Factor XI Inhibition for the Prevention of Catheter-Associated Thrombosis in Patients With Cancer Undergoing Central Line Placement: A Phase 2 Clinical Trial.

BACKGROUND: Despite the ubiquitous utilization of central venous catheters in clinical practice, their use commonly provokes thromboembolism. No prophylactic strategy has shown sufficient efficacy to justify routine use. Coagulation factors FXI (factor XI) and FXII (factor XII) represent novel targets for device-associated thrombosis, which may mitigate bleeding risk. Our objective was to evaluate the safety and efficacy of an anti-FXI mAb (monoclonal antibody), gruticibart (AB023), in a prospective, single-arm study of patients with cancer receiving central line placement. METHODS: We enrolled ambulatory cancer patients undergoing central line placement to receive a single dose of gruticibart (2 mg/kg) administered through the venous catheter within 24 hours of placement and a follow-up surveillance ultrasound at day 14 for evaluation of catheter thrombosis. A parallel, noninterventional study was used as a comparator. RESULTS: In total, 22 subjects (n=11 per study) were enrolled. The overall incidence of catheter-associated thrombosis was 12.5% in the interventional study and 40.0% in the control study. The anti-FXI mAb, gruticibart, significantly prolonged the activated partial thromboplastin time in all subjects on day 14 compared with baseline (P<0.001). Gruticibart was well tolerated and without infusion reactions, drug-related adverse events, or clinically relevant bleeding. Platelet flow cytometry demonstrated no difference in platelet activation following administration of gruticibart. T (thrombin)-AT (antithrombin) and activated FXI-AT complexes increased following central line placement in the control study, which was not demonstrated in our intervention study. CRP (C-reactive protein) did not significantly increase on day 14 in those who received gruticibart, but it did significantly increase in the noninterventional study. CONCLUSIONS: FXI inhibition with gruticibart was well tolerated without any significant adverse or bleeding-related events and resulted in a lower incidence of catheter-associated thrombosis on surveillance ultrasound compared with the published literature and our internal control study. These findings suggest that targeting FXI could represent a safe intervention to prevent catheter thrombosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04465760.

Psychological toxicity in classical hematology.

Although considered "benign," mild blood count abnormalities, genetic factors imparting inconsequential thrombotic risk, and low-risk premalignant blood disorders can have significant psychological and financial impact on our patients. Several studies have demonstrated that patients with noncancerous conditions have increased levels of anxiety with distress similar to those with malignancy. Additionally, referral to a classical hematologist can be a daunting process for many patients due to uncertainties surrounding the reason for referral or misconstrued beliefs in a cancer diagnosis ascribed to the pairing of oncology and hematology in medical practice. If not properly triaged, incidental laboratory abnormalities can trigger extensive and costly evaluation. These challenges are compounded by a lack of consensus guidance and generalizability of modern reference ranges that do not adequately account for common influencing factors. Although often benign, incidental hematologic findings can lead to emotional suffering and careful consideration of the potential psychological and financial duress imparted to an individual must be considered. In this article, we will review the current literature describing the psychological effect of some commonly known hematologic conditions, identify benign causes for variations in hematologic laboratory values, and provide recommendations to reduce psychological toxicity as it pertains to hematologic testing.

Considerations in the reliability and fairness audits of predictive models for advance care planning.

Multiple reporting guidelines for artificial intelligence (AI) models in healthcare recommend that models be audited for reliability and fairness. However, there is a gap of operational guidance for performing reliability and fairness audits in practice. Following guideline recommendations, we conducted a reliability audit of two models based on model performance and calibration as well as a fairness audit based on summary statistics, subgroup performance and subgroup calibration. We assessed the Epic End-of-Life (EOL) Index model and an internally developed Stanford Hospital Medicine (HM) Advance Care Planning (ACP) model in 3 practice settings: Primary Care, Inpatient Oncology and Hospital Medicine, using clinicians' answers to the surprise question ("Would you be surprised if [patient X] passed away in [Y years]?") as a surrogate outcome. For performance, the models had positive predictive value (PPV) at or above 0.76 in all settings. In Hospital Medicine and Inpatient Oncology, the Stanford HM ACP model had higher sensitivity (0.69, 0.89 respectively) than the EOL model (0.20, 0.27), and better calibration (O/E 1.5, 1.7) than the EOL model (O/E 2.5, 3.0). The Epic EOL model flagged fewer patients (11%, 21% respectively) than the Stanford HM ACP model (38%, 75%). There were no differences in performance and calibration by sex. Both models had lower sensitivity in Hispanic/Latino male patients with Race listed as "Other." 10 clinicians were surveyed after a presentation summarizing the audit. 10/10 reported that summary statistics, overall performance, and subgroup performance would affect their decision to use the model to guide care; 9/10 said the same for overall and subgroup calibration. The most commonly identified barriers for routinely conducting such reliability and fairness audits were poor demographic data quality and lack of data access. This audit required 115 person-hours across 8-10 months. Our recommendations for performing reliability and fairness audits include verifying data validity, analyzing model performance on intersectional subgroups, and collecting clinician-patient linkages as necessary for label generation by clinicians. Those responsible for AI models should require such audits before model deployment and mediate between model auditors and impacted stakeholders.

Low prevalence (0.13%) of COVID-19 infection in asymptomatic pre-operative/pre-procedure patients at a large, academic medical center informs approaches to perioperative care.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in reduced performance of elective surgeries and procedures at medical centers across the United States. Awareness of the prevalence of asymptomatic disease is critical for guiding safe approaches to operative/procedural services. As COVID-19 polymerase chain reaction (PCR) testing has been limited largely to symptomatic patients, health care workers, or to those in communal care centers, data regarding asymptomatic viral disease carriage are limited. METHODS: In this retrospective observational case series evaluating UCLA Health patients enrolled in pre-operative/pre-procedure protocol COVID-19 reverse transcriptase (RT)-PCR testing between April 7, 2020 and May 21, 2020, we determine the prevalence of COVID-19 infection in asymptomatic patients scheduled for surgeries and procedures. RESULTS: Primary outcomes include the prevalence of COVID-19 infection in this asymptomatic population. Secondary data analysis includes overall population testing results and population demographics. Eighteen of 4,751 (0.38%) patients scheduled for upcoming surgeries and high-risk procedures had abnormal (positive/inconclusive) COVID-19 RT-PCR testing results. Six of 18 patients were confirmed asymptomatic and had positive test results. Four of 18 were confirmed asymptomtic and had inconclusive results. Eight of 18 had positive results in the setting of recent symptoms or known COVID-19 infection. The prevalence of asymptomatic COVID-19 infection was 0.13%. More than 90% of patients had residential addresses within a 67-mile geographic radius of our medical center, the median age was 58, and there was equal male/female distribution. CONCLUSION: These data demonstrating low levels (0.13% prevalence) of COVID-19 infection in an asymptomatic population of patients undergoing scheduled surgeries/procedures in a large urban area have helped to inform perioperative protocols during the COVID-19 pandemic. Testing protocols like ours may prove valuable for other health systems in their approaches to safe procedural practices during COVID-19.

Feasibility study of an EHR-integrated mobile shared decision making application.

INTRODUCTION: Integrating mobile applications (apps) into users' standard electronic health record (EHR) workflows may be valuable, especially for apps that both read and write data. This report details the lessons learned during the integration of a patient decision aid - prostate specific antigen (PSA) testing for prostate cancer screening - into our users' standard EHR workflow for a small usability assessment. MATERIALS AND METHODS: This feasibility study included two steps. First we enabled realtime, secure bidirectional data exchange between the mobile app and EHR for 14 data elements, and second we pilot tested the production environment app with 9 primary care patients aged 60-65 years. Our primary usability metric was a net promoter score (NPS), based on users' recommendation of the app to a friend or family member; we also assessed the proportion of users who 1) updated their prostate cancer risk factor information present in the EHR and 2) submitted more than one unique response regarding their preference to have PSA testing. RESULTS: The seven web services necessary to read and write data required considerable configuration, but successfully delivered risk factor-specific educational content and recorded patients' values and decision preference directly within the EHR. Seven of the 9 patients (78%) would recommend this app to a friend/family member (NPS = 55.6%), one patient used the app to update risk factor information, and 4/9 (44%) changed their decision preference while using the app. CONCLUSIONS: It is feasible to implement a decision aid directly into users' standard EHR workflow for limited usability testing. Broad scale implementation may have a positive effect on patient engagement and improve shared decision making, but several challenges exist with proprietary EHR vendor application programming interfaces (API)s.

Impact of Open Access to Physician Notes on Radiation Oncology Patients: Results from an Exploratory Survey.

PURPOSE: There is an increasing effort to allow patients open access to their physician notes through electronic medical record portals. However, limited data exist on the impact of such access on oncology patients, and concerns remain regarding potential harms. Therefore, we determined the baseline perceptions and impact of open access to oncology notes on radiation oncology patients. METHODS AND MATERIALS: Patients receiving radiation therapy were provided instructional materials on accessing oncology notes at the time of their initial evaluation. Patients were prospectively surveyed to evaluate baseline interest and expectations before access and to determine the actual usage and impact at the end of their radiation treatment course. RESULTS: A total of 220 patients were surveyed; 136 (62%) completed the baseline survey, of which 88 (40%) completed the final survey. The majority of participants were age >60 years (n = 83; 61%), and 70 were male (51%). Before accessing the notes, the majority of patients agreed that open access to oncology notes would improve understanding of diagnosis (99%), understanding of treatment side effects (98%), reassurance about treatment goals (96%), and communication with family (99%). All patients who accessed the notes found them to be useful. After accessing the notes, approximately 96%, 94%, and 96% of patients reported an improved understanding of their diagnosis, an improved understanding of treatment side effects, and feeling more reassured about their treatment, respectively. Approximately 11%, 6%, and 4% of patients noted increased worry, increased confusion, and finding information they now regret reading, respectively. Patient age, sex, and specific cancer diagnoses were not predictive of experiencing negative effects from accessing the notes. CONCLUSIONS: Radiation oncology patients have a strong interest in open access to their physician notes, and the majority of patients expect and actually report meaningful benefits. These data support strategies to allow more patients with cancer access to their physicians' notes.

Resolvin D1 and aspirin-triggered resolvin D1 promote resolution of allergic airways responses.

Asthma is a disease of airway inflammation that in most cases fails to resolve. The resolution of inflammation is an active process governed by specific chemical mediators, including D-series resolvins. In this study, we determined the impact of resolvin D1 (RvD1) and aspirin-triggered RvD1 (AT-RvD1) on the development of allergic airway responses and their resolution. Mice were allergen sensitized, and RvD1, AT-RvD1 (1, 10, or 100 ng), or vehicle was administered at select intervals before or after aerosol allergen challenge. RvD1 markedly decreased airway eosinophilia and mucus metaplasia, in part by decreasing IL-5 and IκBα degradation. For the resolution of established allergic airway responses, AT-RvD1 was even more efficacious than RvD1, leading to a marked decrease in the resolution interval for lung eosinophilia, decrements in select inflammatory peptide and lipid mediators, and more rapid resolution of airway hyperreactivity to methacholine. Relative to RvD1, AT-RvD1 resisted metabolic inactivation by macrophages, and AT-RvD1 significantly enhanced macrophage phagocytosis of IgG-OVA-coated beads in vitro and in vivo, a new proresolving mechanism for the clearance of allergen from the airways. In conclusion, RvD1 and AT-RvD1 can serve as important modulators of allergic airway responses by decreasing eosinophils and proinflammatory mediators and promoting macrophage clearance of allergen. Together, these findings identify D-series resolvins as potential proresolving therapeutic agents for allergic responses.

Resolution of Toll-like receptor 4-mediated acute lung injury is linked to eicosanoids and suppressor of cytokine signaling 3.

The purpose of this study was to investigate roles for Toll-like receptor 4 (TLR4) in host responses to sterile tissue injury. Hydrochloric acid was instilled into the left mainstem bronchus of TLR4-defective (both C3H/HeJ and congenic C.C3-Tlr4(Lps-d)/J) and control mice to initiate mild, self-limited acute lung injury (ALI). Outcome measures included respiratory mechanics, barrier integrity, leukocyte accumulation, and levels of select soluble mediators. TLR4-defective mice were more resistant to ALI, with significantly decreased perturbations in lung elastance and resistance, resulting in faster resolution of these parameters [resolution interval (R(i)); ∼6 vs. 12 h]. Vascular permeability changes and oxidative stress were also decreased in injured HeJ mice. These TLR4-defective mice paradoxically displayed increased lung neutrophils [(HeJ) 24×10(3) vs. (control) 13×10(3) cells/bronchoalveolar lavage]. Proresolving mechanisms for TLR4-defective animals included decreased eicosanoid biosynthesis, including cysteinyl leukotrienes (80% mean decrease) that mediated CysLT1 receptor-dependent vascular permeability changes; and induction of lung suppressor of cytokine signaling 3 (SOCS3) expression that decreased TLR4-driven oxidative stress. Together, these findings indicate pivotal roles for TLR4 in promoting sterile ALI and suggest downstream provocative roles for cysteinyl leukotrienes and protective roles for SOCS3 in the intensity and duration of host responses to ALI.

Corticosteroid suppression of lipoxin A4 and leukotriene B4 from alveolar macrophages in severe asthma.

BACKGROUND: An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B4 (LTB4), and lipoxin A4 (LXA4) production by alveolar macrophages (AMs) and studied the impact of corticosteroids. METHODS: AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 microg/ml) with or without dexamethasone (10(-6)M). LTB4 and LXA4 were measured by enzyme immunoassay. RESULTS: LXA4 biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA4 induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB4 were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB4 was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB4 and LXA4, with lesser suppression of LTB4 in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA4 and FEV1 (% predicted) (r(s) = 0.60; p < 0.01). CONCLUSIONS: Decreased LXA4 and increased LTB4 generation plus impaired corticosteroid sensitivity of LPS-induced LTB4 but not of LXA4 support a role for AMs in establishing a pro-inflammatory balance in severe asthma.