Pulmonary Health Effects of Electronic Cigarettes: A Scoping Review.

BACKGROUND: There is global concern regarding the public health impact of electronic cigarettes (ECs). ECs are commonly promoted as safer than conventional cigarettes (CCs), however there is limited knowledge of the long-term health effects. This scoping review examined the pulmonary health effects of ECs reported in the literature from 2009 to 2019. METHOD: PubMed, CINAHL, and Science Direct databases were used. Search terms included "vaping, electronic nicotine delivery systems, electronic cigarettes, lung diseases, respiratory diseases, and pulmonary." Original research articles in English that used human subjects between January 1, 2009 and January 31, 2020 and reported pulmonary outcomes were included. RESULTS: Forty-five studies met the inclusion criteria. There were 14 (31.1%) randomized experimental, 7 (15.6%) nonrandomized experimental, 6 (13.3%) cohort, and 18 (40.0%) cross-sectional studies. Sixteen (35.6%) studies were conducted in the United States; the rest were conducted across 11 other countries. The total number of subjects was 1,465,292 and ages ranged from 12 to 99 years across studies. Eligible studies demonstrated an association between EC use and pulmonary symptoms, asthma and chronic obstructive pulmonary disease diagnosis and exacerbations. The degree of this association varied based on the use of additional tobacco products. EC use resulted in worse outcomes than nonsmoking, but resulted in improved outcomes when compared with CC use or dual use of CC and EC. CONCLUSION: Evidence indicates that EC use, especially dual use, leads to negative pulmonary effects and adverse outcomes. Education on the potential risks and publishing of EC ingredients on labels could help improve public health safety communication and reduce EC use.

A network meta-analysis of efficacy and safety of first-line and second-line therapies for the management of metastatic renal cell carcinoma.

WHAT IS KNOWN AND OBJECTIVE: Metastatic renal cell carcinoma (mRCC) is the most common type of kidney cancers. Disease-specific survival for mRCC has been significantly improved with the introduction of new targeted agents since 2005. However, there is a lack of head-to-head clinical trials comparing the efficacy between therapies. This study compared indirectly progression-free survival (PFS) and overall survival (OS) among first-line and second-line therapies in patients with mRCC using network meta-analysis (NMA). METHODS: The PubMed, MEDLINE, Cochrane Library and Web of Science were searched to identify phase II or phase III randomized controlled trials (RCTs) of targeted and biological therapies in patients with mRCC published between January 2000 and June 2020. The Bayesian fixed-effect NMA was performed to evaluate relative PFS and OS of first-line and second-line therapies of axitinib, bevacizumab, cabozantinib, everolimus, lenvatinib, nivolumab, ipilimumab, pazopanib, sorafenib, sunitinib, temsirolimus, tivozanib, avelumab and pembrolizumab, which were approved by the Food and Drug Administration or European Medicines Agency. End points were compared using hazard ratio (HR) and 95% credible interval (CrI). The surface under the cumulative ranking curve (SUCRA) was estimated to assess the probability of being the best treatment. RESULTS AND DISCUSSION: A total of 26 RCTs (first line: 19, second line: 9) with 13 893 patients were included in the NMA. For the first-line therapy, cabozantinib was associated with the highest improved PFS (HR = 0.26, 95% CrI = 0.14-0.44) followed by avelumab + axitinib and pembrolizumab + axitinib (HR = 0.27, SUCRA = 90%). Pembrolizumab + axitinib had a high likelihood of being the preferred treatment when using OS as the outcome measure (HR = 0.41, 95% CrI = 0.16-0.85). Avelumab + axitinib had the lowest HR compared with placebo + interferon on discontinuations due to AE (HR = 1.04, 95% CrI = 0.54-1.86). For second-line therapy, cabozantinib was identified as the most effective treatment option when assessing PFS (HR = 0.17, 95% CrI = 0.12-0.24). Axitinib had the lowest HR of OS and discontinuation due to AE (HR = 0.54, 95% CrI = 0.40-0.71; HR = 0.98, 95% CrI = 0.42-1.97, respectively). Pazopanib was the second choice in terms of OS (HR = 0.56, 95% CrI = 0.28-1.00; SUCRA = 76%) compared with placebo. WHAT IS NEW AND CONCLUSION: With respect to PFS and OS improvement, cabozantinib, avelumab + axitinib and pembrolizumab + axitinib are likely to be the preferred options for the first-line therapy and cabozantinib and axitinib for the second-line therapy in the management of mRCC. Regarding safety, avelumab + axitinib and temsirolimus were considered preferred treatment options in first-line and second-line therapies. More future research is needed to establish subgroup analyses, allowing evaluation of the impact of some of the differences in patient characteristics, including treatment effect modifiers.

A general strategy for the synthesis of cyclic N-aryl hydroxamic acids via partial nitro group reduction.

We describe a generalized approach to stereocontrolled synthesis of substituted cyclic hydroxamic acids (3-amino-1-hydroxy-3,4-dihydroquinolinones) by selective reduction of substituted 2-nitrophenylalanine substrates. Compounds in this series have antibacterial properties and have also recently been reported as KAT II inhibitors. The key nitrophenyl alanine intermediates are prepared enantioselectively in excellent yield by phase transfer catalyzed alkylation of the corresponding nitrobenzyl bromides. The scope and limitations of the reductive cyclization transformation have been explored with attention to the effects of substitution pattern and electronics on reaction efficiency and byproduct formation. In addition, a novel activated trifluoroethyl ester cyclization strategy has been developed as an alternate approach to the most sterically demanding systems in this series.

Health Behaviors and Health-Related Quality of Life Among U.S. Adults Aged 18-64 Years.

INTRODUCTION: This study aims to (1) describe the prevalence and clustering of 3 health behaviors, (2) examine the association between individual health behaviors and health-related quality of life, and (3) explore the association between the clustering of the health behaviors and health-related quality of life. METHODS: Investigators analyzed a sample of U.S. adults aged 18-64 years using data from the 2016-2018 Behavioral Risk Factor Surveillance System survey in March 2020. Logistic regression models examined the associations among 3 healthy behaviors (currently not smoking, physical activity, and nonheavy alcohol consumption) and 4 indicators of health-related quality of life (general health, physical health, mental health, and activity limitation). Alpha was set at 0.01. RESULTS: A total of 450,870 individuals were included in the analysis (weighted n=100,102,329). Of these, 82.0% were current nonsmokers, 92.8% were nonheavy drinkers, and 77.6% reported physical activity. The prevalence of having none, 1, 2, and 3 of the health behaviors was 0.7%, 7.7%, 30.1%, and 61.5%, respectively. Smoking status and physical activity status were significantly associated with all the 4 health-related quality of life indicators. Alcohol status was significantly associated with mental health and activity limitation. The associations demonstrated a higher health-related quality of life among individuals who reported healthy behaviors than among those who did not engage in healthy behaviors. Compared with respondents who reported none of the health behaviors, people with all 3 health behaviors were more likely to report higher health-related quality of life. CONCLUSIONS: Health behaviors were significantly associated with health-related quality of life among U.S. adults. Healthy behaviors should be encouraged because adopting these behaviors may contribute to a higher health-related quality of life.

Predictors of Annual Base Salary for Health Economics, Outcomes Research, and Market Access Professionals in the Biopharmaceutical Industry.

BACKGROUND: Analysis of salary data for health economics, outcomes research, and market access professionals in biopharmaceutical space plays an important role in hiring talent, benchmarking remuneration, and evaluating income discrepancies. OBJECTIVES: To (a) identify predictors of annual base salary (ABS) for health economics, outcomes research, and market access professionals who participated in the 2017 Global Salary Survey by HealthEconomics.Com and (b) evaluate salary-related gender disparity among survey respondents. METHODS: 501 professionals from the HealthEconomics.Com global subscriber list participated in a survey that assessed salary, bonus, benefits, and job satisfaction in June 2017. Two multivariable regression models identified significant predictors of ABS for U.S. and non-U.S. regions separately. Analysis of variance determined interaction effects between gender, organizational size, job title, and people management responsibilities separately. RESULTS: Of the 501 respondents, 385 were included in the analysis because they reported ABS. Median ABS for male (n = 117) and female (n = 111) U.S.-based respondents was $172,500 and $162,500, respectively. For male (n = 75) and female (n = 65) non-U.S.-based respondents, the median was identical at $92,500. Mean (SD) ABS between male ($180,534 [$77,755]) and female ($165,113 [$64,604]; t [226] = 1.62; P = 0.106) U.S. respondents was not significantly different. Mean (SD) ABS for male ($110,900 [$65,898]) and female ($98,039 [$48,639]; t [138] = 1.30; P = 0.196) non-U.S. respondents was not significantly different, as well. Multivariable regression models for U.S. and non-U.S. respondents accounted for 62.7% and 63.9% of variance in ABS (P < 0.001), respectively. In both models, significantly higher salaries were associated with professionals aged > 40 years; biopharmaceutical employment; having a PhD, PharmD, or MD; and having a job title of president or director (all P < 0.05). CONCLUSIONS: After controlling for covariates, gender was not statistically significantly associated with ABS. Age, organization type, terminal degree, and job title were significant predictors of higher salaries inside and outside of the United States. Additional research should be conducted to increase generalizability of results, which were based on a convenience sample. DISCLOSURES: No funding supported this research. Shah and Peeples are employed by HealthEconomics.Com, which administered the survey used in this study. The authors report no other potential conflicts of interest.

A Systematic Review of the Effect of Cancer Treatment on Work Productivity of Patients and Caregivers.

BACKGROUND: Cancer is a leading cause of death with substantial financial costs. While significant data exist on the economic burden of care, less is known about the indirect costs of treatment and, specifically, the effect on work productivity of patients and their caregivers. To examine the full effect of cancer and the potential value of new therapies, all aspects of care, including indirect costs and patient-reported outcomes, should be evaluated. OBJECTIVE: To perform a systematic review of the literature examining the effect of cancer treatment on work productivity in patients and their caregivers. METHODS: Articles, abstracts, and bibliographies were searched in MEDLINE, Cochrane, Scopus, CINAHL, and conference lists from the American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Academy of Managed Care Pharmacy up to January 2016. The PRISMA guidelines were used. Controlled search terminology included individual pharmacologic therapies for cancer and terms related to patient and caregiver work productivity. Citations were included if they evaluated the effect of cancer treatment on work productivity, used and described productivity assessments and instruments, and were written in English. Studies that reported only clinical outcomes or assessed only nonpharmacological treatments were excluded. Identified studies were screened and extracted for study inclusion by 2 independent reviewers, with adjudication by 2 secondary reviewers during the final eligibility phase. RESULTS: Of 978 potential citations, 62 articles or abstracts were included. Forty-six studies (74.2%) evaluated patient-related productivity; 10 studies (16.1%) focused on caregivers, and 6 studies (9.7%) were a combination. Sixteen countries contributed literature, including 26 studies (41.2%) conducted in the United States. The most commonly studied cancer was breast cancer (53.2%). Nearly 22% of the studies were conducted on multiple types of cancer. The significant diversity of study methodologies and measurements rendered a single unifying conclusion difficult. A variety of metrics were used to quantify productivity (hours lost, return to work, change of status, and activity impairment). The Work Productivity and Activity Impairment questionnaire was the most commonly used standardized tool (n = 9; 14.5%). Factors found to be associated with impairment in productivity included disease- and treatment-related effects, such as disease progression and severity, cognitive and neurological impairments, poor physical and psychological status, receipt of chemotherapy, and time and expenses required to receive therapy. CONCLUSIONS: This review highlights the considerable variety of studies that have assessed work productivity for cancer treatment and the multifaceted reasons affecting patients and caregivers. With increasing emphasis being given to understanding the value that patients assign to various aspects of cancer treatment, more streamlined information on productivity may be important to patients as they play a greater role in selecting treatment goals through shared decision making with their providers. DISCLOSURES: This study was funded by Novartis Pharmaceuticals, which provided the concept, general oversight, and research collaboration on the project. Covvey and Kamal received research funding from Novartis Pharmaceuticals and the College of Psychiatric and Neurologic Pharmacists. Zacker is employed by, and owns stock in, Novartis Pharmaceuticals. A related poster abstract was presented at the Academy of Managed Care Pharmacy April 2016 Annual Meeting and published as Kamal KM, Covvey JR, Dashputre A, Ghosh S, Zacker C. A conceptual framework for valuebased oncology treatment: a societal perspective. J Manag Care Spec Pharm. 2016;22(4 Suppl A):S28. A publication-only abstract was presented at the American Society of Clinical Oncology 2016 Annual Meeting and published as Covvey JR, Kamal KM, Dashputre A, Ghosh S, Zacker C. The impact of cancer treatment on work productivity of patients and caregivers: a systematic review of the evidence. J Clin Oncol. 2016;34(Suppl):e18249. Study concept and design were contributed by Zacker, Kamal, and Covvey. Dashputre and Ghosh took the lead in data collection, along with Kamal and Covvey, and data interpretation was performed primarily by Shah and Bhosle, along with Ghosh, Dashputre, Covvey, and Kamal. The manuscript was written by Kamal, Covvey, Shah, and Bhosle and revised primarily by Zacker, along with Shah, Bhosle, Kamal, and Covvey.

Discovery and Characterization of (R)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates.

We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.

Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions.

A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure-activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact/K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.

Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.

Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

Metalated nitriles: internal 1,2-asymmetric induction.

Alkylations of conformationally constrained acyclic nitriles containing vicinal dimethyl groups and an adjacent phenyl group or trisubstituted alkene are exceptionally diastereoselective. Probing the alkylation stereoselectivity with a series of C- and N-metalated nitriles implicates a reactive conformation in which an sp2-hybridized substituent projects over the metalated nitrile to avoid allylic strain. Steric screening thereby directs the electrophilic attack to the face of the metalated nitrile opposite the projecting substituent. Excellent stereoselectively is maintained in a diverse range of alkylations that efficiently install quaternary centers, even with isopropyliodide in which a contiguous array of tertiary-quaternary-tertiary stereocenters is created! Screening the conformational requirements with a series of acyclic nitriles and esters reveals the key structural requirements for high selectivity while providing a robust, predictive model that accounts for comparable ester alkylations affording the opposite diastereomer! The intensive survey of metalated nitrile alkylations identifies the key structural features required for high 1,2-asymmetric induction, addresses the long-standing challenge of asymmetric alkylations with acylic metalated nitriles, and provides a versatile method for installing hindered quaternary centers with excellent stereocontrol.