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.

In patients with chronic heart failure which polypharmacy pheno-groups are associated with adverse health outcomes? (Polypharmacy pheno-groups and heart failure outcomes).

BACKGROUND: Patients with heart failure are living longer with the inevitable morbidity of rising medication counts. It remains uncertain what fraction of this ensuing polypharmacy exactly predicts adverse clinical outcomes. METHODS: This prospective study examined records of patients admitted to a Weill Cornell-affiliated tertiary medical institution with a confirmed diagnosis of heart failure between January 2018 to January 2022. Each patient's medications for the past four months were tallied, and a definitional threshold of ≤4, ≥5, ≥10 medications was established. The primary outcome was all-cause mortality within the study period. RESULTS: Out of a total of 7354 patients included in the study, 70 % were males with a median age of 59 years IQR (48-71). The median (IQR) age-adjusted Charlson Comorbidity Index (CCI) was 21-5. A total of 1475 (20 %) participants died within the study period. Patient cohorts with excessive polypharmacy (≥9 medications) had the highest probability of survival up to 1.6 years compared to those with lower medication thresholds (≤4); the mortality rate decreased by 18 % for patients with excessive polypharmacy [HR = 0.82, 95 % CI: 0.71-0.94]). Conversely, patients with non-heart failure-related polypharmacy had increased risks of ICU admissions (aOR = 1.78, 95 % CI: 1.13-2.70). CONCLUSION: In an examination of a database of patients with chronic heart failure, major non-heart failure-related polypharmacy was associated with increased risks in intensive care admissions. Excessive polypharmacy was associated with increased rates of survival.

Prevalence and global trends of polypharmacy among people living with HIV: a systematic review and meta-analysis.

Background: There has been a rising prevalence of polypharmacy among people living with HIV (PLWH). Uncertainty however remains regarding the exact estimates of polypharmacy among these cohorts of patients. Methods: We conducted a systematic search of PubMed; EMBASE, CROI, Cochrane Database of Systematic Reviews; Science Citation Index and Database of Abstracts of Reviews of Effects for studies between 1 January 2000 and 30 June 2021 that reported on the prevalence of polypharmacy (ingestion of > 5 non-ART medications) among PLWH on antiretroviral therapy regimen (ART). Prevalence of polypharmacy among HIV-positive patients on ART with Clopper-Pearson 95% confidence intervals were presented. The heterogeneity between studies was evaluated using I 2 and τ 2 statistics. Results: One hundred ninety-seven studies were initially identified, 23 met the inclusion criteria enrolling 55,988 PLWH, of which 76.7% [95% confidence interval (CI): 76.4-77.1] were male. The overall pooled prevalence of polypharmacy among PLWH was 33% (95% CI: 25-42%) (I 2 = 100%, τ2 = 0.9170, p < 0.0001). Prevalence of polypharmacy is higher in the Americas (44%, 95% CI: 27-63%) (I 2 = 100%, τ2 = 1.0886, p < 0.01) than Europe (29%, 95% CI: 20-40%) (I 2 = 100%, τ2 = 0.7944, p < 0.01). Conclusion: The pooled prevalence estimates from this synthesis established that polypharmacy is a significant and rising problem among PLWH. The exact interventions that are likely to significantly mitigate its effect remain uncertain and will need exploration by future prospective and systematic studies. Registration: PROSPERO: CRD42020170071. Plain Language Summary: Background: In people living with HIV (PLWH), what is the prevalence of polypharmacy and is this influenced by sociodemographic factors?Methods and Results: In this systematic review and meta-analysis of 23 studies comprising 55,988 participants, we have for the first time found an estimated polypharmacy pooled prevalence of 33% among PLWH. There was a relatively higher pooled prevalence of polypharmacy among the America's compared with European cohorts of PLWH.Conclusion: Polypharmacy among PLWH is a rising morbidity that needs urgent intervention both at policy and patient levels of care.

Efficacy of chloroquine and hydroxychloroquine in treating COVID-19 infection: A meta-review of systematic reviews and an updated meta-analysis.

OBJECTIVE: To synthesize findings from systematic reviews and meta-analyses on the efficacy and safety of chloroquine (CQ) and hydroxychloroquine (HCQ) with or without Azithromycin for treating COVID-19, and to update the evidence using a meta-analysis. METHODS: A comprehensive search was carried out in electronic databases for systematic reviews, meta-analyses and experimental studies which investigated the efficacy and safety of CQ, HCQ with or without Azithromycin to treat COVID-19. Findings from the reviews were synthesised using tables and forest plots and the quality effect model was used for the updated meta-analysis. The main outcomes were mortality, the need for intensive care services, disease exacerbation, viral clearance and occurrence of adverse events. RESULTS: Thirteen reviews with 40 primary studies were included. Two meta-analyses reported a high risk of mortality, with ORs of 2.2 and 3.0, and the two others found no association between HCQ and mortality. Findings from two meta-analyses showed that HCQ with Azithromycin increased the risk of mortality, with similar ORs of 2.5. The updated meta-analysis of experimental studies showed that the drugs were not effective in reducing mortality (RR 1.1, 95%CI 1.0-1.3, I2 = 0.0%), need for intensive care services (OR 1.1, 95%CI 0.9-1.4, I2 = 0.0%), virological cure (OR 1.5, 95%CI 0.5-4.4, I2 = 39.6%) or disease exacerbation (OR 1.2, 95%CI 0.3-5.9, I2 = 31.9%) but increased the odds of adverse events (OR 12,3, 95%CI 2.5-59.9, I2 = 76.6%). CONCLUSION: There is conclusive evidence that CQ and HCQ, with or without Azithromycin are not effective in treating COVID-19 or its exacerbation. REGISTRATION: PROSPERO: CRD42020191353.

Identification of potential transcription factors that enhance human iPSC generation.

Although many factors have been identified and used to enhance the iPSC reprogramming process, its efficiency remains quite low. In addition, reprogramming efficacy has been evidenced to be affected by disease mutations that are present in patient samples. In this study, using RNA-seq platform we have identified and validated the differential gene expression of five transcription factors (TFs) (GBX2, NANOGP8, SP8, PEG3, and ZIC1) that were associated with a remarkable increase in the number of iPSC colonies generated from a patient with Parkinson's disease. We have applied different bioinformatics tools (Gene ontology, protein-protein interaction, and signaling pathways analyses) to investigate the possible roles of these TFs in pluripotency and developmental process. Interestingly, GBX2, NANOGP8, SP8, PEG3, and ZIC1 were found to play a role in maintaining pluripotency, regulating self-renewal stages, and interacting with other factors that are involved in pluripotency regulation including OCT4, SOX2, NANOG, and KLF4. Therefore, the TFs identified in this study could be used as additional transcription factors that enhance reprogramming efficiency to boost iPSC generation technology.