Optimal Dose of Intranasal Dexmedetomidine for Laceration Repair in Children: A Phase II Dose-Ranging Study.

STUDY OBJECTIVE: To determine the optimal sedative dose of intranasal dexmedetomidine for children undergoing laceration repair. METHODS: This dose-ranging study employing the Bayesian Continual Reassessment Method enrolled children aged 0 to 10 years with a single laceration (<5 cm), requiring single-layer closure, who received topical anesthetic. Children were administered 1, 2, 3, or 4 mcg/kg intranasal dexmedetomidine. The primary outcome was the proportion with adequate sedation (Pediatric Sedation State Scale score of 2 or 3 for ≥90% of the time from sterile preparation to tying of the last suture). Secondary outcomes included the Observational Scale of Behavior Distress-Revised (range: 0 [no distress] to 23.5 [maximal distress]), postprocedure length of stay, and adverse events. RESULTS: We enrolled 55 children (35/55 [64%] males; median [interquartile range {IQR}] age 4 [2, 6] years). At 1, 2, 3, and 4 mcg/kg intranasal dexmedetomidine, respectively, the proportion of participants "adequately" sedated was 1/3 (33%), 2/9 (22%), 13/21 (62%), and 12/21 (57%); the posterior mean (95% equitailed credible intervals) for the probability of adequate sedation was 0.38 (0.04, 0.82), 0.25 (0.05, 0.54), 0.61 (0.41, 0.80), and 0.57 (0.36, 0.76); the median (IQR) Observational Scale of Behavior Distress-Revised scores during suturing was 2.7 (0.3, 3), 0 (0, 3.8), 0.6 (0, 5), and 0 (0, 3.7); the median (IQR) postprocedure length of stay was 67 (60, 78), 76 (60, 100), 89 (76, 109), and 113 (76, 150) minutes. There was 1 adverse event, a decrease in oxygen saturation at 4 mcg/kg, which resolved with head repositioning. CONCLUSION: Despite limitations, such as our limited sample size and subjectivity in Pediatric Sedation State Scale scoring, sedation efficacy for 3 and 4 mcg/kg were similarly based on equitailed credible intervals suggesting either could be considered optimal.

Implementation of a novel learning experience in scientific writing, publishing, and peer review into a first year pharmacy practice residency.

BACKGROUND: Pharmacists with competency in writing, publishing, and peer review are essential to continue advancing the pharmacy profession, but structured training of these skills may vary. OBJECTIVE: The authors set out to implement and assess the impact of a structured learning experience into a postgraduate year 1 pharmacy residency training program that provides tangible experience in the processes of scientific writing, publishing, and peer reviewing. METHODS: A quarterly pharmacy newsletter process was augmented to include an editorial board that consisted of residency trained pharmacists with varying levels of experience in scientific writing, publishing, and peer reviewing. The process was designed to provide a structured writing learning experience, to reinforce important concepts and terminology, and to simulate the process of submitting a manuscript to a peer-reviewed publication. Impact of the learning experience on quality of article submissions was assessed by comparing first quarter and last quarter writing submission scores for residents between 2017 and 2020. RESULTS: A statistically significant difference was observed in both raw scores (27 vs. 42.5 points out of 50 points possible, P < 0.05) and the proportion of pass or fail when comparing writing submission scores from the first quarter of the learning experience to submission scores from the last quarter (25% passing rate vs. 83% passing rate, P = 0.007). CONCLUSION: This novel learning experience was successfully integrated into a quarterly pharmacy newsletter and resulted in improved writing scores. This structured writing learning experience can be readily integrated into pharmacy residency training programs, and it provides hands-on training in scientific writing, publishing, and peer review for both residents and preceptors.

Who Benefits from Aggressive Rapid Response System Treatments Near the End of Life? A Retrospective Cohort Study.

BACKGROUND: Many patients near the end of life are subject to rapid response system (RRS) calls. A study was conducted in a large Sydney teaching hospital to identify a cutoff point that defines nonbeneficial treatment for older hospital patients receiving an RRS call, describe interventions administered, and measure the cost of hospitalization. METHODS: This was a retrospective cohort of 733 adult inpatients with data for the period three months before and after their last placed RRS call. Subgroup analysis of patients aged ≥ 80 years was conducted. Log-rank, chi-square, and t-tests were used to compare survival, and logistic regression was used to examine predictors of death. RESULTS: Overall, 65 (8.9%) patients had a preexisting not-for-resuscitation (NFR) or not-for-RRS order; none of those patients survived to three months. By contrast, patients without an NFR or not-for-RRS order had three-month survival probability of 71% (log-rank χ2 145.63; p < 0.001). Compared with survivors, RRS recipients who died were more likely to be older, to be admitted to a medical ward, and to have a larger mean number of admissions before the RRS. The average cost of hospitalization for the very old transferred to the ICU was higher than for those not requiring treatment in the ICU (US$33,990 vs. US$14,774; p = 0.045). CONCLUSION: Identifiable risk factors clearly associated with poor clinical outcomes and death can be used as a guide to administer less aggressive treatments, including reconsideration of ICU transfers, adherence to NFR orders, and transition to end-of-life management instead of calls to the RRS team.

Examining differences in time to appointment and no-show rates between rural telehealth users and non-users.

Background: Telehealth has undergone widespread implementation since 2020 and is considered an invaluable tool to improve access to healthcare, particularly in rural areas. However, telehealth's applicability may be limited for certain populations including those who live in rural, medically underserved communities. While broadband access is a recognized barrier, other important factors including age and education influence a person's ability or preference to engage with telehealth via video telehealth or a patient portal. It remains unclear the degree to which these digital technologies lead to disparities in access to care. Purpose: The purpose of this analysis is to determine if access to healthcare differs for telehealth users compared with non-users. Methods: Using electronic health record data, we evaluated differences in "time to appointment" and "no-show rates" between telehealth users and non-users within an integrated healthcare network between August 2021 and January 2022. We limited analysis to patient visits in endocrinology or outpatient behavioral health departments. We analyzed new patients and established patients separately. Results: Telehealth visits were associated with shorter time to appointment for new and established patients in endocrinology and established patients in behavioral health, as well as with lower no-show rates for established patients in both departments. Conclusions: The findings suggest that those who are unwilling or unable to engage with telehealth may have more difficulty accessing timely care.

Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules.

Targeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster of E3 ligases that can be utilized for TPD, we describe the discovery and biochemical characterization of small-molecule ligands targeting the E3 ligase KLHDC2. Furthermore, we functionalize these KLHDC2-targeting ligands into KLHDC2-based BET-family and AR PROTAC degraders and demonstrate KLHDC2-dependent target-protein degradation. Additionally, we offer insight into the assembly of the KLHDC2 E3 ligase complex. Using biochemical binding studies, X-ray crystallography and cryo-EM, we show that the KLHDC2 E3 ligase assembles into a dynamic tetramer held together via its own C terminus, and that this assembly can be modulated by substrate and ligand engagement.

Trends in telehealth use among a cohort of rural patients during the COVID-19 pandemic.

Objective: Rural populations faced unique challenges to healthcare access during the COVID-19 pandemic. This analysis assesses trends in digital health technology use at the onset of the pandemic and describes digital health behaviors among a cohort of patients within a rural integrated healthcare network throughout the first 3 years of the pandemic. Methods: We used data from both the electronic health record (EHR) and a patient survey. EHR data was used to longitudinally assess change over time in patient portal use and telehealth visits. Survey responses were used to provide additional context. Results: Telehealth appointments peaked in the first quarter of 2020 at 28% of all office visits, before leveling off to 8-10% in 2022. Women and those younger than 65 were more likely to have participated in telehealth appointments. Active patient portal users increased from 34.1% in January 2019 to 63.7% in January 2022. There were no differences noted in portal use trends based on rurality. Conclusions: Our findings corroborate previous research, as well as add context regarding digital health technology use throughout the COVID pandemic in a rural patient population. Future research must focus on understanding constraints to digital health expansion in order to continue providing safe, equitable care.

Exploring Multiple Dimensions of Access to and Preferences for Telehealth Use.

Introduction: During the pandemic, telehealth became critically important in care provision. Yet, research exposed the inequities facing various groups of people in terms of accessing telehealth. The purpose of this analysis was to examine the various dimensions of access that impact a person's ability to use and preference for telehealth. Methods: We used a mixed-methods approach framed by Levesque's Access to Health care model. In August, 2021, a stratified random sample of 500 patients of an integrated rural health care network was invited to participate in a survey designed to capture familiarity with, use of, and preference for digital technologies in general as well as with telehealth. In addition, key informant interviews were conducted between January 2022 and June 2022. Results: Patients' willingness to use telehealth was influenced by multiple dimensions of access, including approachability of the resource, acceptability, availability, affordability, and appropriateness. Clinician beliefs and attitudes as well as health care system policies affected how a patient perceived, sought, reached, and engaged with telehealth. Conclusions: Access is a dynamic, multifaceted concept that is influenced by individual-, organization-, and systemic-level factors. Looking beyond patient determinants and examining different dimensions of access is important to better facilitate implementation and sustainment of telehealth.

Ligand-Directed GPCR Antibody Discovery.

Developing affinity reagents recognizing and modulating G-protein coupled receptors (GPCR) function by traditional animal immunization or in vitro screening methods is challenging. Some anti-GPCR antibodies exist on the market, but the success rate of development is still poor compared with antibodies targeting soluble or peripherally anchored proteins. More importantly, most of these antibodies do not modulate GPCR function. The current pipeline for antibody development primarily screens for overall affinity rather than functional epitope recognition. We developed a new strategy utilizing natural ligand affinity to generate a library of antibody variants with an inherent bias toward the active site of the GPCR. Instead of using phage libraries displaying antibodies with random CDR sequences at polymorphism sites observed in natural immune repertoire sequences, we generated focused antibody libraries with a natural ligand encoded within or conjugated to one of the CDRs or the N-terminus. To tailor antibody binding to the active site, we limited the sequence randomization of the antibody in regions holstering the ligand while leaving the ligand-carrying part unaltered in the first round of randomization. With hits from the successful first round, the second round of randomization of the ligand-carrying part was then performed to eliminate the bias of the ligand. Based on our results on three different GPCR targets, the proposed pipeline will enable the rapid generation of functional antibodies (both agonists and antagonists) against high-value targets with poor function epitope exposures including GPCR, channels, transporters as well as cell surface targets whose binding site is heavily masked by glycosylation.

MILKSHAKE: novel validation method for antibodies to post-translationally modified targets by surrogate Western blot.

Antibody (Ab) validation is the procedure in which an Ab is thoroughly assayed for sensitivity and specificity in a given application. Validation of Abs against post-translationally modified (PTM) targets is particularly challenging because it requires specifically prepared antigen. Here we describe a novel validation method using surrogate proteins in a Western blot. The surrogate protein, which we termed 'MILKSHAKE,' is a modified maltose binding protein enzymatically conjugated to a peptide from the chosen target that is either modified or nonmodified at the residue of interest. The certainty of the residue's modification status can be used to confirm Ab specificity. This method also allows for Ab validation even in the absence or limited availability of treated cell lysates.

Nutritional screening, assessment and implementation strategies for adults in an Australian acute tertiary hospital: a best practice implementation report.

OBJECTIVE: The project aimed to improve the effectiveness of nutritional screening and assessment practices through clinical audits and the implementation of evidence-based practice recommendations. INTRODUCTION: In the absence of optimal nutrition, health may decline and potentially manifest as adverse health outcomes. In a hospitalized person, poor nutrition may adversely impact on the person's outcome. If the nutritional status can be ascertained, nutritional needs can be addressed and potential risks minimized.The overall purpose of this project was to review and monitor staff compliance with nutritional screening and assessment best practice recommendations ensuring there is timely, relevant and structured nutritional therapeutic practices that support safe, compassionate and person-centered care in adults in a tertiary hospital in South Western Sydney, Australia, in the acute care setting. METHODS: A baseline retrospective chart audit was conducted and measured against 10 best practice criteria in relation to nutritional screening and assessment practices. This was followed by a facilitated multidisciplinary focus group to identify targeted strategies, implementation of targeted strategies, and a post strategy implementation chart audit.The project utilized the Joanna Briggs Institute Practical Application of Clinical Evidence System (JBI PACES) and Getting Research into Practice (GRIP) tool, including evidence from other available supporting literature, for promoting change in healthcare practice. RESULTS: The baseline audit revealed deficits between current practice and best practice across the 10 criteria. Barriers for implementation of nutritional screening and assessment best practice criteria were identified by the focus group and an education strategy was implemented. There were improved outcomes across all best practice criteria in the follow-up audit. CONCLUSIONS: The baseline audit revealed gaps between current practice and best practice. Through the implementation of a targeted education program and resource package, outcomes improved in the follow up audit. The findings indicated that engagement from multidisciplinary team members and consumers was effective in developing tailored education that improved knowledge of best practice. This was demonstrated by an increase in the percentage of compliance across the 10 criteria, although leaving room for more improvement. A policy has been developed for implementation and future audits are planned to measure whether improved practices have been sustained.

Pre-existing risk factors for in-hospital death among older patients could be used to initiate end-of-life discussions rather than Rapid Response System calls: A case-control study.

AIM: To investigate associations between clinical parameters - beyond the evident physiological deterioration and limitations of medical treatment - with in-hospital death for patients receiving Rapid Response System (RRS) attendances. METHODS: Retrospective case-control analysis of clinical parameters for 328 patients aged 60 years and above at their last RRS call during admission to a single teaching hospital in the 2012-2013 calendar years. Generalised estimating equation modelling was used to compare the deceased with a randomly selected sample of those who had RRS calls and survived admission (controls), matched by age group, sex, and hospital ward. RESULTS: In addition to a pre-existing order for limitation of treatment or cardiac arrest (OR 6.92; 95%CI 4.61-10.27), nursing home residence, proteinuria, advanced malignancy, acute myocardial infarction, chronic kidney disease, cognitive impairment and frailty were associated with high risk of death. After adjusting for all the clinical indicators investigated, the strongest risk factors for in-hospital death for patients with a RRS call were advanced malignancy (OR 3.95; 95%CI 2.16-7.21) and new myocardial infarction (OR 2.79; 95%CI 1.86-4.20). Patients with cognitive impairment, frailty indicator or chronic kidney disease were twice as likely to die as patients without those risk factors. CONCLUSION: In a sample of older deteriorated patients requiring a RRS attendance, multiple indicators of chronic illness, cognitive impairment and frailty were significantly associated with high risk of death. These clinical features beyond the evident orders for limitation of medical treatment should signal the need for clinicians to initiate end-of-life discussions that may prevent futile interventions.

Hospital outcomes associated with introduction of a two-tiered response to the deteriorating patient.

BACKGROUND: Liverpool Hospital introduced the medical emergency team system in 1990 and it has recently been adopted at a national and international level. New South Wales, Australia, has introduced a standardised rapid response system in over 250 acutecare hospitals: the two-tiered (clinical review call [CRC] and rapid response call [RRC]) "between the flags" (BTF) program. OBJECTIVES: To describe the effect of the introduction of a twotiered response to the deteriorating patient on the number of RRCs, cardiac arrests and hospital deaths. METHODS: Our study was undertaken at an 850-bed teaching hospital in the south-west of Sydney, Australia, with about 80 000 hospital admissions each year. Rates of RRCs, cardiac arrests and all hospital deaths (with and without not-for-resuscitation orders) were compared before the introduction of the BTF program (2009) and after implementation, until June 2013. The rates of CRCs after implementation were measured. Changes in the reasons for RRCs were also compared for the 12-month period before and the 36 months after the introduction of the BTF program. RESULTS: The monthly rate of RRCs before introduction of the program was 18.8 per 1000 hospital admissions (95% CI, 17.8- 19.8 per 1000 admissions) and was estimated to increase by 4% after program implementation (95% CI, 3.2%-4.7%; P < 0.001). The rate of CRCs increased by 13.2% (95% CI, 10.9%-15.6%) during the study period. The cardiac arrest rate before implementation of clinical review was 1.1 per 1000 admissions (95% CI, 0.9-1.3 per 1000 admissions) and after implementation was estimated to have changed by 1% (95% CI, - 1.9 to 3.9; P = 0.48). The hospital death rate before implementation of the BTF program was 10.8 per 1000 admissions (95% CI, 10.1-11.5 per 1000 admissions), and after implementation was estimated to increase by 2% (95% CI, 1.2%-3%, P < 0.001). The reasons for RRCs before and after the introduction of the BTF program did not change (all P values > 0.2), apart from the "worried" criterion, that decreased from 30% to 17% of all calls after implementation (P < 0.001). CONCLUSION: After introduction of the BTF program, there was a progressive increase in documented CRCs and an increase in RRCs. There was no decrease in cardiac arrests or hospital deaths. RRCs based on objective physiological criteria increased. More research is needed to evaluate two-tiered response systems.