Sedation Weaning Initiative Targeting Methadone Exposure: Single Center Improvements in Withdrawal Symptoms and Hospital Length of Stay for Pediatric Cardiac Critical Care.

OBJECTIVES: Sedation and pain medications are necessary in the management of postoperative pediatric cardiac patients. Prolonged exposure to these medications can lead to negative side effects including withdrawal. We hypothesized that standardized weaning guidelines would decrease exposure to sedation medications and decrease withdrawal symptoms. The primary aim was to decrease average days of methadone exposure to within goal for moderate- and high-risk patients within 6 months. DESIGN: Quality improvement methods were used to standardize sedation medication weaning in a pediatric cardiac ICU. SETTING: This study took place at Duke Children's Hospital Pediatric Cardiac ICU in Durham, North Carolina from January 1, 2020, to December 31, 2021. PATIENTS: Children less than 12 months old admitted to the pediatric cardiac ICU who underwent cardiac surgery. INTERVENTIONS: Sedation weaning guidelines were implemented over the course of 12 months. Data were tracked every 6 months and compared with the 12 months pre-intervention. Patients were stratified into low, moderate, and high risk withdrawal categories based on duration of opioid infusion exposure. MEASUREMENTS AND MAIN RESULTS: Total sample size was 94 patients in the moderate and high risk categories. Process measures included documentation of Withdrawal Assessment Tool scores and appropriate methadone prescription in patients which increased to 100% post-intervention. For outcome measures, we observed decreased dexmedetomidine infusion duration, decreased methadone wean duration, decreased frequency of elevated Withdrawal Assessment Tool scores, and decreased hospital length of stay post-intervention. For the primary aim, methadone wean duration consistently decreased after each study period. Our intervention did not adversely impact balancing measures. CONCLUSIONS: A quality improvement initiative to standardize sedation weaning in a Pediatric Cardiac ICU was successfully implemented and was correlated with decreased duration of sedation medications, decreased withdrawal scores, and decreased length of stay.

Gamification educational intervention improves pediatric nurses' comfort and speed drawing up code-dose epinephrine.

PURPOSE: Drawing up weight-based doses of epinephrine is a vital skill for pediatric nurses; however, non-intensive care unit (ICU) nurses may not routinely perform this skill and may not be as efficient or comfortable doing so during pediatric resuscitations. This study aimed to evaluate the impact of a gamification program on non-ICU pediatric nurses' knowledge and skills regarding epinephrine for pediatric cardiac arrest. DESIGN AND METHODS: Comfort and time to draw up three doses of epinephrine during out-of-ICU in-hospital pediatric cardiac arrest were measured pre- and post- a gamification-centered educational intervention. RESULTS: Nursing comfort improved from 2.93 ± 1.90 to 6.68 ± 1.46 out of 10 (mean difference 3.6 +/- 2.1, p < 0.001). Overall time to draw up three doses of epinephrine decreased after the intervention by an average of 27.1 s (p = 0.019). The number of nurses who could complete the task in under 2 min improved from 23% to 59% (p = 0.031). CONCLUSIONS: At baseline few non-ICU nurses could draw up multiple weight-based doses of epinephrine in under two minutes. A gamification simulation-based educational intervention improved pediatric non-ICU nurses' comfort and speed drawing up epinephrine. PRACTICE IMPLICATIONS: Wide-spread implementation of gamification-centered educational initiatives could result in faster epinephrine administration and improved mortality rates from in-hospital pediatric cardiac arrest.

A systematic review of the evidence supporting post-operative medication use in congenital heart disease.

BACKGROUND: Targeted drug development efforts in patients with CHD are needed to standardise care, improve outcomes, and limit adverse events in the post-operative period. To identify major gaps in knowledge that can be addressed by drug development efforts and provide a rationale for current clinical practice, this review evaluates the evidence behind the most common medication classes used in the post-operative care of children with CHD undergoing cardiac surgery with cardiopulmonary bypass. METHODS: We systematically searched PubMed and EMBASE from 2000 to 2019 using a controlled vocabulary and keywords related to diuretics, vasoactives, sedatives, analgesics, pulmonary vasodilators, coagulation system medications, antiarrhythmics, steroids, and other endocrine drugs. We included studies of drugs given post-operatively to children with CHD undergoing repair or palliation with cardiopulmonary bypass. RESULTS: We identified a total of 127 studies with 51,573 total children across medication classes. Most studies were retrospective cohorts at single centres. There is significant age- and disease-related variability in drug disposition, efficacy, and safety. CONCLUSION: In this study, we discovered major gaps in knowledge for each medication class and identified areas for future research. Advances in data collection through electronic health records, novel trial methods, and collaboration can aid drug development efforts in standardising care, improving outcomes, and limiting adverse events in the post-operative period.

An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020.

BACKGROUND: Infants with moderate-to-severe CHD frequently undergo cardiopulmonary bypass surgery in childhood. Morbidity and mortality are highest in those who develop post-operative low cardiac output syndrome. Vasoactive and inotropic medications are mainstays of treatment for these children, despite limited evidence supporting their use. METHODS: To help inform clinical practice, as well as the conduct of future trials, we performed a systematic review of existing literature on inotropes and vasoactives in children after cardiac surgery using the PubMed and EMBASE databases. We included studies from 2000 to 2020, and the patient population was defined as birth - 18 years of age. Two reviewers independently reviewed studies to determine final eligibility. RESULTS: The final analysis included 37 papers. Collectively, selected studies reported on 12 different vasoactive and inotropic medications in 2856 children. Overall evidence supporting the use of these drugs in children after cardiopulmonary bypass was limited. The majority of studies were small with 30/37 (81%) enrolling less than 100 patients, 29/37 (78%) were not randomised, and safety and efficacy endpoints differed widely, limiting the ability to combine data for meta-analyses. CONCLUSION: Vasoactive and inotropic support remain critical parts of post-operative care for children after cardiopulmonary bypass surgery. There is a paucity of data for the selection and dosing of vasoactives and inotropes for these patients. Despite the knowledge gaps that remain, numerous recent innovations create opportunities to rethink the conduct of clinical trials in this high-risk population.

Maximizing Operational Efficiency Using an In-House Ambulatory Surgery Model at an Academic Medical Center.

EXECUTIVE SUMMARY: Given the rising costs of healthcare delivery and reimbursement constraints, large academic medical centers (AMCs) must improve efficiency while delivering high-quality care. With standardized cases and high volumes, ambulatory surgery is a high-value target for efficiency improvement. Mining a data set of more than 7,500 cases consisting of the three highest-volume ambulatory procedures in orthopedics, otolaryngology-head and neck surgery, and urology, we analyzed process times and wait times involved in patient flow. We examined differences among delayed versus early versus on-time cases, as well as differences in scheduled start times, day of the week, and each individual operating room. Our analysis found statistically and clinically significant differences in registration and setup wait times when comparing delayed versus early versus on-time cases. We then developed recommendations to increase value-added time. Using activity-based cost accounting, we created a model to quantify economic impact. Hospitals can adopt these methods to identify operational bottlenecks and employ our financial model to forecast changes in revenue. Application of this model can position AMCs for success in an increasingly competitive landscape.

Association of Hematocrit and Red Blood Cell Transfusion with Outcomes in Infants Undergoing Norwood Operation.

The objective of this study was to investigate the association between red blood cell (RBC) transfusion and hematocrit values with outcomes in infants undergoing Norwood operation. This study included infants ≤2 months of age who underwent Norwood operation with either a modified Blalock-Taussig shunt or a right ventricle-pulmonary artery shunt. Demographics, preoperative, operative, daily laboratory data, and postoperative variables were collected. The primary outcome measures evaluated included mortality, ICU length of stay, length of mechanical ventilation, and days to chest closure. The secondary outcome measures evaluated included lactate levels, estimated glomerular filtration rate, and inotrope score in the first 14 days after heart operation. Cox proportional hazard models were fitted to study the probability of study outcomes as a function of hematocrit values and RBC transfusions after operation. Eighty-nine patients qualified for inclusion. With a median hematocrit of 46 (IQR 44, 49), and a median RBC transfusion of 92 ml/kg (IQR 31, 384) in the first 14 days after operation, 81 (91 %) patients received RBC transfusions. A multivariable analysis adjusted for risk factors, including the age, weight, prematurity, cardiopulmonary bypass and cross-clamp time, and postoperative need for nitric oxide and dialysis, demonstrated no association between hematocrit and RBC transfusion with majority of study outcomes. This single-center study found that higher hematocrit values and increasing RBC transfusions are not associated with improved outcomes in infants undergoing Norwood operation.

Retail Packaging Affects Colour, Water Holding Capacity, Texture and Oxidation of Sheep Meat more than Breed and Finishing Feed.

This study investigated the CIELab colour, water holding capacity, texture and oxidative stability of sheep meat from different breeds, finishing feeds, and retail packaging methods. Leg primal cuts from a subset of Composite wether lambs (n = 21) and Merino wether yearlings (n = 21) finished on a standard diet containing grain and cereal hay, a standard diet with camelina forage, or a standard diet with camelina meal, were used in this study. Semimembranosus and Vastus lateralis were packaged in vacuum skin packaging (VSP), or modified atmosphere packaging with 80% O2 and 20% CO2 (HioxMAP), or with 50% O2, 30% N2, and 20% CO2 (TrigasMAP). Packaging had a greater effect (p < 0.001) on L*, a*, b*, hue, and chroma than the effects from breed and finishing feed. Purge loss was affected by packaging. Cooking loss was affected by breed for Semimembranosus and packaging for both muscle types. HioxMAP and TrigasMAP increased WBSF and Texture Profile Analysis hardness of the meat compared to VSP. Lipid oxidation, assessed by TBARS, were lower in camelina forage or camelina meal supplemented diets and TrigasMAP compared to standard diet and HioxMAP, respectively. Total carbonyl and free thiol content were lower in VSP. Thus, supplementing feed with camelina forage or meal and lowering oxygen content in retail packaging by TrigasMAP or VSP are recommended to ensure optimal sheep meat quality.

Enhancer RNA Transcription Is Essential for a Novel CSF1 Enhancer in Triple-Negative Breast Cancer.

Enhancers are critical regulatory elements in the genome that help orchestrate spatiotemporal patterns of gene expression during development and normal physiology. In cancer, enhancers are often rewired by various genetic and epigenetic mechanisms for the activation of oncogenes that lead to initiation and progression. A key feature of active enhancers is the production of non-coding RNA molecules called enhancer RNAs, whose functions remain unknown but can be used to specify active enhancers de novo. Using a combination of eRNA transcription and chromatin modifications, we have identified a novel enhancer located 30 kb upstream of Colony Stimulating Factor 1 (CSF1). Notably, CSF1 is implicated in the progression of breast cancer, is overexpressed in triple-negative breast cancer (TNBC) cell lines, and its enhancer is primarily active in TNBC patient tumors. Genomic deletion of the enhancer (via CRISPR/Cas9) enabled us to validate this regulatory element as a bona fide enhancer of CSF1 and subsequent cell-based assays revealed profound effects on cancer cell proliferation, colony formation, and migration. Epigenetic silencing of the enhancer via CRISPR-interference assays (dCas9-KRAB) coupled to RNA-sequencing, enabled unbiased identification of additional target genes, such as RSAD2, that are predictive of clinical outcome. Additionally, we repurposed the RNA-guided RNA-targeting CRISPR-Cas13 machinery to specifically degrade the eRNAs transcripts produced at this enhancer to determine the consequences on CSF1 mRNA expression, suggesting a post-transcriptional role for these non-coding transcripts. Finally, we test our eRNA-dependent model of CSF1 enhancer function and demonstrate that our results are extensible to other forms of cancer. Collectively, this work describes a novel enhancer that is active in the TNBC subtype, which is associated with cellular growth, and requires eRNA transcripts for proper enhancer function. These results demonstrate the significant impact of enhancers in cancer biology and highlight their potential as tractable targets for therapeutic intervention.

Standard treatments induce antigen-specific immune responses in prostate cancer.

PURPOSE: Prostate tumors express antigens that are recognized by the immune system in a significant proportion of patients; however, little is known about the effect of standard treatments on tumor-specific immunity. Radiation therapy induces expression of inflammatory and immune-stimulatory molecules, and neoadjuvant hormone therapy causes prominent T-cell infiltration of prostate tumors. We therefore hypothesized that radiation therapy and hormone therapy may initiate tumor-specific immune responses. EXPERIMENTAL DESIGN: Pretreatment and posttreatment serum samples from 73 men with nonmetastatic prostate cancer and 50 cancer-free controls were evaluated by Western blotting and SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen arrays to examine whether autoantibody responses to tumor proteins arose during the course of standard treatment. RESULTS: Western blotting revealed the development of treatment-associated autoantibody responses in patients undergoing neoadjuvant hormone therapy (7 of 24, 29.2%), external beam radiation therapy (4 of 29, 13.8%), and brachytherapy (5 of 20, 25%), compared with 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%) controls. Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups. Similarly, in the murine Shionogi tumor model, hormone therapy induced tumor-associated autoantibody responses in 5 of 10 animals. In four patients, SEREX immunoscreening of a prostate cancer cDNA expression library identified several antigens recognized by treatment-associated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2. CONCLUSION: We show for the first time that standard treatments induce antigen-specific immune responses in prostate cancer patients. Thus, immunologic mechanisms may contribute to clinical outcomes after hormone and radiation therapy, an effect that could potentially be exploited as a practical, personalized form of immunotherapy.

Temperature responses of carbon monoxide and hydrogen uptake by vegetated and unvegetated volcanic cinders.

Ecosystem succession on a large deposit of volcanic cinders emplaced on Kilauea Volcano in 1959 has resulted in a mosaic of closed-canopy forested patches and contiguous unvegetated patches. Unvegetated and unshaded surface cinders (Bare) experience substantial diurnal temperature oscillations ranging from moderate (16 °C) to extreme (55 °C) conditions. The surface material of adjacent vegetated patches (Canopy) experiences much smaller fluctuations (14-25 °C) due to shading. To determine whether surface material from these sites showed adaptations by carbon monoxide (CO) and hydrogen (H(2)) consumption to changes in ambient temperature regimes accompanying succession, we measured responses of CO and H(2) uptake to short-term variations in temperature and long-term incubations at elevated temperature. Based on its broader temperature optimum and lower activation energy, Canopy H(2) uptake was less sensitive than Bare H(2) uptake to temperature changes. In contrast, Bare and Canopy CO uptake responded similarly to temperature during short-term incubations, indicating no differences in temperature sensitivity. However, during extended incubations at 55 °C, CO uptake increased for Canopy but not Bare material, which indicated that the former was capable of thermal adaptation. H(2) uptake for material from both sites was completely inhibited at 55 °C throughout extended incubations. These results indicated that plant development during succession did not elicit differences in short-term temperature responses for Bare and Canopy CO uptake, in spite of previously reported differences in CO oxidizer community composition, and differences in average daily and extreme temperatures. Differences associated with vegetation due to succession did, however, lead to a notable capacity for thermophilic CO uptake by Canopy but not Bare material.