4009 Background: Survival outcomes are historically poor in patients (pts) with advanced/metastatic iCCA, with median overall survival (mOS) times of approximately 1 year with first-line gemcitabine plus cisplatin and approximately 6 months with second-line chemotherapy. Futibatinib, a highly selective, irreversible FGFR1–4 inhibitor, demonstrated efficacy with durable responses in pts with iCCA harboring FGFR2 fusion/rearrangements in the pivotal FOENIX-CCA2 phase 2 study (NCT02052778). At the primary analysis of this trial (data cutoff: October 1, 2020), an objective response rate (ORR) of 41.7% was observed, with a median duration of response (mDOR) of 9.7 mo. Here, we report updated efficacy (including mature OS data) and safety data from the final analysis with an additional 8 mo of follow-up. Methods: FOENIX-CCA2 was a single-arm phase 2 study that enrolled pts with advanced/metastatic iCCA with FGFR2 fusion/rearrangement and progressive disease (PD) after ≥1 prior treatment (tx; including gemcitabine plus platinum-based chemotherapy). Pts received futibatinib 20 mg once daily until PD/intolerability. The primary endpoint was ORR per RECIST v1.1 by independent central review. Secondary endpoints were DOR, disease control rate (DCR), progression-free survival (PFS), OS, safety, and patient-reported outcomes. Results: At the time of the final data cutoff (May 29, 2021), median follow-up was 25.0 mo, and 96/103 pts (93%) had discontinued tx. The median number of tx cycles was 13.0 for a median tx duration of 9.1 mo. The confirmed ORR was 41.7% (43/103) and thereby the same as of the primary analysis, as was the DCR (at 82.5%). The ORR was consistent across pt subgroups. The mDOR was 9.5 mo, and 74% of responses lasted ≥6 mo. mPFS was 8.9 mo, with a 12-mo PFS rate of 35.4%. Mature mOS was 20.0 mo, with a 12-mo OS rate of 73.1% . No new safety signals were identified. Common tx-related adverse events (TRAEs) included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). TRAEs resulted in tx discontinuation in 4 pts (4%). No tx-related deaths occurred. Quality of life was maintained from baseline to tx cycle 13. Conclusions: Findings from the final analysis of FOENIX-CCA2 confirm the results of the primary analysis and reinforce the durable efficacy and continued tolerability of futibatinib in previously treated pts with advanced/metastatic iCCA harboring FGFR2 fusion/rearrangements. Mature OS data were consistent with data from the primary analysis and far exceed historical data in this patient population. Clinical trial information: NCT02052778.

Many nitrosamines are potent carcinogens, with more than 30 listed under California’s Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl-n-alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California’s Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.

| INTRODUC TI ONUnderstanding appropriate staffing levels and skill mix is an essential prerequisite in the quest for better quality, patient safety, patient experience, and efficiency. Most of the literature on staffing levels has focused on the nursing staff. Registered nurse (RN) staffing levels are associated with lower readmission rates, 1 lower mortality rates, 2 lower hospital-acquired infections rates, 3 and higher patient satisfaction. 4 Kane et al performed a meta-analysis on RN staffing levels and concluded that higher RN staffing levels are associated with better patient outcomes and quality. 5 Little, however, is known on the association between physician staffing Abstract Objective (or Study Question): To examine the association between hospitalists staffing levels and contract type with CMS Total Performance Score (TPS). Data Sources/Study Setting: Total performance scores were obtained from CMS, hospital-level data from the 2015 American Hospital Association Annual Survey Database, and unemployment rates from the Area Resource Health File. Study Design: We used cluster analysis to classify hospitals based on the distribution of various hospitalist contracts, and we used regression analysis to examine the association between TPS and hospitalist staffing levels and contract distributions. Hospital-level predictors included hospitalists staffing levels, RN staffing levels, and Magnet status. Market-level variables were unemployment rates and competition. Principal Findings: Higher staffing levels of employed hospitalists or hospitalists with a group contract are associated with higher TPS (with coefficient estimates of 0.85 and 0.83, respectively, and the same standard error of 0.22). Higher staffing levels of hospitalists under individual contract are negatively associated with TPS (with coefficient estimate of −0.43 and standard error of 0.21). Based on the regression analysis using hospital clusters as independent variables, hospitals with individual contractsor without hospitalists providing care had significantly worse TPS compared to hospitals that predominantly employ hospitalists (with coefficient estimate of −1.80 and standard error of 0.61). Magnet status, RN staffing levels, and small and medium size were positively associated with TPS. Medicare share of inpatient days, teaching status, AMCs, and for-profit and public nonfederal ownership were negatively associated with TPS. Conclusions:Adequate hospitalist staffing level is important for hospitals to achieve better performance. Hospitals need to consider the mix of arrangements or contracts that they have with hospitalists. K E Y W O R D Shospitalists, hospitals, staffing, total performance score, value-based purchasing | 45Health Services Research

Coumarin is a naturally occurring sweet-smelling benzopyrone that may be extracted from plants or synthesized for commercial uses. Its uses include as a flavoring agent, fragrance enhancer, and odor-masking additive. We reviewed and evaluated the scientific evidence on the carcinogenicity of coumarin, integrating information from carcinogenicity studies in animals with mechanistic and other relevant data, including data from toxicogenomic, genotoxicity, and metabolism studies, and studies of human variability of a key enzyme, CYP2A6. Increases in tumors were observed in multiple studies in rats and mice in multiple tissues. Our functional pathway analysis identified several common cancer-related biological processes/pathways affected by coumarin in rat liver following in vivo exposure and in human primary hepatocytes exposed in vitro. When coumarin 7-hydroxylation by CYP2A6 is compromised, this can lead to a shift in metabolism to the 3,4-epoxidation pathway and increased generation of electrophilic metabolites. Mechanistic data align with 3 key characteristics of carcinogens, namely formation of electrophilic metabolites, genotoxicity, and induction of oxidative stress. Considerations of metabolism, human variability in CYP2A6 activity, and coumarin hepatotoxicity in susceptible individuals provide additional support for carcinogenicity concern. Our analysis illustrates the importance of integrating information on human variability in the cancer hazard identification process.

Background The gamification of digital health provisions for older adults (eg, for rehabilitation) is a growing trend; however, many older adults are not familiar with digital games. This lack of experience could cause stress and thus impede participants’ motivations to adopt these technologies. Objective This crossover longitudinal multifactorial study aimed to examine the interactions between game difficulty, appraisal, cognitive ability, and physiological and cognitive responses that indicate game stress using the Affective Game Planning for Health Applications framework. Methods A total of 18 volunteers (mean age 71 years, SD 4.5; 12 women) completed a three-session study to evaluate different genres of games in increasing order of difficulty (S1-BrainGame, S2-CarRace, and S3-Exergame). Each session included an identical sequence of activities (t1-Baseline, t2-Picture encode, t3-Play, t4-Stroop test, t5-Play, and t6-Picture recall), a repeated sampling of salivary cortisol, and time-tagged ambulatory data from a wrist-worn device. Generalized estimating equations were used to investigate the effect of session×activity or session×activity×cognitive ability on physiology and cognitive performance. Scores derived from the Montreal Cognitive Assessment (MoCA) test were used to define cognitive ability (MoCA-high: MoCA>27, n=11/18). Kruskal-Wallis tests were used to test session or session×group effects on the scores of the postgame appraisal questionnaire. Results Session×activity effects were significant on all ambulatory measures (χ210>20; P<.001) other than cortisol (P=.37). Compared with S1 and S2, S3 was associated with approximately 10 bpm higher heart rate (P<.001) and approximately 5 muS higher electrodermal activity (P<.001), which were both independent of the movement caused by the exergame. Compared with S1, we measured a moderate but statistically significant drop in the rate of hits in immediate recall and rate of delayed recall in S3. The low-MoCA group did not differ from the high-MoCA group in general characteristics (age, general self-efficacy, and perceived stress) but was more likely to agree with statements such as digital games are too hard to learn. In addition, the low-MoCA group was more likely to dislike the gaming experience and find it useless, uninteresting, and visually more intense (χ21>4; P<.04). Group differences in ambulatory signals did not reach statistical significance; however, the rate of cortisol decline with respect to the baseline was significantly larger in the low-MoCA group. Conclusions Our results show that the experience of playing digital games was not stressful for our participants. Comparatively, the neurophysiological effects of exergame were more pronounced in the low-MoCA group, suggesting greater potential of this genre of games for cognitive and physical stimulation by gamified interventions; however, the need for enjoyment of this type of challenging game must be addressed.

Goal: The COVID-19 pandemic has left a significant impact on hospitals' operations, expenses, and revenues. However, little is known about the pandemic's financial impact on rural and urban hospitals. Our main objective was to analyze how hospital profitability changed during the first year of the pandemic. We specifically studied the association between COVID-19 infections and hospitalizations and county-level variables with operating margins (OMs) and total margins (TMs). Methods: We obtained data from Medicare Cost Reports, the American Hospital Association Annual Survey Database, and the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (CDC/ATSDR) for 2012–2020. Our final dataset consisted of an unbalanced panel with 17,510 observations for urban hospitals and 17,876 observations for rural hospitals. We estimated separate hospital fixed-effects models for urban and rural hospitals' OMs and TMs. The fixed-effects models controlled for time-invariant differences across hospitals. Principal Findings: In our review of the early impact of the COVID-19 pandemic on rural and urban hospitals' profits as well as trends in OMs and TMs from 2012 to 2020, we found that OMs were inversely related to the duration of hospitals' exposure to infections in urban and rural locations. In contrast, TMs and hospitals' exposures had a positive relationship. Government relief funds, a source of nonoperating revenue, apparently allowed most hospitals to avoid financial distress from the pandemic. We also found a positive relationship between the magnitude of weekly adult hospitalizations and OMs in urban and rural hospitals. Size, participation in group purchasing organizations (GPOs), and occupancy rates were positively related to OMs, with size and participation in GPOs relating to scale economies and occupancy rates reflecting capital efficiencies. Practical Applications: Hospitals' OMs have been declining since 2014. The pandemic made this decline worse, especially for rural hospitals. Federal relief funds, along with investment income, helped hospitals remain financially solvent during the pandemic. However, investment income and temporary federal aid are insufficient to sustain financial well-being. Executives need to explore cost-saving opportunities such as joining a GPO. Small rural hospitals with low occupancy and low community COVID-19 hospitalization rates have been particularly vulnerable to the financial impact of the pandemic. Although federal relief funds have limited hospital financial distress induced by the pandemic, we maintain that the funds should have been more effectively targeted, as the mean TM increased to its highest level in a decade. The disparate results of our analysis of OMs and TMs illustrate the utility of using multiple measures of profitability.

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Purpose The purpose of this article was to investigate the organizational and market-level variables associated with sustained superior hospital performance on Value-Based Purchasing total performance scores (TPS). Methodology TPS for 2014 through 2017 was obtained from the Centers for Medicare & Medicaid Services Hospital Compare website. Market-level data were from the 2017 Area Health Resource File, and hospital-level data were from the 2014 American Hospital Association Annual Survey database. We specified a logistic regression model to identify significant predictors of hospitals with sustained superior performance on TPS, that is, “sustainers.” Principal Findings Only 8.4% of hospitals were classified as sustainers. Hospitals located in rural markets with a high Medicare Advantage penetration had a higher likelihood of being classified as sustainers. High RN staffing levels, lower Medicare share of inpatient days, not-for-profit ownership, and small size were all significant organizational predictors of sustained superior performance. Conclusions Both modifiable characteristics, such as nurse staffing levels, and nonmodifiable characteristics, such as rural markets and small hospital size, are associated with the likelihood of hospitals sustaining superior performance over time. Practice Implications Managers need to carefully examine their staffing levels as they pursue interventions to sustain high TPS overtime. Moreover, factors such as Medicare share of inpatient days and size need to be considered when understanding barriers to sustained performance on Value-Based Purchasing domains.