Meta-EA: A Gene-Specific Combination of Available Computational Tools for Predicting Missense Variant Effects

Computational methods for estimating missense variant impact suffer from inconsistent performance across genes, which poses a major challenge for their reliable use in clinical practice. While ensemble scores leverage multiple prediction methods to enhance consistency, the overrepresentation of certain genes in the training data can bias their outcomes. To address this critical limitation, we propose a gene-specific ensemble framework trained on reference computational annotations rather than on clinical or experimental data. Accordingly, we generate Meta-EA ensemble scores that achieve comparable performance to the top individual predicting method for each gene set. Incorporating the effects of splicing and the allele frequency of human polymorphisms further enhances the performance of Meta-EA, achieving an area under the receiver operating characteristic curve of 0.97 for both gene-balanced and imbalanced clinical assessments. In conclusion, this work leverages the wealth of existing variant impact prediction approaches to generate improved estimations for clinical interpretation

Genome-Wide Association Study Reveals Shared and Distinct Genetic Architecture of Fatty Acids and Oxylipins in the Hispanic Community Health Study/Study of Latinos

Bioactive fatty acid-derived oxylipin molecules play key roles mediating inflammation and oxidative stress. Circulating levels of fatty acids and oxylipins are influenced by environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biology. We performed a genome-wide association study (GWAS) of 81 fatty acids and oxylipins in 11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years (standard deviation 13.8)). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Thirty-three of the 81 oxylipins and fatty acids were significantly heritable (heritability range: 0-32.7%). Forty (49.4%) oxylipins and fatty acids had at least one genome-wide significant (p \u3c 6.94E-11) variant resulting in 19 independent genetic loci. Six loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including desaturase-encoding FADS and OATP1B1 transporter protein-encoding SLCO1B1, exhibited associations with two or more fatty acids and oxylipins. At several of these loci, there was evidence of colocalization of the top variant across fatty acids and oxylipins. The remaining loci were only associated with one oxylipin or fatty acid and included several CYP loci. We also identified an additional rare variant (MAF = 0.002) near CARS2 in two-degree-of-freedom tests. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating work to characterize these compounds and elucidate their roles in disease

Framework, Design, and Baseline Data of a Collective Impact Initiative to Strengthen the Community Health Worker Workforce Ecosystem in Texas

BACKGROUND: The Health Equity Collective (HEC), a multi-sector systems-level collective impact coalition in the Greater Houston region, partnered with the City of Houston Health Department (HHD) to launch a 2-year effort to implement a comprehensive approach towards strengthening the regional Community Health Workers (CHW) workforce infrastructure as a pathway to advancing health equity. Our paper presents the logic model, methods, and baseline qualitative and quantitative data from this initiative. METHODS: In the fall of 2022, the Health Equity Collective brought together a Network of CHW-employing or training organizations in the Greater Houston region. This Network was the working group of CHW employer/training organizations tasked with developing the shared agenda for collaborative action toward strengthening the regional CHW workforce. As part of the baseline needs assessment qualitative interviews were conducted to understand the role and add-value of CHWs in advancing health equity. A landscape scan survey was administered to assess CHW employer organization\u27s funding and sustainability mechanisms for their CHWs job stability, CHW focus areas, organizational health equity priorities, etc. A journey mapping exercise was also conducted to capture CHWs lived experiences in their own voices. RESULTS: The qualitative interviews outlined three themes that describe the role, barriers, and needs of CHWs. Landscape scan survey responses were obtained from 21 out of 29 organizations in the CHW Network. Responses provided insight into CHW employer organizational funding and sustainability mechanisms for CHWs job stability, CHW focus areas, etc. The journey mapping exercise outlines the various paths that brought the participants to pursue a CHW career path and their journey through CHW training and work. CONCLUSION: In summary, our paper outlines the collective impact approach and baseline data guiding efforts to strengthen the regional CHW workforce. Strategies and priorities were developed based on CHW voices and engaging stakeholders across organizations employing and training CHWs

Improving Nurse Retention Through Unit-Based Mentoring

PURPOSE A quality improvement (QI) project was implemented and aimed to improve nurse retention through a unit-based mentoring program, develop nurses with less than three years of experience, and increase clinical nurse job satisfaction. BACKGROUND Over one year, an impatient surgical unit onboarded more than ten new registered nurses, resulting in an uneven skill mix. The unit’s clinical nurse turnover in 2022 reached 32%. The goal of the QI project was to support nurses\u27 professional development and improve nurse retention and satisfaction. METHODOLOGY Nurses with less than three years of experience were paired with nurses with more than three years of experience. Through the direct support of unit leadership, nurse mentors/mentees were matched and supported in monthly meetings where individualized structured goals were developed. Validated tools such as Intent to Stay and Index of Work Satisfaction surveys were utilized to measure the outcome of the evidence-based quality improvement project. The unit’s clinical nurse retention was measured tracked via an electronic dashboard. RESULTS Eleven mentor/mentee pairs continued to completion of the program. The pairs met monthly with the support of the unit leader, who scheduled and attended meetings. After implementing unit-based mentoring, the unit’s retention increased by 8.3%, to 100%, in four months. Validated tools supported this success by indicating a 0.09 increase in nurse communication. IMPLICATIONS Unit leaders can improve their nurse’s satisfaction and retain front-line staff by implementing a unit-based mentoring program

Open-Chest Cardiac Ultrasound-Mediated Imaging With a Vacuum Coupler

BACKGROUND: A fundamental obstacle for the preclinical development of ultrasound-(US) mediated cardiac imaging remains cardiac motion, which limits interframe correlation during extended acquisition periods. PURPOSE: To address this need, we present the design and implementation of a 3D-printed vacuum coupler that stabilizes a US transducer on the epicardial surface of the heart for feasibility assessment and development of advanced, cardiac, US-mediated imaging approaches. METHODS: The vacuum coupler was 3D printed with biocompatible resins and secured with a standard intraoperative suction aspirator. US-mediated imaging (i.e., B-mode and photoacoustic [PA] imaging) was performed in an open-chest porcine model with and without the vacuum coupler. Based on inter-frame displacement tracking and cross-correlation (CC) coefficients, changes in frame motion and stability were compared for each imaging mode/configuration through a prolonged (∼1 min) acquisition, while the impact on PA-based SO RESULTS: When compared to conventional handheld imaging, stand-off imaging, and coupler without suction, epicardial imaging with the vacuum coupler and suction applied led to a significantly reduced mean axial displacement of 0.15 mm versus 0.89, 0.49, & 0.49 mm, respectively (p-values ≤ 8.65e-7). Comparing the coupler without suction to that with suction applied, physiologically unrealistic SO CONCLUSIONS: Epicardial US-mediated imaging with a vacuum coupler reduces cardiac motion artifact, providing a consistent sampling of an intended region of interest (ROI) over multiple cardiac cycles. This could help facilitate the development of advanced US-mediated imaging, which is often hindered by cardiac motion. Stable implementation of these imaging techniques could allow for intra-operative assessments of local cardiac perfusion as well as tissue characterization

Assessing Cancer Therapeutic Efficacy In Vivo Using [2H7]glucose Deuterium Metabolic Imaging

Metabolic imaging produces powerful visual assessments of organ function in vivo. Current techniques can be improved by safely increasing metabolic contrast. The gold standard, 2-[18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, is limited by radioactive exposure and sparse assessment of metabolism beyond glucose uptake and retention. Deuterium magnetic resonance imaging (DMRI) with [6,6-2H2]glucose is nonradioactive, achieves tumor metabolic contrast, but can be improved by enriched contrast from deuterated water (HDO) based imaging. Here, we developed a DMRI protocol employing [2H7]glucose. Imaging 2H-signal and measuring HDO production in tumor-bearing mice detected differential glucose utilization across baseline tumors, tumors treated with vehicle control or anti-glycolytic BRAFi and MEKi therapy, and contralateral healthy tissue. Control tumors generated the most 2H-signal and HDO. To our knowledge this is the first application of DMRI with [2H7]glucose for tumoral treatment monitoring. This approach demonstrates HDO as a marker of tumor glucose utilization and suggests translational capability in humans due to its safety, noninvasiveness, and suitability for serial monitoring

Cell Cycle Progression of Under-Replicated Cells

Cell cycle checkpoints are the regulatory mechanisms that secure the strict order of cellular events for cell division that ensure genome integrity. It has been proposed that mitosis initiation depends on the completion of DNA replication, which must be tightly controlled to guarantee genome duplication. Contrary to these conventional hypotheses, we showed here that cells were able to enter mitosis without completion of DNA replication. Although DNA replication was not completed in cells upon depletion of MCM2, CDC45 or GINS4, these under-replicated cells progressed into mitosis, which led to cell death. These unexpected results challenge current model and suggest the absence of a cell cycle checkpoint that monitors the completion of DNA replication

Intelligent Biology and Medicine: Accelerating Innovative Computational Approaches

In this editorial, we summarize the 2023 International Conference on Intelligent Biology and Medicine (ICIBM 2023) conference which was held on July 16-19, 2023 in Tampa, Florida, USA. We then briefly describe the nine research articles included in this special issue. ICIBM 2023 scientific program included four tutorials and workshops, four keynote lectures, four eminent scholars\u27 presentations, 11 concurrent scientific sessions, and a poster session. We had total of 88 scientific oral presentations, including 62 regular oral presentations and 26 flash talks, as well as 46 poster presentations. The topics of these presentations covered artificial intelligence (AI), data sciences, bioinformatics, computational biology, genomics, biomedical informatics, among others. This special issue included nine peer reviewed manuscripts selected from those submitted to our conference. These articles cover a range of topics on the methods and applications of ML and AI models in the biomedical domain

Increasing Premedication for Neonatal Intubation: A Quality Improvement Initiative

INTRODUCTION: Endotracheal intubation is frequent in the neonatal intensive care unit (NICU) but may result in neonatal distress and instability. Premedication reduces adverse effects, such as hypoxia, bradycardia, and pain. The Specific, Measurable, Achievable, Relevant and Time-Bound aim for this project was to increase premedication use for nonemergent neonatal intubation in a specific NICU from 22% to 80% from March 2021 to May 2023. METHODS: We use quality improvement methodology to explain our theory for improvement. Our key driver diagram depicts this initiative\u27s aims, key drivers, and interventions to increase premedication use for neonatal intubation. We defined exclusion criteria and medications, and one author collected demographic data retrospectively after the procedure. The stakeholders summarized the baseline data, performed plan-do-study-act cycles, and showed outcome measures in a statistical process control chart. Statistical analysis used Fisher\u27s exact test to compare categorical variables. RESULTS: Between 2021 and 2023, 333 infants underwent endotracheal intubation; 130 infants were included. The most common indication for intubation was hypoxemic respiratory failure-52% (68/130). Premedication use increased from 22% to 52%. Among the exclusion criteria, the most common indication for nonpremedication was intubation in the delivery room, 38.4% (78/203). In the premedication group, intubation on the first attempt occurred in 77.6% (52/67) of the cases, versus the nonpremedication group, 66.7% (32/48) ( CONCLUSIONS: Premedication for neonatal intubation increased by 30%, although we did not reach the desired 80% goal. Establishing a premedication bundle, alongside a unit-specific protocol and effective teamwork, marks the initial stride toward enhancing analgesia/sedation practices in the NICU

Outcomes in Pediatric Cholesteatoma

OBJECTIVE: The objective of the study is to evaluate the outcomes of surgical management options for cholesteatoma using a national database. STUDY DESIGN: Database analysis of the Pediatric Health Information System database to identify children undergoing surgical intervention for cholesteatoma from October 2015 to December 2022. METHODS: Patients were categorized by initial surgical modality: tympanoplasty (TM), tympanoplasty with canal wall-up tympanomastoidectomy (TM-CWU), and tympanoplasty with canal wall-down tympanomastoidectomy (TM-CWD). Group comparisons were done on number of surgical revisions and number of patients identified with recommendations for hearing aids. RESULTS: A total of 6304 patients were identified in the database who underwent surgery for cholesteatoma. Of these children, 3405 underwent TM (54.0%), 3116 underwent TM-CWU (49.4%), and 825 underwent TM-CWD (8.2%). The estimated difference in mean number of procedures was significantly higher in the TM-CWU group compared to TM-CWD (-0.34, 95% confidence interval [CI] -0.406,-0.279, P \u3c .0001) and the TM group (9.352, 95% CI 0.315, 0.390, P \u3c .0001). The rate of significant hearing loss necessitating hearing aids was significantly lower in the TM group, but there was no difference between the TM-CWU and TM-CWD groups (1.2%, P \u3c .03, 1.9% vs 2.7%, P = .13). There was no difference in the number of speech delays/therapy diagnoses between TM and TM-CWU or TM-CWU and TM-CWD (3.5%vs 4.4% P = .07, 4.4% vs 5.2%., P = .38). CONCLUSION: TM and TM-CWD had lower total surgical procedures than the TM-CWU group, and the TM group had a lesser rate of recommendation for hearing aids. The difference between number of procedures is likely due to the complexity of the disease; for instance, TM was likely chosen for small, less severe disease cases, whereas TM-CWD was chosen as more definitive treatment in aggressive cases. TM-CWD is associated with a lower rate of recidivism and recurrence, which also likely contributed to the lower number of procedures