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524 Background: OFS is an important treatment component for premenopausal women with early and advanced HR+ BC and optimal efficacy may depend on complete E2 suppression with GnRHa, especially when combined with aromatase inhibitors (AI). However, standard assays lack sensitivity and accuracy at very low E2 concentrations, rendering detection of breakthrough ovarian function challenging. More informative data regarding endocrine effects of GnRHa are needed, particularly in young women who derive the most benefit from OFS yet more frequently had breakthrough E2 levels in the SOFT trial substudy, SOFT-EST. Methods: Using a prospective cohort study of women with BC diagnosed at age ≤ 40 years, we identified participants with stage I-IV HR+ BC on OFS treatment with leuprolide, goserelin or triptorelin and blood collected 1 year after diagnosis. Clinical data were obtained through surveys and medical records. Plasma estrogens were measured by liquid chromatography-tandem mass spectrometry, with a limit of detection of 0.2 pg/mL compared to 10 pg/mL with standard assays. We assessed the proportion of women on OFS with E2 > 2.72 pg/mL (10 pmol/L) and > 10 pg/mL. Patient characteristics, estrone (E1) and FSH levels, and disease-free (DFS) and overall survival (OS) were compared between those with and without elevated E2 using Fischer’s exact, Wilcoxon rank sum and log rank tests, respectively. Results: Of 84 patients who met inclusion criteria, 72 (86%) had stage I-III and 12 (14%) had stage IV BC; 25 were on OFS plus AI and 59 were on OFS plus tamoxifen (TAM). Median E2 was 3.1 pg/mL (range 0.2-30.9). 46 patients (55%) had E2 > 2.72 pg/mL, including 8 on AI and 38 on TAM; 4 (5%) had E2 > 10 pg/mL, including 1 on AI and 3 on TAM. Factors associated with E2 > 2.72 pg/mL were no prior chemotherapy, TAM and high E1 ( P ≤.05), but not age, BMI or GnRHa schedule (Table). After a median follow-up of 7 years, DFS events were seen in 6 patients with E2 > 2.72 pg/mL and 5 without ( P =.232); OS events were seen in 7 patients with E2 > 2.72 pg/mL and 5 without ( P =.608). Conclusions: More than half of young women with ER+ BC had E2 > 2.72 pg/mL on OFS, 91% of whom would not have been detected by standard assays. This may be an area amenable to intervention to improve outcomes in young women. However, larger studies are needed to elucidate the optimal E2 target on OFS and clinical implications of incomplete E2 suppression on ultrasensitive assays. [Table: see text]

Abstract Background The COVID-19 pandemic produced unprecedented demands and rapidly changing evidence and practices within critical care settings. The purpose of this study was to identify factors and strategies that hindered and facilitated effective implementation of new critical care practices and policies in response to the pandemic. Methods We used a cross-sectional, qualitative study design to conduct semi-structured in-depth interviews with critical care leaders across the United States. The interviews were audio-taped and professionally transcribed verbatim. Guided by the Consolidated Framework for Implementation Research (CFIR), three qualitative researchers used rapid analysis methods to develop relevant codes and identify salient themes. Results: Among the 17 hospitals that agreed to participate in this study, 31 clinical leaders were interviewed. The CFIR-driven rapid analysis of the interview transcripts generated 12 major themes, which included six implementation facilitators (i.e., factors that promoted the implementation of new critical care practices) and six implementation barriers (i.e., factors that hindered the implementation of new critical care practices). These themes spanned the five CFIR domains (Intervention Characteristics, Outer Setting, Inner Setting, Characteristics of Individuals, and Process) and 11 distinct CFIR constructs. Salient facilitators to implementation efforts included staff resilience, commitment, and innovation, which were supported through collaborative feedback and decision-making mechanisms between leadership and frontline staff. Major identified barriers included lack of access to reliable and transferable information, available resources, uncollaborative leadership and communication styles. Conclusions: Through applying the CFIR to organize and synthesize our qualitative data, this study revealed important insights into implementation determinants that influenced the uptake of new critical care practices during COVID-19. As the pandemic continues to burden critical care units, clinical leaders should consider emulating the effective change management strategies identified. The cultivation of streamlined, engaging, and collaborative leadership and communication mechanisms not only supported implementation of new care practices across sites, but it also helped reduce salient implementation barriers, particularly resource and staffing shortages. Future critical care implementation studies should seek to capitalize on identified facilitators and reduce barriers.

Abstract Internal validation is the most popular evaluation strategy used for drug–target predictive models. The simple random shuffling in the cross-validation, however, is not always ideal to handle large, diverse and copious datasets as it could potentially introduce bias. Hence, these predictive models cannot be comprehensively evaluated to provide insight into their general performance on a variety of use-cases (e.g. permutations of different levels of connectiveness and categories in drug and target space, as well as validations based on different data sources). In this work, we introduce a benchmark, BETA, that aims to address this gap by (i) providing an extensive multipartite network consisting of 0.97 million biomedical concepts and 8.5 million associations, in addition to 62 million drug–drug and protein–protein similarities and (ii) presenting evaluation strategies that reflect seven cases (i.e. general, screening with different connectivity, target and drug screening based on categories, searching for specific drugs and targets and drug repurposing for specific diseases), a total of seven Tests (consisting of 344 Tasks in total) across multiple sampling and validation strategies. Six state-of-the-art methods covering two broad input data types (chemical structure- and gene sequence-based and network-based) were tested across all the developed Tasks. The best-worst performing cases have been analyzed to demonstrate the ability of the proposed benchmark to identify limitations of the tested methods for running over the benchmark tasks. The results highlight BETA as a benchmark in the selection of computational strategies for drug repurposing and target discovery.

Abstract Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.

Abstract Background The COVID-19 pandemic produced unprecedented demands and rapidly changing evidence and practices within critical care settings. The purpose of this study was to identify factors and strategies that hindered and facilitated effective implementation of new critical care practices and policies in response to the pandemic. Methods We used a cross-sectional, qualitative study design to conduct semi-structured in-depth interviews with critical care leaders across the United States. The interviews were audio-taped and professionally transcribed verbatim. Guided by the Consolidated Framework for Implementation Research (CFIR), three qualitative researchers used rapid analysis methods to develop relevant codes and identify salient themes. Results Among the 17 hospitals that agreed to participate in this study, 31 clinical leaders were interviewed. The CFIR-driven rapid analysis of the interview transcripts generated 12 major themes, which included six implementation facilitators (i.e., factors that promoted the implementation of new critical care practices) and six implementation barriers (i.e., factors that hindered the implementation of new critical care practices). These themes spanned the five CFIR domains (Intervention Characteristics, Outer Setting, Inner Setting, Characteristics of Individuals, and Process) and 11 distinct CFIR constructs. Salient facilitators to implementation efforts included staff resilience, commitment, and innovation, which were supported through collaborative feedback and decision-making mechanisms between leadership and frontline staff. Major identified barriers included lack of access to reliable and transferable information, available resources, uncollaborative leadership and communication styles. Conclusions Through applying the CFIR to organize and synthesize our qualitative data, this study revealed important insights into implementation determinants that influenced the uptake of new critical care practices during COVID-19. As the pandemic continues to burden critical care units, clinical leaders should consider emulating the effective change management strategies identified. The cultivation of streamlined, engaging, and collaborative leadership and communication mechanisms not only supported implementation of new care practices across sites, but it also helped reduce salient implementation barriers, particularly resource and staffing shortages. Future critical care implementation studies should seek to capitalize on identified facilitators and reduce barriers.

AbstractPurposeDental fixtures are commonplace in an aging, radiation treatment population. The current, local standard of practice in particle therapy is to employ treatment geometries to avoid delivery through implanted dental fixtures. The present study aims to observe the physical effect of delivering therapeutic proton beams through common dental fixture materials as prelude to an eventual goal of assessing the feasibility of using treatment geometries not specified for avoidance of oral implants. A sampling of common dental materials was selected based on prosthodontic consult and was evaluated in terms of relative stopping power and three‐dimensional (3D) dose perturbation.MethodsAmalgams, porcelain‐fused‐to‐metal (PFM) crowns consisting of zirconia and non‐noble base metals, and lithium disilicate implants were chosen for analysis. Theoretical stopping power (S) and mass stopping power (S/ρ) were calculated using the Stopping and Range of Ions in Matter (SRIM) application, basing stoichiometric compositions of each fixture on published materials data. S and S/ρ were calculated for a range of historically available compositions of amalgams from 1900 until the current era. The perturbance of S and S/ρ as a function of clinically relevant ranges of amalgam compositions for the modern era was analyzed. Water equivalent thickness (WET) and relative stopping power (Srel) of each material was measured for a clinical spot‐scanning proton beam with monoenergies of 159.9 and 228.8 MeV with a multi‐layer ionization chamber (MLIC). Subsequently, 3D dose perturbation was assessed by delivering proton beams through a custom phantom designed to simulate both en‐face and on‐edge treatment geometries through the selected materials. A treatment plan mimicking the experimental delivery was constructed in the institutional treatment planning system and calculated using TOPAS‐based Monte Carlo simulation (MCS). Experimental results were used to validate the MCS. Finally, treatment planning system (TPS) outputs were compared to MCS to determine the accuracy of the dose calculation model.ResultsHistorical compositions of amalgams ranged in S from 44.8 to 42.9 MeV/cm, with the greatest deviation being observed for the 1900–1959 era. Deviation as a function of amalgam composition from the modern era was most sensitive to proportion of Hg, accounting for deviations up to ‐4.2% at the greatest clinically relevant concentration. S/ρ was not found to vary greatly between each porcelain and metal alloy material for PFM type crowns. Relative stopping powers ranged between 1.3 and 5.4 for all studied materials, suggesting substantial changes in proton range with respect to water. Film measurements of pristine spots confirm dose perturbance and shortening of proton range, with an upstream shift of each Bragg peak being observed directly behind the installed fixture. At high energies, cold spots were found in all cases directly behind each material feature with a medial fill‐in of dose occurring distally. Qualitative agreement of spot perturbance was confirmed between film measurements and MCS. Finally, when comparing integrated depth doses (IDD) by summing over all axial directions, good agreement is observed between TPS and MCS.ConclusionsAll dental materials studied substantially perturbed the dosimetry of pristine proton spots both in terms of WET/Srel as well as the spatial distribution of dose. Proton range was quantifiably shortened, and each dental material affected a cold spot directly behind the object with medial dose back‐filling was observed distally. MCS and Eclipse dose calculations exhibited good agreement with measurements, suggesting that treatment planning without employing avoidance strategies may be possible with further investigation.

AbstractPurposeRural populations are disproportionately affected by the COVID‐19 pandemic. We characterized urban‐rural disparities in patient portal messaging utilization for COVID‐19, and, of those who used the portal during its early stage in the Midwest.MethodsWe collected over 1 million portal messages generated by midwestern Mayo Clinic patients from February to August 2020. We analyzed patient‐generated messages (PGMs) on COVID‐19 by urban‐rural locality and incorporated patients’ sociodemographic factors into the analysis.FindingsThe urban‐rural ratio of portal users, message senders, and COVID‐19 message senders was 1.18, 1.31, and 1.79, indicating greater use among urban patients. The urban‐rural ratio (1.69) of PGMs on COVID‐19 was higher than that (1.43) of general PGMs. The urban‐rural ratios of messaging were 1.72‐1.85 for COVID‐19‐related care and 1.43‐1.66 for other health care issues on COVID‐19. Compared with urban patients, rural patients sent fewer messages for COVID‐19 diagnosis and treatment but more messages for other reasons related to COVID‐19‐related health care (eg, isolation and anxiety). The frequent senders of COVID‐19‐related messages among rural patients were 40+ years old, women, married, and White.ConclusionsIn this Midwest health system, rural patients were less likely to use patient online services during a pandemic and their reasons for its use differ from urban patients. Results suggest opportunities for increasing equity in rural patient engagement in patient portals (in particular, minority populations) for COVID‐19. Public health intervention strategies could target reasons why rural patients might seek health care in a pandemic, such as social isolation and anxiety.