Implementation of a multi-site neonatal simulation improvement program: a cost analysis.

BACKGROUND: To improve patient outcomes and provider team practice, the California Perinatal Quality Care Collaborative (CPQCC) created the Simulating Success quality improvement program to assist hospitals in implementing a neonatal resuscitation training curriculum. This study aimed to examine the costs associated with the design and implementation of the Simulating Success program. METHODS: From 2017-2020, a total of 14 sites participated in the Simulating Success program and 4 of them systematically collected resource utilization data. Using a micro-costing approach, we examined costs for the design and implementation of the program occurring at CPQCC and the 4 study sites. Data collection forms were used to track personnel time, equipment/supplies, space use, and travel (including transportation, food, and lodging). Cost analysis was conducted from the healthcare sector perspective. Costs incurred by CPQCC were allocated to participant sites and then combined with site-specific costs to estimate the mean cost per site, along with its 95% confidence interval (CI). Cost estimates were inflation-adjusted to 2022 U.S. dollars. RESULTS: Designing and implementing the Simulating Success program cost $228,148.36 at CPQCC, with personnel cost accounting for the largest share (92.2%), followed by program-related travel (6.1%), equipment/supplies (1.5%), and space use (0.2%). Allocating these costs across participant sites and accounting for site-specific resource utilizations resulted in a mean cost of $39,210.69 per participant site (95% CI: $34,094.52-$44,326.86). In sensitivity analysis varying several study assumptions (e.g., number of participant sites, exclusion of design costs, and useful life span of manikins), the mean cost per site changed from $35,645.22 to $39,935.73. At all four sites, monthly cost of other neonatal resuscitation training was lower during the program implementation period (mean = $1,112.52 per site) than pre-implementation period (mean = $2,504.01 per site). In the 3 months after the Simulating Success program ended, monthly cost of neonatal resuscitation training was also lower than the pre-implementation period at two of the four sites. CONCLUSIONS: Establishing a multi-site neonatal in situ simulation program requires investment of sufficient resources. However, such programs may have financial and non-financial benefits in the long run by offsetting the need for other neonatal resuscitation training and improving practice.

The activin A antagonist follistatin inhibits asthmatic airway remodelling.

BACKGROUND: Current pharmacotherapy is highly effective in the clinical management of the majority of patients with stable asthma, however severe asthma remains inadequately treated. Prevention of airway remodelling is a major unmet clinical need in the management of patients with chronic severe asthma and other inflammatory lung diseases. Accumulating evidence convincingly demonstrates that activin A, a member of the transforming growth factor (TGF)-ß superfamily, is a key driver of airway inflammation, but its role in chronic asthmatic airway remodelling is ill-defined. Follistatin, an endogenously produced protein, binds activin A with high affinity and inhibits its bioactivity. The aim of this study was to test the potential of follistatin as a therapeutic agent to inhibit airway remodelling in an experimental model of chronic allergic airway inflammation. METHODS: BALB/c mice were systemically sensitised with ovalbumin (OVA), and challenged with OVA intranasally three times a week for 10 weeks. Follistatin was instilled intranasally during allergen challenge. RESULTS: Chronic allergen challenge induced mucus hypersecretion and subepithelial collagen deposition which persisted after cessation of challenge. Intranasal follistatin (0.05, 0.5, 5 µg) inhibited the airway remodelling and dose-dependently decreased airway activin A and TGF-ß1, and allergen-specific T helper 2 cytokine production in the lung-draining lymph nodes. Follistatin also impaired the loss of TGF-ß1 and activin RIB immunostaining in airway epithelium which occurred following chronic allergen challenge. CONCLUSIONS: These data demonstrate that follistatin attenuates asthmatic airway remodelling. Our findings point to the potential of follistatin as a therapeutic for prevention of airway remodelling in asthma and other inflammatory lung diseases.

Head and Neck Radiation Therapy Patterns of Practice Variability Identified as a Challenge to Real-World Big Data: Results From the Learning from Analysis of Multicentre Big Data Aggregation (LAMBDA) Consortium.

Purpose: Outside of randomized clinical trials, it is difficult to develop clinically relevant evidence-based recommendations for radiation therapy (RT) practice guidelines owing to lack of comprehensive real-world data. To address this knowledge gap, we formed the Learning from Analysis of Multicenter Big Data Aggregation consortium to cooperatively implement RT data standardization, develop software solutions for data analysis, and recommend clinical practice change based on real-world data analyzed. The first phase of this "Big Data" study aimed at characterizing variability in clinical practice patterns of dosimetric data for organs at risk (OARs) that would undermine subsequent use of large-scale, electronically aggregated data to characterize associations with outcomes. Evidence from this study was used as the basis for practical recommendations to improve data quality. Methods and Materials: Dosimetric details of patients with head and neck cancer treated with radiation therapy between 2014 and 2019 were analyzed. Institutional patterns of practice were characterized, including structure nomenclature, volumes, and frequency of contouring. Dose volume histogram (DVH) distributions were characterized and compared with institutional constraints and literature values. Results: Plans for 4664 patients treated to a mean plan dose of 64.4 ± 13.2 Gy in 32 ± 4 fractions were aggregated. Before implementation of TG-263 guidelines in each institution, there was variability in OAR nomenclature across institutions and structures. With evidence from this study, we identified a targeted and practical set of recommendations aimed at improving the quality of real-world data. Conclusions: Quantifying similarities and differences among institutions for OAR structures and DVH metrics is the launching point for next steps to investigate potential relationships between DVH parameters and patient outcomes.

Development and Clinical Implementation of an Automated Virtual Integrative Planner for Radiation Therapy of Head and Neck Cancer.

Purpose: Head and neck (HN) radiation (RT) treatment planning is complex and resource intensive. Deviations and inconsistent plan quality significantly affect clinical outcomes. We sought to develop a novel automated virtual integrative (AVI) knowledge-based planning application to reduce planning time, increase consistency, and improve baseline quality. Methods and Materials: An in-house write-enabled script was developed from a library of 668 previously treated HN RT plans. Prospective hazard analysis was performed, and mitigation strategies were implemented before clinical release. The AVI-planner software was retrospectively validated in a cohort of 52 recent HN cases. A physician panel evaluated planning limitations during initial deployment, and feedback was enacted via software refinements. A final second set of plans was generated and evaluated. Kolmogorov-Smirnov test in addition to generalized evaluation metric and weighted experience score were used to compare normal tissue sparing between final AVI planner versus respective clinically treated and historically accepted plans. A t test was used to compare the interactive time, complexity, and monitor units for AVI planner versus manual optimization. Results: Initially, 86% of plans were acceptable to treat, with 10% minor and 4% major revisions or rejection recommended. Variability was noted in plan quality among HN subsites, with high initial quality for oropharynx and oral cavity plans. Plans needing revisions were comprised of sinonasal, nasopharynx, P-16 negative squamous cell carcinoma unknown primary, or cutaneous primary sites. Normal tissue sparing varied within subsites, but AVI planner significantly lowered mean larynx dose (median, 18.5 vs 19.7 Gy; P < .01) compared with clinical plans. AVI planner significantly reduced interactive optimization time (mean, 2 vs 85 minutes; P < .01). Conclusions: AVI planner reliably generated clinically acceptable RT plans for oral cavity, salivary, oropharynx, larynx, and hypopharynx cancers. Physician-driven iterative learning processes resulted in favorable evolution in HN RT plan quality with significant time savings and improved consistency using AVI planner.

Combination of a Big Data Analytics Resource System With an Artificial Intelligence Algorithm to Identify Clinically Actionable Radiation Dose Thresholds for Dysphagia in Head and Neck Patients.

PURPOSE: We combined clinical practice changes, standardizations, and technology to automate aggregation, integration, and harmonization of comprehensive patient data from the multiple source systems used in clinical practice into a big data analytics resource system (BDARS). We then developed novel artificial intelligence algorithms, coupled with the BDARS, to identify structure dose volume histograms (DVH) metrics associated with dysphagia. METHODS AND MATERIALS: From the BDARS harmonized data of ≥22,000 patients, we identified 132 patients recently treated for head and neck cancer who also demonstrated dysphagia scores that worsened from base line to a maximum grade ≥2. We developed a method that used both physical and biologically corrected (α/ß = 2.5) DVH curves to test both absolute and percentage volume based DVH metrics. Combining a statistical categorization algorithm with machine learning (SCA-ML) provided more extensive detailing of response threshold evidence than either approach alone. A sensitivity guided, minimum input, machine learning (ML) model was iteratively constructed to identify the key structure DVH metric thresholds. RESULTS: Seven swallowing structures producing 738 candidate DVH metrics were ranked for association with dysphagia using SCA-ML scoring. Structures included superior pharyngeal constrictor (SPC), inferior pharyngeal constrictor (IPC), larynx, and esophagus. Bilateral parotid and submandibular gland (SG) structures were categorized by relative mean dose (eg, SG_high, SG_low) as a dose versus tumor centric analog to contra and ipsilateral designations. Structure DVH metrics with high SCA-ML scores included the following: SPC: D20% (equivalent dose [EQD2] Gy) ≥47.7; SPC: D25% (Gy) ≥50.4; IPC: D35% (Gy) ≥61.7; parotid_low: D60% (Gy) ≥13.2; and SG_high: D35% (Gy) ≥61.7. Larynx: D25% (Gy) ≥21.2 and SG_low: D45% ≥28.2 had high SCA-ML scores but were segmented on less than 90% of plans. A model based on SPC: D20% (EQD2 Gy) alone had sensitivity and area under the curve of 0.88 ± 0.13 and 0.74 ± 0.17, respectively. CONCLUSIONS: This study provides practical demonstration of combining big data with artificial intelligence to increase volume of evidence in clinical learning paradigms.

Characterization of very late dysphagia after chemoradiation for oropharyngeal squamous cell carcinoma.

OBJECTIVES: Improved prognosis for p16+ oropharyngeal squamous cell carcinoma (OPSCC) has led to efforts to mitigate long-term complications of treatment, which remains poorly defined in late survivors. Here we characterize very late dysphagia in OPSCC. MATERIALS AND METHODS: Long-term review of 93 p16+ OPSCC patients treated with chemoradiation was performed. We scored videofluoroscopic swallow studies (VFSS) according to the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. Very late dysphagia was defined >2.5 years from end of treatment. Fine-Gray regression models were used to assess dysphagia with competing risk of death. RESULTS: Median follow up was 10.5 years. 402 total VFSS were assessed (median 4 per patient, range 0-8). 15.1% of patients had a DIGEST score ≥2 very late after treatment. Very late DIGEST score ≥2 correlated with T-stage (HR 1.7, p = 0.049), second cancer (HR 6.5, p = 0.004), superior pharyngeal constrictor dose (HR 1.11, p = 0.050), total tongue dose (HR 1.07, p = 0.045), but not hypoglossal nerve dose (p > 0.2). Seven patients (7.5%) had late progressive dysphagia, defined as DIGEST score that increased by ≥2 beyond one year after treatment, and this correlated with higher ipsilateral hypoglossal nerve D1cc dose (75 vs 72 Gy, p = 0.037). CONCLUSION: In p16+ OPSCC patients treated with definitive chemoradiation, at least 7.5% developed late progressive dysphagia, and 15.1% experienced moderate dysphagia >2.5 years from treatment. Our study suggests that dose to tongue musculature may be associated with very late dysphagia, and hypoglossal nerve dose may be associated with late progressive dysphagia. More intensive long-term dysphagia survivorship monitoring is suggested.

Submandibular gland sparing when irradiating neck level IB in the treatment of oral squamous cell carcinoma.

Patients with oral squamous cell carcinoma (OSqCCA) frequently require postoperative radiation (PORT), which may include contralateral level IB within the clinical target volume (CTV). The submandibular gland (SMG) is typically included within the level IB CTV; however, the SMG does not contain lymph nodes or lymphatic vessels. We hypothesized that level IB could be adequately irradiated while sparing the SMG to reduce xerostomia. Twelve patients with OSqCCA receiving PORT, which included the contralateral level IB within the planning target volume (PTV), were retrospectively reviewed and replanned using volumetric modulated arc therapy. CTV contouring, including contralateral level IB, was in accordance with the consensus contouring atlas but excluded the SMG. The contralateral neck PTVs were planned to 54 Gray (Gy) (PTV54). Dose requirements were per Radiation Therapy Oncology Group-1008: PTV54 D95% >54 Gy, with an allowable variation of >48.6 Gy. The dose constraint for the SMG was mean dose ≤39 Gy based on published dose-effect data for the SMGs. Mean SMG and PTV54 doses were 38.5 Gy and 56.3 Gy, respectively. Median PTV54 D95% was 53.0 Gy (range 52.5 to 54.6 Gy), with all cases meeting our allowable coverage goal. When assessing the portion of the PTV associated with level IB only (PTV_IB), mean PTV_IB dose was 54.4 Gy and median PTV_IB D95% was 43.3 Gy (range 42.5 to 52.2). Median D95% to CTV_IB was 50.2 Gy. SMG sparing resulted in 10% to 20% underdosing of the part of the PTV corresponding to level IB, as a portion of the PTV lies within the SMG. The SMG can be spared to a mean dose ≤39 Gy with slight underdosing of the surrounding PTV where the PTV overlaps with the SMG. Clinical trials evaluating SMG sparing are warranted.

Big data analysis of associations between patient reported outcomes, observer reported toxicities, and overall quality of life in head and neck cancer patients treated with radiation therapy.

PURPOSE: To assess associations between a variety of patient-reported outcomes (PROs), observer reported toxicities (ORTs), and patient-reported overall quality of life (QOL) for head and neck cancer patients treated with radiotherapy, in order to identify important items for inclusion in prospective patient reporting in the clinic. METHODS: 612 patients completed 27 PRO items from three questionnaires at 1273 follow-up visits, and clinicians provided ORTs according to CTCAE criteria. Using a big data approach, we measured associations among all PROs, between all PROs and ORTs, and between PROs/ORTs and QOL with Pearson (ρ) and Kendall (τ) correlation coefficients, and a novel analysis method based on receiver operating characteristic (ROC) curves used to detect thresholds in response levels demonstrating strong interactions. RESULTS: PROs most strongly associated with QOL were recreation/entertainment, activity, and fatigue, with ρ = 0.51-0.60. Several PROs assessing a common functional outcome (eg. xerostomia) were highly associated with each other (PRO-PRO), with maximum ρ = 0.84. Maximum ORT-PRO correlations were ρ = 0.61 (dysgeusia versus taste), and ρ = 0.5 for ORT-QOL (dry mouth - day). The ROC method identified response thresholds with high area under the curve (AUC) scores for many ORT-PRO associations with maximum AUCavg = 0.78. CONCLUSIONS: PRO associations identified activity, lifestyle and fatigue as items for strong consideration for inclusion in questionnaires in the clinic, and suggest that outcome information can be captured in fewer items than the 27 in this study. The ability of clinicians to assess patient toxicities is highest with more severe toxicities, underscoring the need for PRO collection in patient visits to understand and address patient symptoms.

Incorporating big data into treatment plan evaluation: Development of statistical DVH metrics and visualization dashboards.

PURPOSE: To develop statistical dose-volume histogram (DVH)-based metrics and a visualization method to quantify the comparison of treatment plans with historical experience and among different institutions. METHODS AND MATERIALS: The descriptive statistical summary (ie, median, first and third quartiles, and 95% confidence intervals) of volume-normalized DVH curve sets of past experiences was visualized through the creation of statistical DVH plots. Detailed distribution parameters were calculated and stored in JavaScript Object Notation files to facilitate management, including transfer and potential multi-institutional comparisons. In the treatment plan evaluation, structure DVH curves were scored against computed statistical DVHs and weighted experience scores (WESs). Individual, clinically used, DVH-based metrics were integrated into a generalized evaluation metric (GEM) as a priority-weighted sum of normalized incomplete gamma functions. Historical treatment plans for 351 patients with head and neck cancer, 104 with prostate cancer who were treated with conventional fractionation, and 94 with liver cancer who were treated with stereotactic body radiation therapy were analyzed to demonstrate the usage of statistical DVH, WES, and GEM in a plan evaluation. A shareable dashboard plugin was created to display statistical DVHs and integrate GEM and WES scores into a clinical plan evaluation within the treatment planning system. Benchmarking with normal tissue complication probability scores was carried out to compare the behavior of GEM and WES scores. RESULTS: DVH curves from historical treatment plans were characterized and presented, with difficult-to-spare structures (ie, frequently compromised organs at risk) identified. Quantitative evaluations by GEM and/or WES compared favorably with the normal tissue complication probability Lyman-Kutcher-Burman model, transforming a set of discrete threshold-priority limits into a continuous model reflecting physician objectives and historical experience. CONCLUSIONS: Statistical DVH offers an easy-to-read, detailed, and comprehensive way to visualize the quantitative comparison with historical experiences and among institutions. WES and GEM metrics offer a flexible means of incorporating discrete threshold-prioritizations and historic context into a set of standardized scoring metrics. Together, they provide a practical approach for incorporating big data into clinical practice for treatment plan evaluations.

Neither Two-State nor Three-State: Dimerization of Lambda Cro Repressor.

Lambda Cro repressor is one of the best studied dimeric transcription factors. However, there has still been an unsettled debate for decades about whether it is a two-state dimer or three-state dimer. We provide a new mechanism model that can reconcile these seemingly conflicting (mutually exclusive) experimental results. From simulations with all-atom structure-based model, we observe that the dimerization process of Lambda Cro repressor starts from one folded monomer with one unfolded monomer. Intrasubunit folding and intersubunit binding are partially coupled, in a fly casting manner.

Design and synthesis of novel pyridoxine 5'-phosphonates as potential antiischemic agents.

On the basis of previous reports that the natural cofactor pyridoxal 5'-phosphate 1 appears to display cardioprotective properties, a series of novel mimetics of this cofactor were envisioned. As pyridoxal 5'-phosphate is a natural compound and is subject to biological degradation and elimination pathways, the objective was to generate active phosphonates that are potentially less light sensitive and more stable in vivo than the parent vitamer. Several phosphonates were designed and synthesized, and in particular, compounds 10 and 14 displayed similar biological traits to natural phosphate 1 in the rat model of regional myocardial ischemia and reperfusion. A reduction in infarct size was observed in animals treated with these compounds. In an effort to identify other relevant cardioprotective models in order to potentially define structure-activity relationships, these three compounds were tested in the rat working heart model. Compounds 1, 10, and 14 were compared to dichloroacetic acid (DCA) as positive control in this model. As with DCA, compounds 1, 10, and 14 were found to induce a shift from fatty acid oxidation toward glucose oxidation.

Pyridoxine as a template for the design of antiplatelet agents.

The B(6) vitamers have been shown to display beneficial therapeutic effects in cardiovascular related disorders. The design of novel antiplatelet agents using pyridoxine as a template has led to the discovery of a class of novel cardio- and cerebro-protective agents. The present study describes the synthesis of several of these derivatives along with the antiplatelet and antiischemic activity of derivative 16.