Development of a light-activated STING agonist.

The STING pathway is critical to innate immunity and is being investigated as a potential therapeutic target. Existing agents targeting STING suffer from several undesirable effects, particularly the possibility of systematic activation, which increases the risk of autoimmune disorders. In this proof-of-concept study, we report the development of a light-activated STING agonist, based on the potent compound SR-717. We first screened the activity of the non-caged agonist toward 5 human STING variants to identify the most viable target. A photocaged agonist was designed and synthesized in order to block an essential interaction between the carboxy acid group of the ligand with the R238 residue of the STING protein. We then investigated the selective activation of STING with the photocaged agonist, demonstrating an irradiation-dependent response. The development and characterization of this selective agonist expands the growing toolbox of conditionally controlled STING agonists to avoid systematic immune activation.

The Health Monitoring of Bonded Composite Joints Using Both Thickness and Radial Impedance Resonance Responses.

With the advent of bonded composites in today's aircraft, there is a need to verify the structural integrity of the bonded joints that comprise their structure. To produce adequate joint integrity, strict process control is required during bonding operations. The latest non-destructive joint inspection techniques cannot quantify the strength of the bond and only indicate the presence of disbonds or delaminations. Expensive and timely proof-load testing of the joints is required to demonstrate structural performance. This work focuses on experimentally evaluating joint-health monitoring with piezoelectric sensors exposed to repeated loadings until failure. Single-lap-shear composite joints are structurally tested while using sensor electromechanical impedance response as a health indicator. Based on these experiments, validation of this novel method is achieved through detailed evaluation of the sensor impedance response characteristics during loading, which enable initial and prognostic joint health assessments. The experimental results indicate that the embedded piezoelectric sensors are able to measure the sensor impedance radial and thickness resonance response changes prior to joint failure, without sacrificing the joints' structural performance.

Genetically Encoded Aminocoumarin Lysine for Optical Control of Protein-Nucleotide Interactions in Zebrafish Embryos.

The strategic placement of unnatural amino acids into the active site of kinases and phosphatases has allowed for the generation of photocaged signaling proteins that offer spatiotemporal control over activation of these pathways through precise light exposure. However, deploying this technology to study cell signaling in the context of embryo development has been limited. The promise of optical control is especially useful in the early stages of an embryo where development is driven by tightly orchestrated signaling events. Here, we demonstrate light-induced activation of Protein Kinase A and a RASopathy mutant of NRAS in the zebrafish embryo using a new light-activated amino acid. We applied this approach to gain insight into the roles of these proteins in gastrulation and heart development and forge a path for further investigation of RASopathy mutant proteins in animals.

Efficacy of Army Combat Fitness Test 12-Week Virtual Exercise Program.

INTRODUCTION: The Army Combat Fitness Test (ACFT) is the fitness assessment used by the Army launched in April of 2022. The ACFT consists of six physically demanding motor movements that parallel to the stressors experienced by the modern-day combat soldier. The aim of this study is to determine the efficacy of a 12-week virtual exercise program on the individual and their overall ACFT scores. MATERIALS AND METHODS: Thirteen soldiers from the Army National Guard (age = 29.8 ± 6.2 years; height = 175.7 ± 6.1 cm; service experience ≥ 18 months to 18 years) volunteered to complete three sessions. In session 1, baseline height, body mass, body composition, and ACFT scores were collected. Session 2 consisted of a suspension trainer (ST) tutorial in which all participants familiarized themselves with the set-up and utilization of the suspension training tool kit. Upon completion of session 2, a TRX Elite ACFT Kit containing one suspension trainer, four resistance bands, and the 12-week virtual exercise training program available via iphone operating system and Android were given to all participants. In session 3, post-assessments of body mass, body composition, and ACFT scores were collected. Data were statistically analyzed using a paired-sample t-test with a Bonferroni correction (P < .00065) to adjust for multiple comparisons. RESULTS: There were no significant changes in mean body mass (83.8 ± 16.5 kg vs. 83.9 ± 16.6 kg; P = .752); however, there was a significant reduction in mean percentage body fat (19.5 ± 6.4% vs. 18.3 ± 6.5%; P < .0001). Mean scores from four of the six individual ACFT assessments, specifically, deadlift, standing power throw, hand-release push-ups, and sprint-drag-carry, displayed improvements, but did not attain statistical significance. The overall mean ACFT scores displayed significant improvements (319.4 ± 39.9 vs. 390.4 ± 68.5; P < .0001). CONCLUSIONS: The TRX Elite ACFT Kit which includes one suspension trainer, four varying resistance bands, and on-demand access to a stepwise 12-week virtual exercise program was deemed effective by increasing the overall mean ACFT scores among participants. From a practitioner's perspective, the TRX Elite ACFT Kit should be widely distributed to all Army units and recruiting commands to provide vital assistance for recruits and soldiers to train and prepare for the ACFT. Moreover, given the ease and portability of the TRX Elite ACFT Kit, recruits and soldiers will be able to effectively train anytime, anywhere.

Effect of transjugular intrahepatic portosystemic shunt placement on renal function: a 7-year, single-center experience.

PURPOSE: Transjugular intrahepatic portosystemic shunt (TIPS) creation has been shown to improve renal function in small series of patients with hepatorenal syndrome. The present study examined the effect of TIPS creation on renal function in a large series of patients undergoing TIPS creation who had varying degrees of baseline renal function. MATERIALS AND METHODS: All de novo TIPS creations during a 7-year period at a single institution were retrospectively reviewed regardless of indication. Pre- and postprocedural laboratory values were obtained and used to calculate Model for End-Stage Liver Disease (MELD) scores and glomerular filtration rates. Subanalysis was performed based on degree of renal insufficiency and indication for the procedure. RESULTS: A total of 201 successful conventional TIPS procedures were identified. Of those, 72 patients were excluded for lack of follow-up, death during the same hospitalization, lack of TIPS function, or end-stage renal failure requiring dialysis before TIPS creation, leaving 129 procedures. Patients with preprocedural creatinine levels of 1.2-1.9 mg/dL (n = 45) showed an improvement in mean creatinine from 1.5 to 1.1 mg/dL (P < 10(-12)) and patients with preprocedure creatinine levels greater than 2.0 mg/dL (n = 21) showed an improvement from 2.8 to 1.5 mg/dL (P < 10(-5)). MELD scores decreased in patients with creatinine levels greater than 2.0 mg/dL from 22.1 to 19.2 (P < 0.005) but increased in all other patient groups. Amount of iodinated contrast medium administered did not affect creatinine level changes. CONCLUSIONS: TIPS creation improves renal dysfunction in chronic liver disease. Patients with poorer renal function benefit the most from TIPS creation.

Influences of context, process and individual differences on nurses' readiness for change to Magnet status.

AIM: The aim of this study was to test hypotheses associated with a model which explains individuals' readiness in early stages of a change. BACKGROUND: In an effort to improve the quality of nursing care, hospitals in the United States of America seek to obtain Magnet recognition. While it is commonly known that Magnet hospitals provide higher quality patient care, little is known about the variability in nurses' attitudes and behaviour within Magnet hospitals. METHOD: We collected data in 2006 from 310 Registered Nurses to investigate the factors that influence their willingness to embrace the changes necessary for the high levels of excellence accompanying Magnet status. Hierarchical linear modelling was used because the data were multi-level. RESULTS: Both change-specific context, such as a culture of research exhibited by the manager, and formal education of the nurse moderated the positive influences of the organization's procedural justice actions. Specifically, procedural justice was stronger when the nurse manager demonstrated a culture of research, and negative effects of low justice were mitigated when nurses had a higher level of formal education. CONCLUSION: Preparing managers beforehand to appreciate and adopt new behaviours associated with a forthcoming organizational change should enhance the success of change practices as new changes are initiated. Moreover, education that exposes employees to the pending realities of their industry, such as nursing research, can play an important role in the development of positive beliefs about changes facing their organizations.

The effects of transformational and change leadership on employees' commitment to a change: a multilevel study.

The effects of transformational leadership on the outcomes of specific change initiatives are not well understood. Conversely, organizational change studies have examined leader behaviors during specific change implementations yet have failed to link these to broader leadership theories. In this study, the authors investigate the relationship between transformational and change leadership and followers' commitment to a particular change initiative as a function of the personal impact of the changes. Transformational leadership was found to be more strongly related to followers' change commitment than change-specific leadership practices, especially when the change had significant personal impact. For leaders who were not viewed as transformational, good change-management practices were found to be associated with higher levels of change commitment.

Beyond change management: a multilevel investigation of contextual and personal influences on employees' commitment to change.

The extent to which attitudes toward organizational changes may be affected by contextual (other changes going on) and personal (self-efficacy) factors was investigated with a multilevel design involving 25 different changes. Even after aspects of the change itself were controlled, the interaction between the context and the individual difference explained significant variance in attitudes toward those specific changes. The positive relationship between self-efficacy and commitment to the change was stronger as the amount of simultaneous and overlapping change in the surroundings increased. The implications for research and practice are discussed.

Access flow in arteriovenous accesses by optodilutional and ultrasound dilution methods.

BACKGROUND: Most large studies evaluating the diagnostic properties of access blood flow (Qa) in arteriovenous (AV) accesses have used the Transonic HD01 (Transonic Systems Inc, Ithaca, NY) device, and recommended thresholds for angiography are based on data from these studies. There has been little exploration of how the use of other devices might affect the feasibility or performance of screening in AV accesses. METHODS: We compared 2 devices for measuring Qa: the Transonic HD01 and the Crit-Line TQA III (Hemametrics, Salt Lake City, UT). We studied 124 adults with end-stage renal disease and a functioning AV access (fistula or graft). Qa was measured with both devices in immediate succession during a single dialysis treatment. The primary outcome was the technical feasibility of the Qa measurement. We also compared mean Qa values measured by the Crit-Line III and Transonic devices. RESULTS: Qa measurements were less likely to be technically feasible when the Crit-Line III device was used compared with the Transonic device (86.3% versus 100%; P < 0.001). In patients with valid measurements, mean Qa measured using the Crit-Line III was significantly less than that measured using the Transonic HD01 device (886 +/- 557 versus 1,148 +/- 685 mL/min; P < 0.001). The mean difference was 261 mL/min (95% confidence interval [CI], 117 to 405) and was greater at higher levels of Qa. On average, Qa measured by means of the Crit-Line III device was 73% as high as that measured using the Transonic device (95% CI, 63 to 84). There was poor agreement between devices about whether criteria for angiography were met (kappa < 0.1). The proportion of patients for whom angiography was indicated (based on results from the Crit-Line device) was significantly greater than when only results from the Transonic device were considered (40.3% versus 7.3%; P < 0.001). CONCLUSION: Consideration should be given to device-specific Qa thresholds for angiography or, alternatively, standardization of Qa results between manufacturers. Clinicians should be aware that Qa results cannot be compared directly between different devices, and access monitoring should be performed using a single technique in any given patient. Additional studies are required before the Crit-Line TQA device can be recommended for widespread use.

Toward an understanding of the relationships among organizational change, individual differences, and changes in person-environment fit: a cross-level study.

Organizational behavior literature has not typically viewed person-environment (P-E) fit as an outcome of change. Whereas the study of antecedents to employees' fit with their work environment has largely been restricted to the selection and socialization of newcomers, this study examines individuals' perceptions of changes in P-E fit in relation to organizational changes occurring in 34 different organizational work units. Results suggest that the relationships between organizational change and perceived changes in fit are best understood as interactions between the characteristics of the change process, the extent of change, and individual differences. Both age and mastery orientation related to perceived changes in P-E fit through interactions with aspects of the change process.

Comparison of the grading of esophageal varices by transnasal endoluminal ultrasound and esophagogastroduodenoscopy.

BACKGROUND & AIMS: Esophagogastroduodenoscopy (EGD) is the current standard for evaluating esophageal varices, yet there is no universally accepted system of grading varices endoscopically and several studies have shown interobserver variability of endoscopic grading. High-resolution endoluminal ultrasound 20 MHz (HRES) has been shown to detect varices accurately and can be performed without sedation. Our aim was to compare the detection of esophageal varices by transnasal HRES and EGD. METHODS: We prospectively studied 37 cirrhotic patients being evaluated for esophageal varices. HRES was used to measure the largest esophageal variceal diameter and then EGD was performed. Photographs were taken for both procedures. Three blinded investigators graded the EGD photographs at 2 periods. End points were as follows: (1) the correlation of HRES variceal diameter and EGD grading of varices, and (2) the assessment of interobserver and intraobserver variation in varix grading by EGD. RESULTS: The correlation between the transnasal HRES and EGD was .63, with a 95% confidence interval of .37-.80. The HRES detected early varices that were not seen by EGD. The interobserver correlation for EGD scoring was .87 or greater in all comparisons and the intraobserver correlation was .91 or greater. CONCLUSIONS: In conclusion, there is a significant correlation between transnasal HRES size measurement of esophageal varices and EGD. HRES is much more sensitive in detecting early esophageal varices and may not require sedation, suggesting that it may be more tolerable to patients and is worth further study.