Implementation of a Nurse-led Clinical Algorithm for Pressure Injury Prevention Associated with Non-Invasive Ventilation Medical Device Use

Purpose and Aims Medical device related pressure injuries (PI) account for as much as 61-81% of all hospital reported wound incidents (Gefen et al., 2020) and are frequently caused by respiratory devices such as non-invasive ventilation (NIV). Use of NIV in critically ill patients dramatically increased during the pandemic. PI are one of the leading causes of injury to hospitalized patients and lengthens hospital stays (National Pressure Injury Advisory Panel [NPIAP], 2019). The NPIAP recommends routine skin assessment under devices, proper mask fit, protective barrier, moisture reduction, and interdisciplinary collaboration to prevent PIs from NIV masks. This feasibility study’s purpose was to evaluate the use of a nurse-led NIV Pressure Injury Prevention (PIP) algorithm for critically ill patients. Study aims focused on reach (utilization), assessment of effectiveness, adoption, implementation fidelity, and potential maintenance of the NIV PIP algorithm. Theoretical Framework The RE-AIM framework was used to guide the delineation of the NIV PIP algorithm implementation plan and evaluation of the algorithm by the critical care nurses. Methods A prospective study design was used for this feasibility study conducted in a large Midwestern community hospital (640 beds) on two critical care units. Nursing staff participated in an educational session, prior to the implementation of the NIV PIP algorithm on the nursing units. Data was collected over the two-week implementation period. Data collection included pre/post NIV PIP educational survey data, bedside rounding with nurses focused on use of the algorithm, usability of algorithm with the Systems Usability Scale (SUS) pre/post implementation, and medical record review of nurse documentation. Results A total of 69 nurses participated in the NIV algorithm educational session. During the study period, 16 NIV patients were hospitalized at study units and no NIV PIs originated on the study units. Nurses completed pre (n=35) and post (n=10) surveys with mean scores increasing from 66.6% (SD 12.82) to 77.8% (SD 20.48). The pre-SUS (n=21) mean was 83.33 (10.73) and the post-SUS (n=4) mean improved to 85.63 (SD 8.26). Bedside rounding revealed that 86% of nurses (n= 20) interviewed reported ease of use of the algorithm and no major disruption to their workflow. Consensus from the nurses was that the NIV PIP algorithm was helpful in their care of NIV patients. Conclusions Further study is warranted to evaluate the impact of the NIV PIP algorithm. The increased need for NIV therapy among critical care patients necessitates the need for use of evidence-based practices such as the NIV PIP algorithm The data from this study can serve as a framework to support practice change, interdisciplinary collaboration, and provide awareness of possible clinical barriers

MK-4101 - a potent inhibitor of the hedgehog pathway - is highly active against medulloblastoma and basal cell carcinoma

Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrated a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidated the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in tumor cells, showing the maximum inhibitory effect on Gli1. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways, were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity

Octreotide Conjugates for Tumor Targeting and Imaging

Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting.Peer reviewe

Activity of recombinant dengue 2 virus NS3 protease in the presence of a truncated NS2B co-factor, small peptide substrates, and inhibitors

Recombinant forms of the dengue 2 virus NS3 protease linked to a 40-residue co-factor, corresponding to part of NS2B, have been expressed in Escherichia coli and shown to be active against para-nitroanilide substrates comprising the P6-P1 residues of four substrate cleavage sequences. The enzyme is inactive alone or after the addition of a putative 13-residue co-factor peptide but is active when fused to the 40-residue co-factor, by either a cleavable or a noncleavable glycine linker. The NS4B/NS5 cleavage site was processed most readily, with optimal processing conditions being pH 9, I = 10 mm, 1 mm CHAPS, 20% glycerol. A longer 10-residue peptide corresponding to the NS2B/NS3 cleavage site (P6-P4') was a poorer substrate than the hexapeptide (P6-P1) para-nitroanilide substrate under these conditions, suggesting that the prime side substrate residues did not contribute significantly to protease binding. We also report the first inhibitors of a co-factor-complexed, catalytically active flavivirus NS3 protease. Aprotinin was the only standard serine protease inhibitor to be active, whereas a number of peptide substrate analogues were found to be competitive inhibitors at micromolar concentrations

Engineered Toxins “Zymoxins” Are Activated by the HCV NS3 Protease by Removal of an Inhibitory Protein Domain

The synthesis of inactive enzyme precursors, also known as “zymogens,” serves as a mechanism for regulating the execution of selected catalytic activities in a desirable time and/or site. Zymogens are usually activated by proteolytic cleavage. Many viruses encode proteases that execute key proteolytic steps of the viral life cycle. Here, we describe a proof of concept for a therapeutic approach to fighting viral infections through eradication of virally infected cells exclusively, thus limiting virus production and spread. Using the hepatitis C virus (HCV) as a model, we designed two HCV NS3 protease-activated “zymogenized” chimeric toxins (which we denote “zymoxins”). In these recombinant constructs, the bacterial and plant toxins diphtheria toxin A (DTA) and Ricin A chain (RTA), respectively, were fused to rationally designed inhibitor peptides/domains via an HCV NS3 protease-cleavable linker. The above toxins were then fused to the binding and translocation domains of Pseudomonas exotoxin A in order to enable translocation into the mammalian cells cytoplasm. We show that these toxins exhibit NS3 cleavage dependent increase in enzymatic activity upon NS3 protease cleavage in vitro. Moreover, a higher level of cytotoxicity was observed when zymoxins were applied to NS3 expressing cells or to HCV infected cells, demonstrating a potential therapeutic window. The increase in toxin activity correlated with NS3 protease activity in the treated cells, thus the therapeutic window was larger in cells expressing recombinant NS3 than in HCV infected cells. This suggests that the “zymoxin” approach may be most appropriate for application to life-threatening acute infections where much higher levels of the activating protease would be expected

NSF grant to support development of new phenotyping instrument

With support from a National Science Foundation grant, University of Nebraska-Lincoln researchers are developing a new tool that will help them better identify plant characteristics that are critical to improving crop performance. The three-year, $534,194 grant will be used to develop an instrument that will improve capacity, sensitivity and throughput for plant phenotyping. Producing enough food and energy for a world population of more than 9 billion by the year2050 is the greatest challenge facing agriculture. To solve the looming global food security challenge, crop stress tolerance and yields must increase. Researchers around the world are studying plant characteristics, or phenotypes, at high throughput and high resolution to identify opportunities to improve crop performance. Currently, it is difficult to reconstruct a three-dimensional structure of a plant from its digital images alone. The multi-wavelength laser imaging and ranging instrument being developed as a result of this grant will simultaneously probe chemical properties of plants, such as water,nitrogen and chlorophyll concentration, while also measuring 3D plant structure, such as leaf orientation and angular distribution. The measurements will tell researchers more information about plant physiology and function. The instrument being developed through this research will allow for more efficient phenotype characterization and analysis, which will lead to accelerated crop improvement, said Yufeng Ge, assistant professor in the Department of Biological Systems Engineering and an investigator on the project

NSF grant to support development of new phenotyping instrument

With support from a National Science Foundation grant, University of Nebraska-Lincoln researchers are developing a new tool that will help them better identify plant characteristics that are critical to improving crop performance. The three-year, $534,194 grant will be used to develop an instrument that will improve capacity, sensitivity and throughput for plant phenotyping. Producing enough food and energy for a world population of more than 9 billion by the year2050 is the greatest challenge facing agriculture. To solve the looming global food security challenge, crop stress tolerance and yields must increase. Researchers around the world are studying plant characteristics, or phenotypes, at high throughput and high resolution to identify opportunities to improve crop performance. Currently, it is difficult to reconstruct a three-dimensional structure of a plant from its digital images alone. The multi-wavelength laser imaging and ranging instrument being developed as a result of this grant will simultaneously probe chemical properties of plants, such as water,nitrogen and chlorophyll concentration, while also measuring 3D plant structure, such as leaf orientation and angular distribution. The measurements will tell researchers more information about plant physiology and function. The instrument being developed through this research will allow for more efficient phenotype characterization and analysis, which will lead to accelerated crop improvement, said Yufeng Ge, assistant professor in the Department of Biological Systems Engineering and an investigator on the project

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