Does the antimicrobial-impregnated peripherally inserted central catheter decrease the CLABSI rate in neonates? Results from a retrospective cohort study.

Background: The use of antimicrobial-impregnated peripherally inserted central catheters (PICCs) has been introduced in the last few years to neonatal units aiming to reduce central line-associated bloodstream infection (CLABSI). Methods: This retrospective observational study aimed to compare the CLABSI rates and other catheter-related parameters including the insertion success rates and catheter-related complications in the antimicrobial-impregnated and conventional (ordinary) PICCs in NICU between 2017 and 2020. Results: Our dedicated PICC team including physicians and nurses inserted 1,242 conventional (PremiCath and NutriLine) and 791 antimicrobial-impregnated PICCs (PremiStar) over the study period from 2017 to 2020. Of those 1,242 conventional PICCs, 1,171 (94.3%) were 1 Fr single lumen and only 71 (5.7%) were 2 Fr double lumen. The mean ± SD [median (IQR)] for the birth weight in all babies who had a PICC line was 1,343.3 ± 686.75 [1,200 (900, 1,500)] g, while the mean ± SD for the gestational age was 29.6 ± 4.03 [29 (27, 31)] weeks. The mean ± SD [median (IQR)] age at the time of insertion for all catheters was 9.3 ± 21.47 [2 (1, 9)] days, while the mean ± SD [median (IQR)] dwell time was 15.7 ± 14.03 [12 (8, 17)] days. The overall success rate of the PICC insertion is 1,815/2,033 (89.3%), while the first attempt success rate is 1,290/2,033 (63.5%). The mean ± SD [median (IQR)] gestational age, birth weight, age at catheter insertion, and catheter dwell time were 28.8 ± 3.24 [29, (26, 31)] weeks, 1,192.1 ± 410.3 [1,150, (900, 1,450)] g, 6.3 ± 10.85 [2, (1, 8)] days, and 17.73 ± 17.532 [13, (9, 18)] days in the antimicrobial-impregnated catheter compared with 30.1 ± 4.39 [29, (27, 32)] weeks (P < 0.001), 1,439.5 ± 800.8 [1,240, (920, 1,520)] g (P < 0.001), 11.1 ± 25.9 [1, (1, 9)] days (P < 0.001), and 14.30 ± 10.964 [12, (8, 17)] days (P < 0.001), respectively, in the conventional PICCs. The use of the antimicrobial-impregnated catheter was not associated with any significant reduction in the CLABSI rate (per 1,000 days dwell time), either the overall [P = 0.11, risk ratio (RR) (95% CI): 0.60 (0.32, 1.13)] or the yearly CLABSI rates. Conclusions: The use of miconazole and rifampicin-impregnated PICCs did not reduce the CLABSI rate in neonates compared with conventional PICCs. However, it has a higher overall rate of elective removal after completion of therapy and less extravasation/infiltration, occlusion, and phlebitis compared with the conventional PICCs. Further large RCTs are recommended to enrich the current paucity of evidence and to reduce the risk of bias. Neonatal PICCs impregnation by other antimicrobials is a recommendation for vascular access device manufacturers.

Neonatal Simulation Program: A 5 Years Educational Journey From Qatar.

We describe the process of implementation, adaptation, expansion and some related clinical intuitional impacts of the neonatal simulation program since its launch in 2016 in a non-simulation neonatal unit. The team has developed 6 types of curricula: 1 full-day course and 5 half-day workshops. A total of 35 free of charge simulation courses/workshops were conducted, 32 in Qatar and 3 abroad with a total of 799 diverse participants. There was a steady increase in the overall success rate of PICC insertion from 81.7% (309/378) to 97.6% (439/450) across 3 years (P < 0.0001). The first attempt PICC insertion success rate has been also increased from 57.7% (218/378) to 66.9% (301/450) across 3 years. The mean duration of PICC insertion has been improved from 39.7 ± 25 to 34.9 ± 12.4 min after implementing the program (P = 0.33). The mean duration of the LISA catheter insertion at the beginning of the workshop was 23.5 ± 15.9 compared to 12.1 ± 8.5 s at the end of the workshop (P = 0.001). When it came to clinical practise in real patients by the same participants, the overall LISA catheter insertion success rate was 100% and the first attempt success rate was 80.4%. The mean duration of LISA catheter insertion in real patients was 26.9 ± 13.9 s compared to the end of the workshop (P = 0.001). The mean duration of the endotracheal intubation at the beginning of the workshop was 12.5 ± 9.2 compared to 4.2 ± 3.8 s at the end of the workshop (P = 0.001). In real patients, the first-attempt intubation success rate has been improved from 37/139 (26.6%) in the first year to 141/187 (75.5%) in the second year after the program implementation (P = 0.001). The mean duration of successful endotracheal intubation attempts has been improved from 39.1 ± 52.4 to 20.1 ± 9.9 s (P = 0.78). As per the participants, the skills learned in the program sessions help in protecting neonates from potential harm and improve the overall neonatal outcome. Implementing a neonatal simulation program is a promising and feasible idea. Our experience can be generalised and replicated in other neonatal care institutions.

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products.

Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.

S-phase checkpoints regulate Apo2 ligand/TRAIL and CPT-11-induced apoptosis of prostate cancer cells.

As S-phase checkpoints play critical roles in maintaining genomic integrity and replicating the human genome correctly, understanding the molecular mechanism by which they regulate the therapeutic response is of great interest. Previously, we reported that the cytotoxic effect of a zinc-bound form of Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), which is currently evaluated in clinical trials, in combination with low-dose CPT-11, induces apoptosis of C4-2 human prostate cancer cells and tissues. Here, we show that apoptosis, induced synergistically by this combination treatment, was associated with accumulation of cells in early S phase, indicated by cell cycle analyses, increased proliferating cell nuclear antigen, and Chk2-Thr(68) phosphorylation in tumors xenografted in mice. The combination treatment induced an S-phase checkpoint response through activation of Chk2 and Chk1 by the ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3 related kinases, leading to phosphorylation and decreased Cdc25A levels. Cdc25A-dependent regulation of cyclin-dependent kinase 2 (Cdk2) and changes in association of p21(WAF1/CIP1) and hSpy1 with Cdk2 resulted in inhibition of Cdk2-associated kinase activity. Knockdown of ataxia telangiectasia mutated/Chk2 and ataxia telangiectasia mutated and Rad3 related/Chk1 by small inhibitory RNAs abrogated the S-phase checkpoint and accelerated apoptosis, resulting in caspase-3 activation and poly(ADP-ribose) polymerase 1 cleavage following combination treatment. Thus, Apo2L/TRAIL + CPT-11 treatment-induced apoptosis is regulated through an S-phase checkpoint controlled by the Chk2-Cdc25A and Chk1-Cdc25A pathways and inhibition of Cdk2-associated kinase activity. Low-dose CPT-11 and aphidicolin increased the proportion of S-phase cells and sensitized cells to Apo2L/TRAIL, by inducing phosphatidylserine externalization, caspase activation, and poly(ADP-ribose) polymerase 1 cleavage. Combinations with S-phase arrest-inducing chemotherapeutic drugs may represent promising avenues for clinical development of Apo2L/TRAIL.