Proton pump inhibitor use and risk of pneumonia: a self-controlled case series study.

BACKGROUND: Recent research indicates that use of proton pump inhibitors (PPIs) is associated with pneumonia, but existing evidence is inconclusive because of methodological issues. This study aimed to answer whether PPI-use increases risk of pneumonia while taking the methodological concerns of previous research into account. METHODS: This population-based and nationwide Swedish study conducted in 2005-2019 used a self-controlled case series design. Data came from national registries for medications, diagnoses, and mortality. Conditional fixed-effect Poisson regression provided incidence rate ratios (IRR) with 95% confidence intervals (CI) for pneumonia comparing PPI-exposed periods with unexposed periods in the same individuals, thus controlling for confounding. Analyses were stratified by PPI-treatment duration, sex, age, and smoking-related diseases. Use of histamine type-2 receptor antagonists (used for the same indications as PPIs) and risk of pneumonia was analysed for assessing the validity and specificity of the results for PPI-therapy and pneumonia. RESULTS: Among 519,152 patients with at least one pneumonia episode during the study period, 307,709 periods of PPI-treatment occurred. PPI-use was followed by an overall 73% increased risk of pneumonia (IRR 1.73, 95% CI 1.71-1.75). The IRRs were increased across strata of PPI-treatment duration, sex, age, and smoking-related disease status. No such strong association was found between histamine type-2 receptor antagonist use and risk of pneumonia (IRR 1.08, 95% CI 1.02-1.14). CONCLUSIONS: PPI-use seems to be associated with an increased risk of pneumonia. This finding highlights a need for caution in using PPIs in individuals with a history of pneumonia.

Identification and characterization of distinct cell cycle stages in cardiomyocytes using the FUCCI transgenic system.

Understanding the regulatory mechanism by which cardiomyocyte proliferation transitions to endoreplication and cell cycle arrest during the neonatal period is crucial for identifying proproliferative factors and developing regenerative therapies. We used a transgenic mouse model based on the fluorescent ubiquitination-based cell cycle indicator (FUCCI) system to isolate and characterize cycling cardiomyocytes at different cell cycle stages at a single-cell resolution. Single-cell transcriptome analysis of cycling and noncycling cardiomyocytes was performed at postnatal days 0 (P0) and 7 (P7). The FUCCI system proved to be efficient for the identification of cycling cardiomyocytes with the highest mitotic activity at birth, followed by a gradual decline in the number of cycling and mitotic cardiomyocytes during the neonatal period. Cardiomyocytes showed premature cell cycle exit at G1/S shortly after birth and delayed G1/S progression during endoreplication at P7. Single-cell RNA-seq confirmed previously described signaling pathways involved in cardiomyocyte proliferation (Erbb2 and Hippo/YAP), and maturation-related transcriptional changes during postnatal development, including the metabolic switch from glycolysis to fatty acid oxidation in cardiomyocytes. Importantly, we generated transcriptional profiles specific to cell division and endoreplication in cardiomyocytes at different developmental stages that may facilitate the identification of genes important for adult cardiomyocyte proliferation and heart regeneration. In conclusion, the FUCCI mouse provides a valuable system to study cardiomyocyte cell cycle activity at single cell resolution that can help to decipher the switch from cardiomyocyte proliferation to endoreplication, and to revert this process to facilitate endogenous repair.

No Evidence for Cardiomyocyte Number Expansion in Preadolescent Mice.

The magnitude of cardiomyocyte generation in the adult heart has been heavily debated. A recent report suggests that during mouse preadolescence, cardiomyocyte proliferation leads to a 40% increase in the number of cardiomyocytes. Such an expansion would change our understanding of heart growth and have far-reaching implications for cardiac regeneration. Here, using design-based stereology, we found that cardiomyocyte proliferation accounted for 30% of postnatal DNA synthesis; however, we were unable to detect any changes in cardiomyocyte number after postnatal day 11. (15)N-thymidine and BrdU analyses provided no evidence for a proliferative peak in preadolescent mice. By contrast, cardiomyocyte multinucleation comprises 57% of postnatal DNA synthesis, followed by cardiomyocyte nuclear polyploidisation, contributing with 13% to DNA synthesis within the second and third postnatal weeks. We conclude that the majority of cardiomyocytes is set within the first postnatal week and that this event is followed by two waves of non-replicative DNA synthesis. This Matters Arising paper is in response to Naqvi et al. (2014), published in Cell. See also the associated Correspondence by Soonpaa et al. (2015), and the response by Naqvi et al. (2015), published in this issue.