Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various significant signaling pathways. Hyperactivation of the PI3K/AKT/mTOR pathways—either via mutations or genomic amplification—confers key oncogenic activity, essential for the development and progression of several solid tumors. Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies. Although the literature reports contradictory prognostic values of PIK3CA in aggressive cancers, most of the available data highlight the important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway. Several inhibitors of PI3K/AKT/mTOR pathways are investigated as potential therapeutic options in solid malignancies. This article reviews the role of PIK3CA mutations and inhibitors of PI3K/AKT/mTOR pathways in major cancer types and examines its association with clinicopathological parameters and prognosis.

Background and aims Micronutrient supplements such as vitamin D, vitamin C, and zinc have been used in managing viral illnesses. However, the clinical significance of these individual micronutrients in patients with Coronavirus disease 2019 (COVID-19) remains unclear. We conducted this meta-analysis to provide a quantitative assessment of the clinical significance of these individual micronutrients in COVID-19. Methods We performed a comprehensive literature search using MEDLINE, Embase, and Cochrane databases through December 5th, 2021. All individual micronutrients reported by ≥3 studies and compared with standard-of-care (SOC) were included. The primary outcome was mortality. The secondary outcomes were intubation rate and length of hospital stay (LOS). Pooled risk ratios (RR) and mean difference (MD) with corresponding 95% confidence intervals (CI) were calculated using the random-effects model. Results We identified 26 studies (10 randomized controlled trials and 16 observational studies) involving 5633 COVID-19 patients that compared three individual micronutrient supplements (vitamin C, vitamin D, and zinc) with SOC. Nine studies evaluated vitamin C in 1488 patients (605 in vitamin C and 883 in SOC). Vitamin C supplementation had no significant effect on mortality (RR 1.00, 95% CI 0.62-1.62, P=1.00), intubation rate (RR 1.77, 95% CI 0.56-5.56, P=0.33), or LOS (MD 0.64; 95% CI -1.70, 2.99; P=0.59). Fourteen studies assessed the impact of vitamin D on mortality among 3497 patients (927 in vitamin D and 2570 in SOC). Vitamin D did not reduce mortality (RR 0.75, 95% CI 0.49-1.17, P=0.21) but reduced intubation rate (RR 0.55, 95% CI 0.32-0.97, P=0.04) and LOS (MD -1.26; 95% CI -2.27, -0.25; P=0.01). Subgroup analysis showed that vitamin D supplementation was not associated with a mortality benefit in patients receiving vitamin D pre or post COVID-19 diagnosis. Five studies, including 738 patients, compared zinc intake with SOC (447 in zinc and 291 in SOC). Zinc supplementation was not associated with a significant reduction of mortality (RR 0.79, 95% CI 0.60-1.03, P=0.08). Conclusions Individual micronutrient supplementations, including vitamin C, vitamin D, and zinc, were not associated with a mortality benefit in COVID-19. Vitamin D may be associated with lower intubation rate and shorter LOS, but vitamin C did not reduce intubation rate or LOS. Further research is needed to validate our findings.

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The crystalloid fluid of choice in sepsis remains debatable. We aimed to perform a comprehensive meta-analysis to compare the effect of balanced crystalloids (BC) vs. normal saline (NS) in adults with sepsis. A systematic search of PubMed, EMBASE, and Web of Sciences databases through 22 January 2022, was performed for studies that compared BC vs. NS in adults with sepsis. Our outcomes included mortality and acute kidney injury (AKI), need for renal replacement therapy (RRT), and ICU length of stay (LOS). Pooled risk ratio (RR) and mean difference (MD) with the corresponding 95% confidence intervals (CIs) were obtained using a random-effect model. Fifteen studies involving 20,329 patients were included. Overall, BC showed a significant reduction in the overall mortality (RR 0.88, 95% CI 0.81–0.96), 28/30-day mortality (RR 0.87, 95% CI 0.79–0.95), and AKI (RR 0.85, 95% CI 0.77–0.93) but similar 90-day mortality (RR 0.96, 95% CI 0.90–1.03), need for RRT (RR 0.91, 95% CI 0.76–1.08), and ICU LOS (MD −0.25 days, 95% CI −3.44, 2.95), were observed between the two groups. However, subgroup analysis of randomized controlled trials (RCTs) showed no statistically significant differences in overall mortality (RR 0.92, 95% CI 0.82–1.02), AKI (RR 0.71, 95% CI 0.47–1.06), and need for RRT (RR 0.71, 95% CI 0.36–1.41). Our meta-analysis demonstrates that overall BC was associated with reduced mortality and AKI in sepsis compared to NS among patients with sepsis. However, subgroup analysis of RCTs showed no significant differences in both overall mortality and AKI between the groups. There was no significant difference in the need for RRT or ICU LOS between BC and NS. Pending further data, our study supports using BC over NS for fluid resuscitation in adults with sepsis. Further large-scale RCTs are necessary to validate our findings.