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We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92–0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79–0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Background Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. Methods Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator’s choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). Results In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610–1.072), p  = 0.1389; rPFS 0.956 (0.759–1.205), p  = 0.7039; OS 0.889 (0.660–1.199), p  = 0.4410; and time to bone ALP progression 0.593 (0.379–0.926), p  = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. Conclusions In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

Academic health centers and other teaching hospitals face higher patient care costs than nonteaching hospitals face, because of their missions of graduate medical education (GME), biomedical research, and the maintenance of standby capacity for medically complex patients. Without a better understanding of the full range of teaching hospital missions and their associated costs, policymakers are likely to underestimate the benefits from public expenditures to teaching hospitals. This study extends previous work on indirect medical education (IME) by separately estimating the costs of teaching hospitals' primary missions. It is estimated that total mission-related costs were $27 billion in 2002 for all teaching hospitals, with GME (including indirect and direct GME) and standby capacity accounting for roughly 60% and 35% of these costs, respectively. To assure their continued ability to perform important social missions in a competitive environment, it may be necessary to reassess the way in which these activities are financed.

Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody–drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab. In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0–1, and who had progressed on first-line platinum–pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed. Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4–5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4–5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1–5·2] vs 4·5 months [4·1–5·8]; hazard ratio 1·22 [0·85–1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. Bayer Healthcare Pharmaceuticals.

The literature on capital gains realizations reflects an inadequate integration of theory and empirical research. An attempt is made to bring theory and the evidence closer together by considering whether investors respond differently to tax rates. In particular, it is found that they exhibit significantly smaller responses to permanent tax rate changes than other investors. Put another way, a larger part of their response to capital gains tax rates reflects timing, consistent with their closer adherence to tax-avoidance strategies emphasizing arbitrage based on tax rate differentials.

Most theories of elections assume that voters and political actors are fully rational. While these formulations produce many insights, they also generate anomalies--most famously, about turnout. The rise of behavioral economics has posed new challenges to the premise of rationality. This groundbreaking book provides a behavioral theory of elections based on the notion that all actors--politicians as well as voters--are only boundedly rational. The theory posits learning via trial and error: actions that surpass an actor's aspiration level are more likely to be used in the future, while those that fall short are less likely to be tried later. Based on this idea of adaptation, the authors construct formal models of party competition, turnout, and voters' choices of candidates. These models predict substantial turnout levels, voters sorting into parties, and winning parties adopting centrist platforms. In multiparty elections, voters are able to coordinate vote choices on majority-preferred candidates, while all candidates garner significant vote shares. Overall, the behavioral theory and its models produce macroimplications consistent with the data on elections, and they use plausible microassumptions about the cognitive capacities of politicians and voters. A computational model accompanies the book and can be used as a tool for further research.

The paper uses a new micro-simulation model to estimate the impact of repealing the employer-sponsored insurance (ESI) exclusion on ESI coverage given two alternative scenarios: a non-group market that is fully underwritten and a modified community-rated market where the low income population receives premium subsidies. When the alternative to ESI is the underwritten market, repeal of the exclusion reduces ESI coverage by 14 percent both overall and for those over 400 percent FPL. In contrast, individuals over 400 percent FPL are less likely to leave ESI when the alternative is a subsidized modified community-rated market.

The ICH E9 (R1) Estimands Guidance1 terminology does not completely address the conceptual needs of time-to-event estimands in the complex oncology context. We previously described how censoring and censoring mechanisms for time-to-event endpoints can be embedded into the ICH E9 (R1) Estimands Guidance terminology. This second paper by the Pharmaceutical Industry Working Group on Estimands in Oncology Censoring Mechanisms Subteam discusses special issues in the oncology clinical context that may require different approaches than some other therapeutic areas as well as an extensions of the ICH E9 (R1) guidance. The concept of censoring is discussed in the broader context of occluding events, with occlusion representing any loss to further follow-up and/or removal of further collected data from analysis. Occlusion constitutes a broader concept than the estimand guidance's intercurrent event and terminal event terminology and is appropriate to describe and handle situations like withdrawal from assessments or situations where the requirements of different estimands conflict. We characterize, provide additional details, practical implications, and examples on the application of each estimands strategy for handling occluding events.

The Affordable Care Act (ACA) has prompted a national conversation about Americans' health system among health care providers, employers, employees, and others. For employers, the ACA provisions -- including the employer mandate -- demand understanding of the complex rules, consideration of the best approach to employee benefits offerings, and a response to implementation of the law. Company size, employee compensation, premium tax credits available to certain employees, the employer mandate excise tax, and more must be taken into account in formulating the right approach to implementing the ACA for your company. Like individual health, each employer's solution will be unique. The ACA provisions may alter employers' considerations for the right balance of offering subsidized health care coverage to their employees. Employers must balance the cost of offering employees subsidized coverage that is affordable and satisfies minimum value versus the cost of \"paying\" the excise tax if affordable coverage is not offered.

Working Paper No. 7532 This paper attempts to bring theoretical and empirical research on capital gains realization behavior closer together by considering whether investors who appear to engage more in strategic tax avoidance activity also respond differently to tax rates. We find that such investors exhibit significantly smaller responses to permanent tax rate changes than other investors. Put another way, a larger part of their response to capital gains tax rates reflects timing, consistent with their closer adherence to tax avoidance strategies emphasizing arbitrage based on tax rate differentials. This finding holds for two alternative specifications of realization behavior, one of which suggests larger permanent responses to capital gains tax rates than those of previous panel studies.