Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma

This subset analysis of data from two phase III studies in patients with relapsed or refractory multiple myeloma (MM) evaluated the benefit of initiating lenalidomide plus dexamethasone at first relapse. Multivariate analysis showed that fewer prior therapies, along with β2-microglobulin (≤2.5 mg/L), predicted a better time to progression (TTP; study end-point) with lenalidomide plus dexamethasone treatment. Patients with one prior therapy showed a significant improvement in benefit after first relapse compared with those who received two or more therapies. Patients with one prior therapy had significantly prolonged median TTP (17.1 vs. 10.6 months; P=0.026) and progression-free survival (14.1 vs. 9.5 months, P=0.047) compared with patients treated in later lines. Overall response rates were higher (66.9% vs. 56.8%, P=0.06), and the complete response plus very good partial response rate was significantly higher in first relapse (39.8% vs. 27.7%, P=0.025). Importantly, overall survival was significantly prolonged for patients treated with lenalidomide plus dexamethasone with one prior therapy, compared with patients treated later in salvage (median of 42.0 vs. 35.8 months, P=0.041), with no differences in toxicity, dose reductions, or discontinuations despite longer treatment. Therefore, lenalidomide plus dexamethasone is both effective and tolerable for second-line MM therapy and the data suggest that the greatest benefit occurs with earlier use

Development of a candidate reference material for adventitious virus detection in vaccine and biologicals manufacturing by deep sequencing.

Unbiased deep sequencing offers the potential for improved adventitious virus screening in vaccines and biotherapeutics. Successful implementation of such assays will require appropriate control materials to confirm assay performance and sensitivity. A common reference material containing 25 target viruses was produced and 16 laboratories were invited to process it using their preferred adventitious virus detection assay. Fifteen laboratories returned results, obtained using a wide range of wet-lab and informatics methods. Six of 25 target viruses were detected by all laboratories, with the remaining viruses detected by 4-14 laboratories. Six non-target viruses were detected by three or more laboratories. The study demonstrated that a wide range of methods are currently used for adventitious virus detection screening in biological products by deep sequencing and that they can yield significantly different results. This underscores the need for common reference materials to ensure satisfactory assay performance and enable comparisons between laboratories

Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients:First data from the TITRATE-HF study

Aims: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. Methods and results: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63–78), 29% were female, and median ejection fraction was 35% (IQR 25–40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. Conclusion: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.</p

Impure Public Goods and Technological Interdependencies

Impure public goods represent an important group of goods. Almost every public good exerts not only effects which are public to all but also effects which are private to the producer of this good. What is often omitted in the analysis of impure public goods is the fact that – regularly – these private effects can also be generated independently of the public good. In our analysis we focus on the effects alternative technologies – independently generating the private effects of the public good – may have on the provision of impure public goods. After the investigation in an analytical impure public good model, we numerically simulate the effects of alternative technologies in a parameterized model for climate policy in Germany

Bargaining with Non-Monolithic Players

This paper analyses strategic bargaining in negotiations between non-monolithic players, i.e. agents starting negotiations can split up in smaller entities during the bargaining process. We show that the possibility of scission in the informed coalition implies that it loses its information advantages. We also show that when the possibility of a scission exists the uninformed player does not focus on his or her beliefs about the strength of the informed coalition but on the proportion of weak/strong players within this coalition. Finally, our results show that the possibility of a scission reduces the incentives for the leader to propose a high offer to ensure a global agreement. We apply this framework to international negotiations on global public goods and to wage negotiations

Urban Environmental Health and Sensitive Populations: How Much are the Italians Willing to Pay to Reduce Their Risks?

We use contingent valuation to elicit WTP for a reduction in the risk of dying for cardiovascular and respiratory causes, the most important causes of premature mortality associated with heat wave and air pollution, among the Italian public. The purpose of this study is three-fold. First, we obtain WTP and VSL figures that can be applied when estimating the benefits of heat advisories, other policies that reduce the mortality effects of extreme heat, and environmental policies that reduce the risk of dying for cardiovascular and respiratory causes. Second, our experimental study design allows us to examine the sensitivity of WTP to the size of the risk reduction. Third, we examine whether the WTP of populations that are especially sensitive to extreme heat and air pollution - such as the elderly, those in compromised health, and those living alone and/or physically impaired - is different from that of other individuals. We find that WTP, and hence the VSL, depends on the risk reduction, respondent age (via the baseline risk), and respondent health status. WTP increases with the size of the risk reduction, but is not strictly proportional to it. All else the same, older individuals are willing to pay less for a given risk reduction than younger individuals of comparable characteristics. Poor health, however, tends to raise WTP, so that the appropriate VSL of elderly individuals in poor health may be quite large. Our results support the notion that the VSL is individuated

Emissions Trading, CDM, JI, and More - The Climate Strategy of the EU

The objective of this paper is to assess the likely allocation effects of the current cli-mate protection strategy as it is laid out in the National Allocation Plans (NAPs) for the European Emissions Trading Scheme (ETS). The multi-regional, multi-sectoral CGE-model DART is used to simulate the effects of the current policies in the year 2012 when the Kyoto targets need to be met. Different scenarios are simulated in or-der to highlight the effects of the grandfathering of permits to energy-intensive instal-lations, the use of the project-based mechanisms (CDM and JI), and the restriction imposed by the supplementarity criterion