Correction: Assessing the consistency of iPSC and animal models in cystic fibrosis modelling: A meta-analysis.

[This corrects the article DOI: 10.1371/journal.pone.0272091.].

CCN3, POSTN, and PTHLH as potential key regulators of genomic integrity and cellular survival in iPSCs.

Reprogramming human somatic cells into a pluripotent state, achieved through the activation of well-defined transcriptional factors known as OSKM factors, offers significant potential for regenerative medicine. While OSKM factors are a robust reprogramming method, efficiency remains a challenge, with only a fraction of cells undergoing successful reprogramming. To address this, we explored genes related to genomic integrity and cellular survival, focusing on iPSCs (A53T-PD1) that displayed enhanced colony stability. Our investigation had revealed three candidate genes CCN3, POSTN, and PTHLH that exhibited differential expression levels and potential roles in iPSC stability. Subsequent analyses identified various protein interactions for these candidate genes. POSTN, significantly upregulated in A53T-PD1 iPSC line, showed interactions with extracellular matrix components and potential involvement in Wnt signaling. CCN3, also highly upregulated, demonstrated interactions with TP53, CDKN1A, and factors related to apoptosis and proliferation. PTHLH, while upregulated, exhibited interactions with CDK2 and genes involved in cell cycle regulation. RT-qPCR validation confirmed elevated CCN3 and PTHLH expression in A53T-PD1 iPSCs, aligning with RNA-seq findings. These genes' roles in preserving pluripotency and cellular stability require further exploration. In conclusion, we identified CCN3, POSTN, and PTHLH as potential contributors to genomic integrity and pluripotency maintenance in iPSCs. Their roles in DNA repair, apoptosis evasion, and signaling pathways could offer valuable insights for enhancing reprogramming efficiency and sustaining pluripotency. Further investigations are essential to unravel the mechanisms underlying their actions.

Use of conditional estimates of effect in cancer epidemiology: An application to lung cancer treatment.

BACKGROUND: In oncology clinical trials, there is the assumption that randomization sufficiently balances confounding covariates and therefore average treatment effects are usually reported. This paper explores the wider benefits provided by conditioning on covariates for reasons other than mitigation of confounding. METHODS: We reanalyzed the data from primary randomized controlled trials listed in two meta-analyses to explore the significance of conditioning on smoking status in terms of the effect magnitude of treatment on progression free survival in non-small cell lung cancer. RESULTS: The reanalysis revealed that conditioning on smoking status using sub-group analyses provided the closest empiric estimate of individual treatment effect based on smoking status and significantly reduced the heterogeneity of treatment effect observed across studies. In addition, smoking status was determined to be a modifier of the effect of treatment. CONCLUSION: Conditioning on prognostic covariates in randomized trials in oncology helps generate the closest empiric estimates of individual treatment benefit, addresses heterogeneity due to varying covariate distributions across trials and facilitates future decision making as well as evidence synthesis. Conditioning using sub-group analyses also allows examination for effect modification in meta-analysis.

What is Polypharmacy in Patients with Chronic Kidney Disease? A Systematic Review.

PURPOSE: Polypharmacy presents an increasing therapeutic challenge for physicians managing patients with chronic kidney disease (CKD). However, there is a lack of consensus regarding the specific medication count threshold that defines polypharmacy in this population. The objective of this review is to establish a unified definition of polypharmacy in the CKD population by examining the diverse definitions used in previously published studies. METHODS: A comprehensive search was conducted in relevant databases (PubMed, SCOPUS, Cochrane, and disease-specific databases) from 2000 to May 2022 to identify studies with polypharmacy threshold definitions in patients with CKD. Studies meeting the inclusion criteria were included in this review, and their methodologic quality was assessed. FINDINGS: Following the screening of the search results, duplicate records and studies that did not meet the inclusion criteria were removed, resulting in a total of 18 studies included in this review. Among these, 61.1% specified the polypharmacy definition to be a threshold of ≥5 medications. In addition, 22.2% specified a high polypharmacy definition at a threshold of ≥10 medications. However, none of the studies reported on the dichotomy between kidney-related and non-kidney-related polypharmacy. IMPLICATIONS: This review indicates that a numerical threshold of ≥5 medications is commonly used to define polypharmacy in patients with CKD. Nevertheless, it remains uncertain whether a kidney-related polypharmacy definition or a high polypharmacy definition would better identify patients with CKD at risk for polypharmacy-related complications.

Prevalence and global trends of polypharmacy in patients with chronic kidney disease: A systematic review and meta-analysis.

Background and objectives: Polypharmacy and chronic kidney disease (CKD) are becoming increasingly common due to an ageing population and the rise of multimorbidity. In line with the therapeutic guidelines, managing CKD and its complications necessitates prescribing multiple medications, which predisposes patients to polypharmacy. The aim of this systematic review and meta-analysis is to describe the prevalence of polypharmacy in patients with CKD and to explore the global trends of factors driving any apparent variability in prevalence estimates. Methods: PubMed, Scopus, the Cochrane Database of Systematic Reviews (CDSR), and Google Scholar were searched from 1999 to November 2021. Study selection, data extraction, and critical appraisal were conducted by two independent reviewers. The pooled prevalence of polypharmacy was estimated utilizing the random effects model using the default double arcsine transformation. Results: This review involved 14 studies comprising of 17 201 participants, a significant proportion of which were males (56.12%). The mean age of the review population was 61.96 (SD ± 11.51) years. The overall pooled prevalence of polypharmacy amongst patients with CKD was 69% (95% CI: 49%-86%) (I2 = 100%, p < 0.0001), with a proportionately higher prevalence in North America and Europe as compared to Asia. Conclusion: The results from this meta-analysis showed a high pooled prevalence estimates of polypharmacy amongst patient cohorts with CKD. The exact interventions that are likely to significantly mitigate its effect remain uncertain and will need exploration by future prospective and systematic studies. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022306572].

Assessing the consistency of iPSC and animal models in cystic fibrosis modelling: A meta-analysis.

INTRODUCTION: Cystic fibrosis (CF) is a hereditary autosomal recessive disorder caused by a range of mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. This gene encodes the CFTR protein, which acts as a chloride channel activated by cyclic AMP (cAMP). This meta-analysis aimed to compare the responsiveness of induced pluripotent stem cells (iPSCs) to cAMP analogues to that of commonly used animal models. METHODS: Databases searched included PubMed, Scopus, and Medline from inception to January 2020. A total of 8 and 3 studies, respectively, for animal models and iPSCs, were analyzed. Studies were extracted for investigating cAMP-stimulated anion transport by measuring the short circuit current (Isc) of chloride channels in different animal models and iPSC systems We utilized an inverse variance heterogeneity model for synthesis. RESULTS: Our analysis showed considerable heterogeneity in the mean Isc value in both animal models and iPSCs studies (compared to their WT counterparts), and both suffer from variable responsiveness based on the nature of the underlying model. There was no clear advantage of one over the other. CONCLUSIONS: Studies on both animal and iPSCs models generated considerable heterogeneity. Given the potential of iPSC-derived models to study different diseases, we recommend paying more attention to developing reproducible models of iPSC as it has potential if adequately developed.