Citations

Abstract Objectives Clinical studies of chloroquine (CQ) and hydroxychloroquine (HCQ) in COVID-19 disease reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin on outcomes of COVID-19 patients. Methods We searched multiple databases, preprints and grey literature up to 17 July 2020. We pooled only adjusted-effect estimates of mortality using a random-effect model. We summarized the effect of CQ or HCQ on viral clearance, ICU admission/mechanical ventilation and hospitalization. Results Seven randomized clinical trials (RCTs) and 14 cohort studies were included (20 979 patients). Thirteen studies (1 RCT and 12 cohort studies) with 15 938 hospitalized patients examined the effect of HCQ on short-term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96–1.15, I2 = 0%). Six cohort studies examined the effect of the HCQ+azithromycin combination with a pooled adjusted OR of 1.32 (95% CI 1.00–1.75, I2 = 68.1%). Two cohort studies and four RCTs found no effect of HCQ on viral clearance. One small RCT demonstrated improved viral clearance with CQ and HCQ. Three cohort studies found that HCQ had no significant effect on mechanical ventilation/ICU admission. Two RCTs found no effect for HCQ on hospitalization risk in outpatients with COVID-19. Conclusions Moderate certainty evidence suggests that HCQ, with or without azithromycin, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19 or risk of hospitalization in outpatients with COVID-19.

Background Nationwide studies documenting temporal trends in permanent pacemaker implantation (PPMI) following transcatheter aortic valve replacement (TAVR) are limited. Methods and Results We selected patients who underwent TAVR between 2012 and 2017 in the National Readmission Database. The primary end point was the 6‐year trend in post‐TAVR PPMI at index hospitalization and at 30, 90, and 180 days after discharge. The secondary end point was the association between PPMI and in‐hospital mortality, stroke, cost, length of stay, and disposition. Among the 89 202 patients who underwent TAVR, 77 405 (86.8%) with no prior pacemaker or defibrillator were included. Patients who required PPMI had a higher prevalence of atrial fibrillation (43.6% versus 38.7%, P <0.001) and conduction abnormalities (28.4% versus 15.3%, P <0.001). The incidence of PPMI during index admission increased from 8.7% in 2012 to 13.2% in 2015, and then decreased to 9.6% in 2017. The incidence of inpatient PPMI within 30 days after discharge increased from 0.5% in 2012 to 1.25% in 2017 ( P trend <0.001). Inpatient PPMI beyond 30 days remained rare (<0.5%) during the study period. After risk adjustment, PPMI was not associated with in‐hospital mortality or stroke but was associated with increased nonhome discharge, longer hospitalization, and higher cost. The incremental expenditure associated with post‐TAVR PPMI during index admission increased from $9.6 million to $72.2 million between 2012 and 2017. Conclusions After an upward trend, rates of PPMI after TAVR in the United States stabilized at ~10% in 2016 to 2017, but there was a notable increase in PPMI within 30 days after the index admission. PPMI was not associated with increased in‐hospital morbidity or mortality but led to longer hospitalization, higher cost, and more nonhome discharges.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

e13106 Background: Chemotherapy resistance remains a significant barrier in the effective treatment of patients with triple negative breast cancer (TNBC). TGF-β signaling is a well characterized oncogenic pathway in TNBC that promotes chemoresistance by inducing epithelial to mesenchymal transition (EMT) and tumor stemness. Aurora-A kinase (AURKA) is a serine/threonine kinase responsible for chromosomal stability during mitosis. Significantly, aberrant expression of AURKA induces breast cancer progression. We hypothesized that aberrant activation of TGF-β and AURKA signaling pathways contributes to chemoresistance in TNBC by promoting EMT and tumor stemness and that dual-targeting of these oncoproteins will enhance chemosensitivity. Methods: RNA-Seq data were analyzed from patient derived xenografts (PDx) established from patients with Stage I-III TNBC who received pre-operative taxane and anthracycline based chemotherapy. Chemoresistance was defined as an RCB score of 1-3, and chemosensitivity was defined as an RCB score of 0. Unique TNBC cell lines developed from brain metastasis PDxs (TNBC M14, TNBC M25) were treated in vitro with 10nM docetaxel (DTX), 50nM LY2157299 (TGF-β inhibitor) and 50nM MLN8237 (AURKA inhibitor). EMT reprogramming was determined by measuring the expression of vimentin, ALDH activity and mammosphere growth. Apoptotic cells following drug treatment were labeled with Red Annexin-V marker and monitored in real time using the IncuCyte instrument. Results: RNA-Seq revealed that there was no baseline difference in expression of AURKA between chemoresistant and chemosensitive TNBC PDxs. However, there was a 2.7-fold increase in AURKA expression in the post-treatment PDx models compared to pre-treatment PDx models. In vitro treatment of the M14 and M25 cell lines with DTX demonstrated no significant increase in apoptotic cells compared to control, whereas treatment with the combination of DTX, LY2157299 and MLN8237 resulted in a two-fold increase in apoptosis compared to treatment with DTX alone (p = 0.0068 M14, p = 0.003 M25). Dual-targeting with LY2157299 and MLN8237 reduced the expression of vimentin and ALDH activity. Conclusions: TGF-β and AURKA play a central role inducing EMT and a stem-cell-like phenotype in TNBC that confers chemoresistance. AURKA is up-regulated after exposure to chemotherapy in chemoresistant TNBC PDx models. LY2157299 and MLN8237 reduce TNBC stemness in M14 and M25 cell lines and enhance DTX chemosensitivity. Dual-targeting of TGF-β and AURKA is a potentially promising approach in chemoresistant TNBC.

Abstract Importance:SARS-CoV-2 virus gains access and infects target cells via angiotensin converting enzyme 2 (ACE2) receptor. Because angiotensin converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) could increase the expression of ACE2, there are growing concerns that their use could increase the risk of SARS-CoV-2 infection. Cardiac societies have called for epidemiological research about this emerging controversy. Objective:We sought to systematically review the literature and perform a meta-analysis about prior use of ACEI/ARBs and risk of SARS-CoV-2 infection.Data source:We searched multiple data sources including PubMed , ClinicalTrial.org , and medrxiv.org from November 2019 through May 16, 2020. Study selection:Any study that reported on the adjusted association of prior use of ACEIs / ARBs and risk of acquiring SARS-CoV-2 infection was eligible. Two authors independently reviewed eligible studies and extracted data into a prespecified data collection form. Data synthesis:An inverse variance meta-analytic approach was used to pool adjusted odds ratios using a random effect model meta-analysis. I2 test was used to assess in-between studies heterogeneity. The Newcastle–Ottawa quality assessment scale (NOS) was used to assess the quality of included studies. Main outcome and Measures:The association between the prior use of ACEIs or ARBs and risk of SARS-CoV-2 infection was assessed using pooled OR and 95% confidence interval. Results:Six case control studies that enrolled a total of 5657 patients (2536 patients in ACEIs arm and 3121 patients in ARBs arm ) and 721,859 controls were included in our meta-analysis. Two of the included studies were from the USA, one from Italy, one from China, one from Spain, and one from South Korea. All included studies scored high based on NOS scale. Prior use of ACEIs was not significantly associated with an increased risk of SARS-CoV-2 infection, OR 0.93, CI (0.85,1.02), I2=20%. Similarly, prior use of ARBs was not significantly associated with an increased risk of SARS-CoV-2 infection, OR 0.86, CI (0.67,1.10), I2=93%. Sensitivity analysis was performed by removing a study that could have been affected by residual confounding; OR for ARB 1.04, CI (0.96,1.12), I2=32%.Conclusion:Findings from this systematic review and meta-analysis suggest that prior use of ACEIs or ARBs is not associated with a higher risk of COVID-19. Our results are in support of the recent recommendations of cardiac societies and provide a reassurance to the public not to discontinue prescribed ACEIs/ARBs due to fear of COVID-19.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Abstract Background: The IMpassion130 study demonstrated prolonged overall survival when atezolizumab, a PD-L1 inhibitor, was added to nab-paclitaxel in PD-L1 positive patients with advanced triple negative breast cancer (TNBC). Approximately 40% of tumors were PD-L1 positive, utilizing a cutoff of ≥ 1% immune cell (IC) staining with the Ventana SP142 immunohistochemical (IHC) assay. The Food and Drug Administration (FDA) approved this assay as a companion test to determine patient eligibility for atezolizumab therapy. However, literature in lung cancer shows that pathologists have a high discordance in assessing PD-L1 on IC. The FDA companion test documentation for SP142 shows high inter-laboratory reproducibility with nearly 95% overall percent agreement (OPA) between 2 readers for 2 category scoring of IC (positive versus negative) in TNBC in a central laboratory. PD-L1 testing for breast cancer is now becoming widespread in pathology laboratories. The goal of this study was to assess concordance in PD-L1 scoring between 19 pathologists from 14 institutions examining the same 86 TNBC tissues stained with the SP142 and SP263 antibodies. We also present a new method to determine the minimum number for evaluators needed to estimate concordance between large numbers of readers as occurs in real life setting. Methods: Full tissue sections were stained exactly as prescribed on the label on the Ventana Benchmark with the SP142 and SP263 PD-L1 assays. Sixty-eight and 76 cases were evaluable respectively. Stained slides were scanned and digital files distributed to pathologists who independently scored cases as either negative (&lt; 1% IC staining) or positive (≥ 1% IC staining) and estimated the % of IC staining for positive cases. We applied a method that we call Observers Needed to Evaluate Subjective Tests (ONEST). For any combination of pathologists, we can quantify the degree of overall agreement using the proportion of tissue samples upon which all selected pathologists agreed, which can lead to a plot of non-increasing trajectory of agreement as the number of pathologists increases. We computed and plotted the empirical estimate of the overall agreement with the 95% confidence interval (CI) from 1000 randomly selected permutations of the pathologists. Results: PD-L1 was interpreted as positive with SP263 in an average of 78% of cases compared to 58% with the SP142 assay (p&lt;.0001). IC positive continuous scores ranged from 1-95% (mean=20%) and 1-90% (mean=10%) for SP263 and SP142. Complete 2 category (positive vs negative) scoring concordance across all observers was achieved in 38 cases (50%) with SP263 and 26 cases (38%) with SP142. The intraclass correlation coefficient (ICC) for 2 category scoring of SP263 and SP142 was 0.513 and 0.560 respectively. ONEST plots made for each assay for 19 pathologists showed a decrease in OPA as number of observers increased, reaching a low plateau of approximately 0.46 at 10 observers for SP263 and 0.42 at 8 observers for SP142. Conclusions: Utilizing the FDA approved SP142 assay, we found a higher prevalence of PD-L1 positive tumors than published in the IMpassion130 trial but lower prevalence than seen with the SP263 assay. The different proportion of positive cases seen with two different assays highlights the need to establish cutoffs for each assay to correspond with clinical benefit. The ICC of scoring immune cells with both PD-L1 assays showed poor reproducibility across multiple pathologists. The ONEST analysis finds a plateau with 10 pathologists, only reaching an OPA of 0.4 for immune cell assessment. This suggests that more than half of the pathologists in real world situations may mis-assign patient IC scores. This could lead to a high percentage of patients either receiving atezolizumab, when they are unlikely to benefit or not receiving atezolizumab when they may benefit. Citation Format: Emily Suzanne Reisenbichler, Gang Han, Vasiliki Pelekanou, Vesal Yaghoobi, Fahad S Ahmed, Andrew Bellizzi, Veerle Bossuyt, Jane Brock, Kimberly Cole, Oluwole Fadare, Omar Hameed, Krisztina Hanley, Beth T Harrison, M G Kuba, Amy Ly, Dylan Miller, Mirna Podoll, Anja C Roden, Mary A Sanders, Kamaljeet Singh, Shi Wei, Hannah Wen, Lajos Pusztai, David L Rimm. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-01.