Background: Inhibitors of the anaplastic lymphoma kinase (ALK) gene mutation are highly effective treatments for ALKpositive lung cancer. We conducted this pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS). Patients and methods: FAERS files from 2012 to 2020 were used. Reports for crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib were filtered. We used the Medical Dictionary for Regulatory Activities (MedDRA version 22.1). Further, we searched for adverse events on the preferred term (PT) level based on case reports in the literature. After filtering duplicate reports, disproportionality analysis was used to detect safety signals by calculating proportional reporting ratios (PRRs), reporting odds ratios (RORs), empirical Bayesian geometric mean, and information component. Reports were considered statistically significant if the 95% confidence interval did not contain the null value. Results: Within the system organ classes, significant safety signals were found, including those for crizotinib [eye disorders (PRR 2.09, ROR 2.12)], ceritinib [gastrointestinal disorders (PRR 2.19, ROR 2.41), hepatobiliary disorders (PRR 4.4, ROR 4.52), respiratory disorders (PRR 1.96, ROR 2.08)], alectinib [hepatobiliary disorders (PRR 2.60, ROR 2.63)], brigatinib [respiratory disorders (PRR 2.15, ROR 2.31)], and lorlatinib [metabolism disorders (PRR 3.34, ROR 3.53)]. For adverse events on the PT level, we found several significant signals, including pneumothorax with crizotinib (

Background This study investigated the association between menopausal hormone therapy (HT) use and the subgingival microbiome, for which published information is limited. Methods This cross‐sectional study included 1270 postmenopausal women, aged 53–81 years, who completed clinical examinations. Detailed information on HT use (type, delivery mode, duration) was obtained from questionnaires. HT use was categorized into three groups (never, former, current). 16S rRNA sequencing was performed on subgingival plaque samples obtained during dental examinations. Operational taxonomic units were centered log2‐ratio (CLR) transformed to account for the compositional data structure. Analysis of variance was used to compare mean microbial relative abundances across HT categories with Benjamini‐Hochberg correction. Results Significantly higher alpha diversity (Shannon Index) and beta diversity (Aitchison distance) was observed in never compared with current HT users (p < 0.05, each). Of the total 245 microbial taxa identified, 18 taxa differed significantly among the three HT groups, 11 of which were higher in current users and seven of which were lower in current users as compared with never users (p < 0.05, each). Differences in relative abundance between never and current HT users were materially unchanged after adjustment for age, body mass index, and oral hygiene. Conclusions Relative abundance of several subgingival bacteria differed significantly between never and current HT users in a cohort of postmenopausal women. Additional studies are needed to determine the extent that these relationships might account for the previously reported inverse association between HT use and periodontal disease in older women.

Background: Accumulating evidence suggests that participating in physical activity (PA) following heart failure (HF) diagnosis is associated with better prognosis, including lower mortality risk. Few studies have focused on this relationship in postmenopausal women, in whom HF burden is high. Methods: The present study, conducted in the Women’s Health Initiative, included 2,181 postmenopausal women (mean age 68 years; 85% white, 10% black, 3% Hispanic at enrollment in 1993-1998) who were diagnosed postbaseline with incident hospitalized acute HF and had at least one self-reported PA assessment before and after (mean age 73 at latter assessment) HF diagnosis. Total recreational PA was summarized in metabolic equivalent (MET) hours per week. Women were followed for all-cause mortality from their post-HF PA assessment through March 2014. Cox regression with age as the time scale was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for mortality associated with PA categories (before/after HF): Inactive (<7.5 MET-hr/wk)/Inactive, n=1,048; Active (≥7.5 MET-hr/wk)/Inactive, n=407; Inactive/Active, n=212; Active/Active, n=514. Results: There were 1,047 (48%) deaths during a mean follow-up of 12 years. Crude mortality rates per 1,000 person-years [number of deaths] across the above PA groups were 42.4 [533], 42.1 [206], 36.9 [94], and 34.7 [214]. After adjusting for age (timescale), race and ethnicity, and WHI study component, HRs (95% CI) for mortality across the PA groups were 1.00 (referent), 0.94 (0.79, 1.10), 0.80 (0.64, 1.01), and 0.60 (0.51, 0.71). Further adjustment for baseline education, BMI, physical function, smoking, menopausal hormone use, history of diabetes, hypertension, myocardial infarction, stroke, coronary revascularization, atrial fibrillation, and incident myocardial infarction during follow-up prior to HF diagnosis attenuated these associations but did not eliminate statistical significance for the Active/Active group: 1.00 (referent), 1.04 (0.87, 1.24), 0.87 (0.69, 1.10), 0.74 (0.62, 0.89). A similar pattern of results was evident when cardiovascular mortality was the study outcome. Conclusions: Maintaining PA levels following hospitalization for acute HF was associated with lower all-cause mortality in older postmenopausal women, an understudied population in this regard. Among women whose PA following HF diagnosis was higher than their pre-HF PA level, there was a trend for lower mortality although this did not achieve statistical significance. Studies are needed to determine whether PA is associated with prognosis in HF subtypes, such as HF with preserved ejection which is a prevalent HF subtype in older women.

Background: The risk of secondary cardiovascular events associated with proton pump inhibitor (PPI) use and their interaction with thienopyridine antiplatelets such as clopidogrel is well established. Recent evidence from in-vitro and animal studies suggests PPIs may impact cardiovascular disease (CVD) irrespective of antiplatelet use. However, whether PPI use is associated with primary cardiovascular events in humans remains uncertain. Methods: Systematic searches were conducted in the MEDLINE and EMBASE databases from their inception to September 2022. Inclusion criteria included studies that examined participants free from cardiovascular disease at baseline who were followed over time to assess any of the following outcomes according to PPI use: incident myocardial infarction (MI), incident ischemic stroke (IS), or CVD mortality. Hazard ratios (HR) and their 95% confidence intervals (CI) were abstracted, combined estimates and heterogeneity (I 2 ) were calculated using the random-effects model in RevMan 5.4 software. Results: A total of 15 observational studies met the inclusion criteria, 2,272,479 participants were studied for MI, 2,689,943 for IS, and 1,591,428 for CVD mortality. The mean age of participants ranged from 49.3 to 82.2 years. Compared to non-use, PPI use was associated with 30% higher risk of incident MI (HR: 1.30, 95%CI: 1.10-1.53, I 2 =91%) and 15% higher risk of CVD mortality (HR: 1.15, 95%CI: 1.05-1.26, I 2 =56%). However, there was no statistically significant association with incident IS (HR: 1.05, 95%CI: 0.91-1.22, I 2 =96%). Conclusion: The meta-analysis results from published studies suggests PPI use is associated with higher risk of incident MI and CVD mortality. However, these findings should be interpreted with caution given the considerable heterogeneity among published studies and the possibility of residual confounding. More studies are needed to address these limitations and determine the validity of these associations.