Extent Of Translation Research Articles

Understanding the implementation and medium-longer term sustainability of the primary care prescribing safety intervention, PINCER: preliminary results from a longitudinal process evaluation

Abstract Introduction Medication errors are an important cause of morbidity and mortality across primary care in England. In the National Health Service, approximately 71% of 237 million medication errors made annually are attributable to primary care(1). The complex pharmacist-led IT-based intervention to reduce clinically important medication errors (PINCER) intervention has been shown to significantly reduce medication errors when tested in a cluster randomised controlled trial and when implemented on a larger scale across one geographical region of England. However, with a national rollout of PINCER now underway across England, there remains a limited understanding of whether and how wider implementation, impact and medium-longer term sustainability across diverse regions is achieved, and what factors may influence these processes. Aim This study aimed to explore the contextual factors that influenced the nature and extent of translation, implementation and sustained use of PINCER in diverse settings over time. Methods Intervention developers and personnel involved in the PINCER rollout and staff members from Academic Health Science Networks (AHSNs), Clinical Commissioning Groups (CCGs) and general practices from four regions of England, UK, were purposively recruited via research team connections and Clinical Research Networks. Interviews aimed to capture short-term (≤6 months), medium-term (6 – 18 months) and long-term (≥ 18 months) use of PINCER. Interview guides were informed by Normalisation Process Theory (NPT). Semi-structured, face-to-face or telephone interviews were conducted and digitally recorded. A preliminary thematic analysis was performed on the data collected. Results Forty-eight participants from 30 establishments, including two intervention developers, three involved in the PINCER rollout and five AHSN, seven CCG and thirty-one general practice employees were interviewed between June 2018 – June 2020. Their engagement with PINCER had either been in the medium (n=13) or long-term (n=17), (range 8 months - 5 years plus). Emerging themes identified in the preliminary analysis were: development and spread which incorporated intervention and training improvements as well as uptake, perceptions of PINCER which included awareness of PINCER as well as opinions on it and factors influencing the use of PINCER and sustainability which were mainly contextual but also related to PINCER functionalities. Within the development and spread theme, and relating to perceptions of PINCER theme, clear communication and ensuring there was an understanding of what PINCER entailed was considered important in initiating interest and uptake. Overall, PINCER was perceived positively. Key challenges to the implementation of PINCER identified were initial IT issues and workload. Policies advocating the use of PINCER, evidencing impact in reductions in the number of patients identified as being ‘at risk’ of hazardous prescribing and being able to benchmark results against other CCGs and practices helped facilitate the implementation and sustainability. Some changes made to prescribing and monitoring processes as a result of the implementation and use of PINCER, appeared to have become embedded into routine practice giving an indication of sustainable use. Conclusion Further interviews will establish if and how PINCER has been more widely adopted and normalised within primary care, in order to generate important learning to support its optimal and sustainable impact.

Survey of Extent of Translation of Oral Healthcare Guidelines for ICU Patients into Clinical Practice by Nursing Staff.

Nosocomial infections in critically ill/ventilated patients result from bacterial load in oropharyngeal regions. Oral decontamination serves as the easiest effective means of controlling infections. Knowledge, attitude, and practices followed by healthcare personnel in intensive care settings need to be assessed to implement concrete measures in health-care. Survey questionnaire was constructed and implemented following its validation on seventy nursing and paramedical staff working in government and private intensive care units throughout Lucknow city. 21-item questionnaire consisted of three parts of seven questions each. 78% of respondents had knowledge regarding oral care and its importance in critical settings but 44% of respondents considered it to be unpleasant task. 36% of respondents claimed to have provided oral care to all patients in ICU. Uniform guidelines for translation of oral healthcare in ICU settings are not being implemented. Previous studies in literature from various geographic diverse regions also point out to similar lacunae. Based on present survey, most respondents were aware of importance of oral care with protocols covered in academic curriculum. Attitude towards oral care is positive but respondents feel a need for specialised training. Practice for oral care is not sufficient and needs improvement and proper implementation.

TU-C-BRB-07: Comparison of Preclinical and Clinical Conformal Radiation Therapy Techniques and Protocols to Establish a Translational Pathway

Purpose: The purpose of this study was to compare the techniques and protocols used in clinical radiation therapy and recently developed preclinical image guided micro irradiation to establish a link between small animal conformal irradiation and clinical treatment protocols. This work will establish protocols that, according to treatment site, will facilitate the translation of conclusions from radiobiological experiments to clinical applications, fostering the advancement of radiotherapy.Methods: Data was gathered using our small animal image guided micro irradiation device, the microIGRT, as an example of preclinical techniques which mimic equivalent clinical treatment protocols. The microIGRT utilizes fractionated treatments, multibeam irradiations, modulated beams, image guided treatment verification, and doses to emulate clinical protocols. Consequently, it is well suited to establish parametric comparisons between clinical and preclinical techniques. In this study, we concentrated on two treatment sites, brain and lung, to define treatment conformality index, homogeneity, penumbra, PDD, and fractionated doses to establish a link to guide radiobiological experiments using clinical protocols as a gold standard. Results: Three and five beam irradiations were delivered to a small animal body and head phantom with radiochromic film to simulate lung and braintreatment. A three beam irradiation to the lung yielded a 625 um penumbra. Compare this value with a human treatment penumbra of 1 cm, and penumbra scales as the ratio between body sizes. The homogeneity of our system is similar to the 10% typically used in clinical treatment planning.Conclusions: By comparing preclinical and clinical treatment metrics, the extent of translation can be determined and improved, leading to better understanding of preclinical results and improved correlation with clinical procedures. This will lead to more clinically based preclinical experiments and improve translation efficiency between the two testing environments, thus providing new clinical treatment strategies and improved human cancer treatment.

The Role of Nitric-oxide Synthase in the Regulation of UVB Light-induced Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2

UV light induces phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2alpha) and inhibits global protein synthesis. Both eIF2 kinases, protein kinase-like endoplasmic reticulum kinase (PERK) and general control of nonderepressible protein kinase 2 (GCN2), have been shown to phosphorylate eIF2alpha in response to UV irradiation. However, the roles of PERK and GCN2 in UV-induced eIF2alpha phosphorylation are controversial. The one or more upstream signaling pathways that lead to the activation of PERK or GCN2 remain unknown. In this report we provide data showing that both PERK and GCN2 contribute to UV-induced eIF2alpha phosphorylation in human keratinocyte (HaCaT) and mouse embryonic fibroblast cells. Reduction of expression of PERK or GCN2 by small interfering RNA decreases phosphorylation of eIF2alpha after UV irradiation. These data also show that nitric-oxide synthase (NOS)-mediated oxidative stress plays a role in regulation of eIF2alpha phosphorylation upon UV irradiation. Treating the cells with the broad NOS inhibitor N(G)-methyl-l-arginine, the free radical scavenger N-acetyl-l-cysteine, or the NOS substrate l-arginine partially inhibits UV-induced eIF2alpha phosphorylation. The results presented above led us to propose that NOS mediates UV-induced eIF2alpha phosphorylation by activation of both PERK and GCN2 via oxidative stress and l-arginine starvation signaling pathways.

Correlation of medial/lateral rotation of the humerus with glenohumeral translation.

OBJECTIVES: To correlate glenohumeral translation in the anterior/posterior direction with medial and lateral rotation of the humerus. In addition, the length of the anterior and posterior component of the glenohumeral...

Role of the 3' untranslated region in the regulation of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase gene expression by selenium supply.

Selenium is an essential nutrient and synthesis of selenoproteins is affected by limited selenium supply. During selenium deficiency there is a differential regulation of selenoprotein synthesis and gene expression; for example, there is a decrease in abundance of mRNA for cytosolic glutathione peroxidase (cGSH-Px) and a preservation of mRNA for phospholipid-hydroperoxide glutathione peroxidase (PHGSH-Px). This difference is not due to an alteration in the rate of transcription but might reflect differences in translation. The aim of the present work was to assess the role of cGSH-Px and PHGSH-Px 3' untranslated regions (UTRs) in the regulation of selenoprotein mRNA stability and translation by using H4-II-E-C3 cells transfected with different constructs containing a type I iodothyronine deiodinase-coding region linked to different selenoprotein mRNA 3' UTRs. Translational efficiency results showed that the efficiency of the 3' UTRs in permitting selenocysteine incorporation is similar in selenium-replete conditions but, when selenium is limiting, the 3' UTR of cGSH-Px is less efficient than the 3' UTR of PHGSH-Px. The results suggest that the 3' UTR of these selenoprotein mRNA species influences their extent of translation when selenium levels are low. The different sensitivity of the 3' UTRs to selenium deficiency can explain the differential effect that selenium deficiency has on cGSH-Px and PHGSH-Px activity and mRNA levels, stability and translation. This might be partly responsible for channelling selenium for synthesis of PHGSH-Px rather than cGSH-Px.

Localized domains of DNA supercoiling: topological coupling between promoters.

According to the twin-supercoiled domain model, a local domain with a high level of DNA supercoiling can be generated between two divergently transcribed promoters. We have tested this model directly using the rate of DNA photo-cross-linking by 4,5', 8-trimethylpsoralen to measure local regions of unconstrained supercoiling in vivo. We demonstrate that, in plasmids, a localized domain of highly supercoiled DNA is generated upstream of the tetA promoter. The level of supercoiling of this domain depends on the activity of the tetA promoter and on the extent of translation of the tetA gene product. The highest level of supercoiling within this localized domain was observed in a topA strain, although the generation of a localized supercoiling domain could also be detected in a topA+ background, consistent with potential physiological significance. The level of supercoiling in this localized domain correlated with activation of the supercoiling-sensitive leu-500 promoter located upstream of tetA. These data provide a direct demonstration that localized domains of increased negative supercoiling can be generated upstream of an actively transcribed promoter, and that this can result in supercoiling-mediated transcriptional coupling between two promoters.

Actin filaments in honeybee‐flight muscle move collectively

To investigate the pattern of actin-filament translation in the intact myofibrillar matrix, we carried out electron micrographic experiments on the "rigor-stretch" model of insect-flight muscle. In this model, thin filaments are mechanically severed from their connections to the Z-line and may then slide freely over the myosin filaments when activated. The model is similar to the in vitro motility assay in that untethered actin filaments slide over myosin, but here the natural filament lattice is retained: sliding takes place through the lattice of thick filaments. We find, in this model, that while the extent of thin filament translation is variable from sarcomere to sarcomere, filaments never translate far enough to enter the opposite I-band. Unlike the in vitro motility assay, where the actin filament translates over the entire thick filament even with "incorrectly" polarized cross-bridges as the sole driver, in this intact filament-lattice model, cross-bridges are apparently unable to move filaments in both directions. We also find that the pattern of filament translation is collective. Although the extent of translation may vary among sarcomeres, in any given half-sarcomere all actin filaments translate by the same degree. Further, the extent of translation is the same in both halves of a given sarcomere. In rare instances where the extent of translation exhibited a transverse gradient across the myofibrillar half-sarcomere, the gradient was similar on both sides of the sarcomere. Filament translation within the sarcomere is thus collective. Some mechanism ensures that nearby but distinctly separated actin filaments move together and that cooperative-like behavior therefore extends to the supramolecular level.

Effects of electrical polarization on inner hair cell receptor potentials

Ac and dc receptor potential components in response to tone-burst stimuli were measured from inner hair cells in the third cochlear turn of the guinea pig. Comparisons were sought between conditions when constant polarizing current was injected into the cell through the recording electrode and when there was no extrinsic current. Hyperpolarization of the cell increased all responses, while depolarization decreased them. The input-output functions were vertically translated by current injection. The extent of translation was a function of current level. In addition, the amount of current-induced change was frequency dependent. Largest changes were seen at low frequencies and the current-induced change tended toward a constant high-frequency asymptote between 1-2 kHz. Changes in the dc response component were considerably in excess of those for the fundamental ac response. The frequency-dependent effects are quantified with the aid of a hair cell circuit model [P. Dallos, Hear. Res. 14, 281-291 (1984)]. It is assumed that the quantity altered by polarizing current (actually by the transmembrane voltage) is the resistance of the cell's basolateral membrane.

Noise from Ducted Rotor Interacting with Unsteady Inflow Fluctuations

Experimental and analytical determination of noise upstream and downstream of a 6-in. three-bladed ducted propeller interacting with controlled unsteady inflow distortion is conducted. The inflow distortion was induced by symmetrically mounting three 38-in.-diameter circular cylinders in the radial direction upstream of the propeller. The cylinders were rotated both in the clockwise and anticlockwise directions. The speed ranges of the propeller and the cylinders were 0-8500 rpm and 0-±800 rpm, respectively. Both velocity and acoustic pressure measurements are carried out in the duct and direct evaluation of the aero-acoustic transfer function is obtained. The amplitude of unsteady loading on rotor blades is shown to be affected by the frequency of the unsteady flow and the order of the flow spatial distortion. For distortion frequencies much lower than the rotor shaft frequency, the unsteady loading on the blade depends mainly on the spatial variation of the distortion. Frequency translation from blade passage frequency and its harmonics in the noise spectrum is demonstrated experimentally and the extent of translation is equal to analytical predictions. Comparisons between the experimentally determined aeroacoustic transfer function arhd analytical predictions indicate that the use of Sears function to calculate the unsteady loading on the rotating blades seems to be adequate for low values of Mach number. [Research supported by the National Research Council of Canada.]