The first is an own-elasticity of transport demand, from i to j, with respect to transport cost changes on this relation. The second is a cross-elasticity of transport demand from alternative import sources, h to j, with respect to transport cost changes on the relation i to j. The empirical work in the paper is an econometric analysis of the model. The method used is non-linear regression analysis based on cross-section data

Tema Vintermodell : nytta och kostnader för vinterväghållning

Ice and snow cause difficulties for road users in winter. These difficulties consist mainly of reduced accessibility and higher risks of various kinds of road accidents, which the road administrations endeavour to alleviate by maintenance measures of various kinds. Snow clearance and skid prevention treatment, such as salting of carriageways, are the two predominant kinds of maintenance measure that are taken. In this way a benefits are created for road users, but at the same time also a lot of inconvenience and costs. The maintenance costs of the road administration for these measures are directly influenced by the maintenance action taken. At the same time, there is reason to believe that road users and third parties also incur costs of various types. Different strategies for winter road maintenance may be expected to give rise to different outcomes as regards the costs and benefits of the kinds referred to above. It can thus be expected that the total costs and benefits for society at large will be affected, as well as the distribution of these among the various interested parties. Different options for infrastructure investments are generally appraised by CBA (Cost/ Benefit Analysis). The same cannot be said to hold for infrastructure maintenance measures, of which winter maintenance of state maintained roads can be taken as an example. There are many reasons for making socio-economic analyses for infrastructure maintenance also, such as the winter maintenance of state maintained roads. For this reason, we have made an analysis of how the principles that are applied concerning CBA for investments in road infrastructure could be transferred to the framework constituted by the VTI Winter Model. The objective of this analysis was to study, with reference to the principles governing traditional CBA and its application by traffic administration agencies on the basis of the recommendations from the Swedish Institute for Transport and Communications Analysis, the way in which the application of CBA to the Winter Model may be formulated

På väg mot marginalkostnadsprissättning inom sjötransportsektorn

Besides the open sea, ports, fairways, pilot services, and ice-breaking are the main maritime infrastructure components. Marginal costs of maritime transport can be divided into the following groups: emissions to water and air, accidents, and costs related to infrastructure usage. The first marginal cost type is the occurrence of negative external effects to third-men outside the transport system. The marginal costs from infrastructure use are related to the parts that invest, maintain, and provide the services in themselves as well as to the users. The latter part is affected by restrictions in capacity, which can affect the user costs of the services. This report considers all these marginal costs components, except emissions to air. The basic purpose of the report is to narrow down the state of knowledge regarding: - Marginal cost pricing in theory; - Empirical research regarding marginal cost pricing; - Review availability of data and how institutional conditions affect the possibilities for implementation of marginal cost based pricing. The scope of the report is limited to the state of knowledge concerning maritime infrastructure of the types mentioned above and external effects from accidents and emissions to water. A secondary purpose of the report is to give suggestions for further research based on the authors' view of the state of knowledge

Closure after gastrostomy button

A gastrostomy device is removed from the gastrostoma when no longer needed. The aim of the study was to test the hypothesis of whether it is possible for the surgeon to decide which stoma has to be closed with a gastroraphy and which to leave for a spontaneous closure within a reasonable period of time. Out of a cohort of 321 patients, who had been operated with a video-assisted gastrostomy, we included all the 48 patients having had their gastrostomy button removed. These patients were carefully followed and the closure of the gastrostoma was registered. According to the institutional routine we waited at least 3 months after the removal of the gastrostomy device before suggesting to the child's guardians an operative closure of the stoma. In 26 patients the stoma closed within 3 months, whereas in 22 patients a surgical gastroraphy was performed. We found no differences between the two groups regarding the patients' diagnoses, the duration of the gastrostoma use or patient's age at the time of removal of the gastrostomy device. This study rejected the hypothesis of predictability of the gastrostoma closure. Thus, we recommend a routine expectance after the removal of a gastrostomy device for at least 1 month. If no spontaneous closure occurs, then a gastroraphy should be performed