Background: New electronic heated tobacco products (HTPs) are being introduced in the global market and are gaining popularity. In 2016, Philip Morris International, Inc. (PMI) submitted a modified risk tobacco product (MRTP) application to the Food and Drug Administration (FDA) to market IQOS in the US with claims of reduced exposure and reduced risk. Methods: We examined PMI’s MRTP application, specifically sections on aerosol chemistry and human exposure assessment, to assess the validity of PMI’s claims of reduced exposure and risk. Findings: PMI reported levels for only 40 of 93 harmful and potentially harmful constituents (HPHCs) on FDA’s HPHC list in IQOS mainstream aerosol. All substances in PMI’s list of 58 constituents (PMI-58) were lower in IQOS emissions compared to mainstream smoke of 3R4F reference cigarettes. However, levels of 56 other constituents, which are not included in the PMI-58 list or FDA’s list of HPHCs, were higher in IQOS emissions; 22 were >200% higher and seven were >1000% higher than in 3R4F reference cigarette smoke. PMI’s studies also show significantly lower systemic exposure to some HPHCs from use of IQOS compared to smoking combustible cigarettes. Conclusion: PMI’s data appear to support PMI’s claim that IQOS reduces exposure to HPHCs. However, PMI’s data also show significantly higher levels of several substances which are not recognized as HPHCs by the FDA in IQOS emissions compared to combustible cigarette smoke. The impact of these substances on the overall toxicity or harm of IQOS is not known.

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Background and Aims Clinical trials on the impact and safety of reduced nicotine content cigarettes (RNCs) are ongoing, and an important methodological concern is participant compliance with smoking only RNCs. Our aims were to measure non-compliance biochemically with urine cotinine (COT) and total nicotine equivalents (TNEs), compare with self-reported non-compliance, and identify associated covariates. Design Secondary analysis of a double-blind, parallel, randomized clinical trial. Setting 10 research centers from the USA, enrolling participants from June 2013 to July 2014. Participants Volunteer sample of 242 participants (55% Caucasian), average age of 41.2 years, smoking at least 5 cigarettes per day (CPD). Intervention Smoking very low nicotine cigarettes (VLNCs; 0.4mg nicotine/g tobacco) for 6-weeks. Measurements The primary outcome was biochemically verified non-compliance, measured as thresholds of COT/CPD and TNE/CPD ratios, considering changes in nicotine content from conventional levels to VLNCs, and as an absolute threshold of Week 6 TNEs. Self-reported non-compliance was measured via daily phone calls. Key predictors included age, sex, race, menthol preference, nicotine metabolite ratio, time to first cigarette, dependence, CPD, TNEs, tar level and cigarette evaluation. Findings Estimates of non-compliance with smoking the VLNC cigarettes exclusively include: the biochemical ratios (both 78%), the Week 6 TNE threshold (76%) and self-report (39%). Of the key covariates, age, dependence and cigarette evaluations of satisfaction were significant; for age, younger participants more likely to be non-compliant (p=0.01; OR=0.98, 95% CI: 0.96–0.99). Dependence was significantly associated with self-reported non-compliance (p=0.01; OR=1.28, 95% CI: 1.06–1.55). Cigarette evaluations of satisfaction were significantly associated with non-compliance (p=0.001; OR=0.71, 95% CI: 0.61–0.82). Conclusions Biochemical assessments detect many more cases of non-compliance than self-report, and non-compliance with smoking VLNCs is observed in the majority of participants. Despite non-compliance, smokers reduced their intake of nicotine by an average of 60%, supporting the utility of nicotine reduction.

Objective To compare the relative effectiveness of methotrexate and mycophenolate mofetil for non-infectious intermediate uveitis, posterior uveitis, or panuveitis. Design Multicenter, block-randomized, observer-masked clinical trial Participants Eighty patients with non-infectious intermediate, posterior or panuveitis requiring corticosteroid-sparing therapy at Aravind Eye Hospitals in Madurai and Coimbatore, India. Intervention Patients were randomized to receive 25mg weekly oral methotrexate or 1g twice daily oral mycophenolate mofetil and were monitored monthly for 6 months. Oral prednisone and topical corticosteroids were tapered. Main Outcome Measures Masked examiners assessed the primary outcome of treatment success, defined by achieving the following at 5 and 6 months: (1) ≤0.5+ anterior chamber cells, ≤0.5+ vitreous cells, ≤0.5+ vitreous haze and no active retinal/choroidal lesions in both eyes, (2) ≤ 10 mg of prednisone and ≤ 2 drops of prednisolone acetate 1% a day and (3) no declaration of treatment failure due to intolerability or safety. Additional outcomes included time to sustained corticosteroid-sparing control of inflammation, change in best spectacle-corrected visual acuity, resolution of macular edema, adverse events, subgroup analysis by anatomic location, and medication adherence. Results Forty-one patients were randomized to methotrexate and 39 to mycophenolate mofetil. A total of 67 patients (35 methotrexate, 32 mycophenolate mofetil) contributed to the primary outcome. Sixty-nine percent of patients achieved treatment success with methotrexate and 47% with mycophenolate mofetil (p=0.09). Treatment failure due to adverse events or tolerability was not significantly different by treatment arm (p=0.99). There were no statistically significant differences between treatment groups in time to corticosteroid-sparing control of inflammation (p=0.44), change in best spectacle-corrected visual acuity (p=0.68), and resolution of macular edema (p=0.31). Conclusions There was no statistically significant difference in corticosteroid-sparing control of inflammation between patients receiving methotrexate or mycophenolate mofetil. However, there was a 22% difference in treatment success favoring methotrexate.