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Abstract Introduction Chronic right ventricular pacing (RVP) has been associated with dyssynchrony, leading to increased mortality. However, there have been discrepancies in previous reports in the effect of RVP levels. Objective To sub-stratify mortality risk by age for different RVP level groups within a large real-world ICD cohort. Methods Optum® de-identified electronic health records were linked to the Medtronic Carelink data to identify dual chamber ICD recipients (2007–2017). RVP level was based on median daily pacing during the first 90 days post-implant and categorized either into groups with a cutoff of 40%, or with groups of 0–9%, 10–19%, 20–29%, 30–39%, 40–49%, and 50–100%. The endpoint was death more than 90 days post-implant. Kaplan-Meier survival curves, log-rank tests, and Cox regression were used to analyze the relationship between RVP and risk of death. Results Among 14,832 ICD patients (median age 67; 74.0% male), there were 2,602 deaths within 10 years after implant. In unadjusted comparisons, high RVP (>40%) increased the risk of death relative to low RVP (≤40%) (p<0.001). This effect remained significant in older cohort (≥67 years old at implant) (p<0.001), but not in younger cohort (<67 years old) (p=0.955) (Figure). After controlling for age, gender, pacing mode, MI, SCA, HF hospitalization, diabetes, and renal dysfunction, similar or increased risk was associated with higher pacing groups relative to the 0–9% pacing group in the older cohort, but not in the younger cohort. Conclusions Our data from a large contemporaneous real-world source suggests that older age or characteristics associated with age make patients more sensitive to chronic RVP effects. These results help reconcile differences observed in prior studies. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Medtronic, Inc.

I. Executive Summary Background The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS.

AbstractClinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

Infection of rat pulmonary microvascular endothelial cells with the bacterium Pseudomonas aeruginosa induces the production and release of cytotoxic oligomeric tau and beta amyloid (Aβ). Here, we characterized these cytotoxic amyloids. Cytotoxic behavior and oligomeric tau were partially resistant to digestion with proteinase K, but cytotoxicity was abolished by various denaturants including phenol, diethylpyrocarbonate (DEPC), and 1,1,1,3,3,3‐hexafluoro‐2‐isopropanol (HFIP). Ultracentrifugation for 8 h at 150 000 g was required to remove cytotoxic activity from the supernatant. Ultracentrifugation, DEPC treatment, and immunodepletion using antibodies against Aβ also demonstrated that cytoprotective protein(s) are released from endothelial cells during P. aeruginosa infection. Mass spectrometry of endothelial cell culture media following P. aeruginosa infection allowed identification of multiple potential secreted modulators of Aβ, including cystatin C, gelsolin, and ApoJ/clusterin. Immunodepletion, co‐immunoprecipitation, and ultracentrifugation determined that the cytoprotective factor released during infection of endothelial cells by P. aeruginosa is cystatin C, which appears to be in a complex with Aβ. Cytoprotective cystatin C may provide a novel therapeutic avenue for protection against the long‐term consequences of infection with P. aeruginosa.

Abstract Measles viruses (MV) are rapidly inactivated by anti-measles neutralizing antibodies, which has limited their clinical performance as oncolytic agents. Here, by substituting the H and F surface glycoproteins of MV with those from the homologous canine distemper virus (CDV) and engineering the CDV H attachment protein to target EGFR or CD38, we generated a fully retargeted MV capable of resisting neutralization by measles-immune human serum. The resultant recombinant MVs encoding retargeted CDV envelope glycoproteins had similar growth kinetics as the control MV, showed the expected engineered receptor specificities for cell entry, intercellular fusion, and target cell killing, and were blind to native CDV receptors. In contrast to the control MV, recombinant MVs incorporating CDV F and H glycoproteins retained full infectivity when exposed to high concentrations of pooled measles-immune human serum. Comparing viruses bearing MV or CDV glycoproteins in the SKOV3ip.1 model, only the virus bearing an EGFR-retargeted CDV envelope glycoprotein complex was capable of limiting tumor growth and extending the survival in measles immune mice. MV, “stealthed” and retargeted using engineered CDV surface glycoproteins, may be a promising platform to advance for systemic cancer therapy in measles immune patients.

1005 Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies. [Table: see text] [Table: see text]

AbstractBackgroundThe clinical course in metastatic castrate‐resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after prior treatment with second generation hormone therapy (second HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing second generation hormone therapy. We sought to evaluate three common chemotherapy regimens in this setting.MethodsWe retrospectively identified 150 mCRPC patients with disease progression on enzalutamide or abiraterone. Of these 150 patients, 92 patients were chemo‐naïve while 58 patients had previously received docetaxel chemotherapy before being started on second HT. After failing second HT, 90 patients were assigned for docetaxel‐alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel‐alone (Group C). A favorable response was defined by more than or equal to 50% reduction in prostate‐specific antigen from the baseline level after a complete course of chemotherapy. Survival outcomes were assessed for 30‐month overall survival.ResultsPatients in group (B) were 2.6 times as likely to have a favorable response compared to patients in group (A) (OR = 2.625, 95%CI: 1.15‐5.99) and almost three times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04–8.54) (P = .0442). 30‐month overall survival was 70.7%, 38.9% and 30.3% for group (B), (A), and (C), respectively (P = .008). We report a Hazard Ratio of 3.1 (95% CI, 1.31‐7.35; P = .0037) between patients in group (A) versus those in group (B) and a Hazard Ratio of 4.18 (95% CI, 1.58‐11.06; P = .0037) between patients in group (C) compared to those in group (B)ConclusionThis data demonstrates improved response and overall survival in treatment‐refractory mCRPC with a chemotherapy regimen of docetaxel plus carboplatin when compared to docetaxel alone or cabazitaxel alone. Further investigations are required.

Radiomics, also known as quantitative imaging or texture analysis, involves extracting a large number of features traditionally unmeasured in conventional radiological cross-sectional images and converting them into mathematical models. This review describes this approach and its use in the evaluation of pancreatic cystic lesions (PCLs). This discipline has the potential of more accurately assessing, classifying, risk stratifying, and guiding the management of PCLs. Existing studies have provided important insight into the role of radiomics in managing PCLs. Although these studies are limited by the use of retrospective design, single center data, and small sample sizes, radiomic features in combination with clinical data appear to be superior to the current standard of care in differentiating cyst type and in identifying mucinous PCLs with high-grade dysplasia. Combining radiomic features with other novel endoscopic diagnostics, including cyst fluid molecular analysis and confocal endomicroscopy, can potentially optimize the predictive accuracy of these models. There is a need for multicenter prospective studies to elucidate the role of radiomics in the management of PCLs.

This expert consensus statement on the interpretation of peripheral arterial and venous spectral Doppler waveforms was jointly commissioned by the Society for Vascular Medicine (SVM) and the Society for Vascular Ultrasound (SVU). The consensus statement proposes a standardized nomenclature for arterial and venous spectral Doppler waveforms using a framework of key major descriptors and additional modifier terms. These key major descriptors and additional modifier terms are presented alongside representative Doppler waveforms, and nomenclature tables provide context by listing previous alternate terms to be replaced by the new major descriptors and modifiers. Finally, the document reviews Doppler waveform alterations with physiologic changes and disease states, provides optimization techniques for waveform acquisition and display, and provides practical guidance for incorporating the proposed nomenclature into the final interpretation report.

This expert consensus statement on the interpretation of peripheral arterial and venous spectral Doppler waveforms was jointly commissioned by the Society for Vascular Medicine (SVM) and the Society for Vascular Ultrasound (SVU). The consensus statement proposes a standardized nomenclature for arterial and venous spectral Doppler waveforms using a framework of key major descriptors and additional modifier terms. These key major descriptors and additional modifier terms are presented alongside representative Doppler waveforms, and nomenclature tables provide context by listing previous alternate terms to be replaced by the new major descriptors and modifiers. Finally, the document reviews Doppler waveform alterations with physiologic changes and disease states, provides optimization techniques for waveform acquisition and display, and provides practical guidance for incorporating the proposed nomenclature into the final interpretation report.