Aims Transthyretin amyloidosis (ATTR amyloidosis) is a heterogeneous disorder with cardiac, neurologic, and mixed phenotypes. We describe the phenotypic and genotypic profiles of this disease in continental Western Europe as it appears from the Transthyretin Amyloidosis Survey (THAOS). Methods and results THAOS is an ongoing, worldwide, longitudinal, observational survey established to study differences in presentation, diagnosis, and natural history in ATTR amyloidosis subjects. At data cut-off, 1411 symptomatic subjects from nine continental Western European countries were enrolled in THAOS [1286 hereditary (ATTRm) amyloidosis; 125 wild-type ATTR (ATTRwt) amyloidosis]. Genotypes and phenotypes varied notably by country. Four mutations (Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu), and ATTRwt, were associated with a mainly cardiac phenotype showing symmetric left ventricular (LV) hypertrophy, normal diastolic LV dimensions and volume, and mildly depressed LV ejection fraction (LVEF). Morphologic and functional abnormalities on echocardiogram were significantly more severe in subjects with cardiac (n‘= 210), compared with a mixed (n = 298), phenotype: higher median (Q1–Q3) interventricular septal thickness [18 (16–21) vs. 16 (13–20) mm; P = 0.0006]; and more frequent incidence of LVEF <50% (38.1 vs. 17.5%; P = 0.0008). Subjects with cardiac mutations or ATTRwt (or cardiac or mixed phenotype) had a lower survival rate than subjects in other genotype (or the neurologic phenotype) categories (P < 0.0001, for both). Conclusion ATTR amyloidosis genotypes and phenotypes are highly heterogeneous in continental Western Europe. A geographic map of the different disease profiles and awareness that a subset of subjects have a dominant cardiac phenotype, mimicking hypertrophic cardiomyopathy, at presentation can facilitate the clinical recognition of this underdiagnosed disease. Trial registration ClinicalTrials.gov: NCT00628745.

Importance Some cigarette smokers may not be ready to quit immediately but may be willing to reduce cigarette consumption with the goal of quitting. Objective To determine efficacy and safety of varenicline for increasing smoking abstinence rates through smoking reduction. Design, Setting, and Participants Randomized, blinded, placebo-controlled, multinational clinical trial with a 24-week treatment period and 28-week follow-up conducted between July 2011 and July 2013 at 61 centers in 10 countries. 1510 cigarette smokers not willing or able to quit smoking within the next month but willing to reduce smoking and make a quit attempt within the next 3 months recruited through advertising. Interventions Twenty-four weeks of varenicline titrated to 1 mg twice daily or placebo with reduction target of ≥ 50% in number of cigarettes smoked by 4 weeks and ≥ 75% by 8 weeks and a quit attempt by 12 weeks. Main Outcome Measures Primary efficacy endpoint was carbon monoxide (CO)-confirmed self-reported abstinence during weeks 15-24. Secondary outcomes were CO-confirmed self-reported abstinence rate for weeks 21-24 and weeks 21-52. Results The varenicline group (N = 760) had significantly higher continuous abstinence rates during weeks 15-24 versus placebo (N = 750) (32.1% vs 6.9%; risk difference (RD) 25.2%; 95% CI 21.4%, 29.0%; relative risk (RR) = 4.6; 95% CI 3.5, 6.1). The varenicline group had significantly higher continuous abstinence rates versus placebo during weeks 21-24 (37.8% vs 12.5%; RD 25.2%; 95 CI 21.1%, 29.4%; RR 3.0; 95% CI 2.4, 3.7) and weeks 21-52 (27.0% vs 9.9%; RD 17.1%; 95% CI 13.3%, 20.9%; RR 2.7; 95% CI 2.1, 3.5). Serious adverse events occurred in 3.7% and 2.2% of the varenicline and placebo groups, respectively (P = 0.07). Conclusions and Relevance Among cigarette smokers not willing or able to quit within the next month but willing to reduce cigarette consumption and make a quit attempt in the next 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates through 6 months of follow up. Varenicline offers a treatment option for smokers whose needs are not addressed by clinical guidelines recommending abrupt smoking cessation. Trial Registration www.clinicaltrials.gov (NCT01370356): https://clinicaltrials.gov/ct2/results?term=NCT01370356&Search=Search

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Significant increases in body weight or BMI were not observed in postmenopausal women receiving CE 0.45 mg/BZA 20 mg or CE 0.625 mg/BZA 20 mg for up to 2 years in the Selective Estrogens, Menopause, and Response to Therapy trials.

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CE/BZA effectively reduces moderate/severe HFs in postmenopausal women. NCT#'s: NCT00675688; NCT00234819.