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Background: Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS “pathway” activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. Methods: In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. Findings: SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. Interpretation: The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. Funding: This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Beatrice E. Gee, Grace G. Kalmus, Jason N. Payne, Amy Tang, and Marianne E.M. Yee report support to the Sickle Cell Disease Health Services and Outcomes Program from the Abraham J. and Phyllis Katz Foundation. Marianne E.M. Yee also reports grant support from the National Institutes of Health (NIH), receipt of honoraria for a presentation at the Advanced Immunohematology & Molecular Symposium in Denver, Colorado, June 5, 2023, and from the American Board of Pediatrics, Pediatric Hematology/Oncology sub-board. Amy Tang reports grants from NIH, Pfizer, and Novo Nordisk; and service as chair of the hemoglobinopathies interest group of the American Society of Pediatric Hematology/Oncology. Jason N. Payne reports support from the American Society of Hematology for participation in the Clinical Research Training Institute. Beatrice E. Gee reports grants from NIH. No other potential conflicts of interest were disclosed.

The microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (T reg ) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral T reg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nT reg cells, but not iT reg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nT reg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nT reg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nT reg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nT reg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nT reg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nT reg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion., Competing Interests: Declaration of Competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Study Objective: The real-world effectiveness and safety of a 0/1-hour accelerated protocol using high-sensitivity cardiac troponin (hs-cTn) to exclude myocardial infarction (MI) compared to routine care in the United States is uncertain. The objective was to compare a 0/1-hour accelerated protocol for evaluation of MI to a 0/3-hour standard care protocol., Methods: The RACE-IT trial was a stepped-wedge, randomized trial across 9 emergency departments (EDs) that enrolled 32,609 patients evaluated for possible MI from July 2020 through April 2021. Patients undergoing high-sensitivity cardiac troponin I testing with concentrations less than or equal to 99th percentile were included. Patients who had MI excluded by the 0/1-hour protocol could be discharged from the ED. Patients in the standard care protocol had 0- and 3-hour troponin testing and application of a modified HEART score to be eligible for discharge. The primary endpoint was the proportion of patients discharged from the ED without 30-day death or MI., Results: There were 13,505 and 19,104 patients evaluated in the standard care and accelerated protocol groups, respectively, of whom 19,152 (58.7%) were discharged directly from the ED. There was no significant difference in safe discharges between standard care and the accelerated protocol (59.5% vs 57.8%; adjusted odds ratio (aOR)=1.05, 95% confidence interval [CI] 0.95 to 1.16). At 30 days, there were 90 deaths or MIs with 38 (0.4%) in the standard care group and 52 (0.4%) in the accelerated protocol group (aOR=0.84, 95% CI 0.43 to 1.68)., Conclusion: A 0/1-hour accelerated protocol using high-sensitivity cardiac troponin I did not lead to more safe ED discharges compared with standard care., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: Imaging for staging ovarian cancer is important to determine the extent of disease. The primary objective of this study was to compare gated 18F-fluorodeoxyglucose positron emission tomography coupled with computed tomography (FDG PET/CT) and standard CT scan with intravenous contrast to diagnose thoracic involvement in patients with advanced ovarian cancer prior to treatment. The secondary objective was to estimate changes in the International Federation of Gynecology and Obstetrics (FIGO) stage and clinical management resulting from gated PET/CT., Methods: The IMAGE trial is a non-randomized phase II clinical trial comparing standard CT scanning with gated PET/CT in diagnosing thoracic involvement in a non-selected group of patients with suspected ovarian cancer on a contrast CT scan. Three sets of PET images were obtained comprising an ungated 2 min whole body image, a static 7.5 min image of the upper abdomen and thorax, and a gated end-expiratory image over the upper abdomen and thorax. Images were evaluated for specificity, sensitivity, diagnostic accuracy, and the proportion of patients with changes in FIGO stage and subsequent clinical management was compared between imaging techniques., Results: A total of 84 patients were enrolled based on a standard CT scan, 67 of whom were eligible for gated PET/CT scans. Diagnostic accuracy with gated PET/CT was more than 80% for lesions in lung, liver, extra-abdominal sites, and pleura, but less than 50% for extra-abdominal lymph nodes. Compared with CT scan at baseline, 46% of patients who had 7.5 min gated PET/CT had disease upstaged from stage III to IV, and 8% had disease downstaged from stage IV to III. However, this led to a change of management in only 5% of patients., Conclusions: Gated PET/CT enables upstaging; however, in our institution it altered clinical management only in a minority of patients., Trial Registration Number: NCT02258165., Competing Interests: Competing interests: AO reports grants, personal fees, and other funding from SurgicalPerformance Pty Ltd, and grants from Medtronic, not directly related to the subject of this manuscript. AO reports consultancy fees from Baxter Healthcare Australia and New Zealand and Astra Zeneca Australia, not directly related to the subject of this manuscript. In addition, AO has a trademark licensed to SurgicalPerformance Pty Ltd. All other authors declare they have nothing to disclose., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Studies have shown that chronic marijuana use is associated with increased vascular inflammation, endothelial damage, myocardial infarctions, strokes, arteritis, and cardiomyopathies; however, cannabis's effect on wound healing in immediate direct-to-implant (DTI) breast reconstruction is unknown. With the increasing prevalence of marijuana use, it is imperative to understand its effects on surgical outcomes., Methods: We performed a retrospective cohort study of consecutive patients in a quaternary-care breast cancer center undergoing immediate DTI reconstruction. Patient demographics, operative details, and surgical complications were extracted through chart review. Active cannabis use was defined as use within 12 weeks of operation. Univariate and multivariable analyses were performed., Results: In total, 243 consecutive patients underwent immediate DTI reconstruction, and 12 reported active cannabis use. There were no significant differences in patient demographics, cancer treatment, or operative details. Active marijuana users demonstrated higher rates of cellulitis treated with IV antibiotics ( P = 0.004), explantation for infection ( P = 0.004), emergency department visits ( P = 0.028), readmission ( P = 0.037), takeback to the operating room in 90 days ( P < 0.001), and overall major complications ( P < 0.001). Multivariable analysis demonstrated that active marijuana users were more likely to experience cellulitis treated with IV antibiotics [odds ratio (OR) = 3.55, P = 0.024], takeback to the OR within 90 days of operation (OR = 4.75, P = 0.001), and major complications (OR = 2.26, P = 0.048)., Conclusions: The consumption of cannabis in the perioperative setting is associated with increased rates of complications in patients undergoing immediate DTI reconstruction; however, an analysis with a larger patient population is needed to conclude that abstinence from its use should be highly encouraged., Competing Interests: Dr. Atisha is a key opinion leader for MTF Biologics. All other authors have no financial interests to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Over the past decade, immunotherapies have brought about significant changes in how we approach the treatment of various solid tumors and blood-related cancers. However, the effectiveness of checkpoint blockade therapy has been constrained to a rate of under 30 %. A significant challenge in the realm of tumor immunotherapy revolves around comprehending the mechanisms through which regulatory T (Treg) cells induce immunosuppression. We have recently discovered that USP22 (ubiquitin-specific peptidase 22) a deubiquitinating enzyme that is increased in various tumors, is an oncogene and controls Treg immune suppressive activity for tumor evasion, providing a rationale for USP22 targeting to achieve both onco- and immuno-therapeutic efficacies. Herein, we identified the traditional Chinese secoiridoid compound gentiopicroside as a USP22 inhibitor. Gentiopicroside treatment decreased the forkhead box P3 (Foxp3) expression, which subsequently reduced Treg immune suppressive activity. Treatment of cancer cells by gentiopicroside resulted in an increase in histone 2B monoubiquitination (H2Bub) in a USP22-dependent manner and a decrease in programmed cell death ligand 1 (PD-L1) expression, both of which are known as USP22-specific substrates. Docking and molecular dynamic simulation revealed that gentiopicroside stably binds to USP22 catalytic pocket, supporting that gentiopicroside is a USP22 inhibitor. Importantly, administration of gentiopicroside to mice significantly inhibited the growth of syngenetic lung adenocarcinoma. Further analysis of intratumoral immune cells revealed a dramatic increase CD8 + T cell production of IFN-γ and granzyme B (GZMB), confirming that gentiopicroside enhances antitumor immunity. Our study revealed that gentiopicroside is a USP22-specific inhibitor with potent antitumor therapeutic potentials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 ( ITGB1 ). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy., Competing Interests: Drs. Deyu Fang and Huiping Liu are co-founders and equity owners of ExoMira Medicine Inc. Dr. Fang is the inventor of USP22 inhibitor-S02 (patent #: 63/201330)., (© 2024 Published by Elsevier Inc.)

Introduction: Despite the importance of timely vaccine completion for protection from infectious disease, there is limited knowledge of the immunization adherence rates of children with sickle cell disease (SCD)., Methods: This is a retrospective cohort study comparing the immunization rates of children with SCD to those with sickle cell trait between 2008 and 2019 in Georgia. Completion rates for each vaccine and the proportion of children with up-to-date status at 24 and 35 months were calculated and compared between the cohorts. Chi-square tests with odds ratios (OR) for differences and 95% confidence intervals (CIs) were reported on the overall up-to-date rates and rates for individual vaccines at 24 and 35 months for the two cohorts., Results: Children with SCD had higher up-to-date rates than children with sickle cell trait at 24 and 35 months. At 35 months, the overall up-to-date rates (OR = 1.17; 95% CI, 1.04-1.31; p = .004) and the four-dose pneumococcal conjugate vaccine series (OR = 1.36; 95% CI, 1.18-1.57; p < .001) were significantly different between the groups. Both cohorts had the highest completion rates for the hepatitis B series and the lowest rates for the varicella vaccine. Doses of diphtheria, tetanus, and acellular pertussis vaccine; varicella; and pneumococcal conjugate vaccines were most commonly missed by children in both cohorts., Conclusions: Children with SCD have better immunization coverage than children with sickle cell trait, but there is an opportunity for improvement. Policymakers and healthcare professionals should focus on increasing access to care coordination services among children with SCD to ensure on-time and preventive healthcare services., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Competing Interests: Su Wang received grants from Gilead. Carla S. Coffin consults for and received grants from Gilead and GSK. She received grants from Janssen Pharmaceuticals, Roche, and Altimmune. Chari Cohen advises and received grants from Gilead. She advises GSK. She received grants from Roche/Genentech and VBI Vaccines. The remaining authors have no conflicts to report.

Abstract: Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy combined with diffuse correlation spectroscopy were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume, and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin-labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA aged 8 to 18 years. CBFi was significantly positively correlated with ASL-MRI-measured blood flow (R2 = 0.651; P = .015). Next, a single-center, open-label pilot study was completed in 8 children with SCA aged 4 to 17 years on voxelotor, monitored before treatment initiation and at 4, 8, and 12 weeks (NCT05018728). By 4 weeks, both OEF and CBFi significantly decreased, and these decreases persisted to 12 weeks (both P < .05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin (Hb) concentration (P = .025), whereas the correlation between decreases in OEF and increases in Hb trended toward significance (P = .12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared with controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments. This trial was registered at www.ClinicalTrials.gov as #NCT05018728., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Protocols to evaluate for myocardial infarction (MI) using high-sensitivity cardiac troponin (hs-cTn) have the potential to drive costs upward due to the added sensitivity. We performed an economic evaluation of an accelerated protocol (AP) to evaluate for MI using hs-cTn to identify changes in costs of treatment and length of stay compared with conventional testing., Methods: We performed a planned secondary economic analysis of a large, cluster randomized trial across nine emergency departments (EDs) from July 2020 to April 2021. Patients were included if they were 18 years or older with clinical suspicion for MI. In the AP, patients could be discharged without further testing at 0 h if they had a hs-cTnI < 4 ng/L and at 1 h if the initial value were 4 ng/L and the 1-h value ≤7 ng/L. Patients in the standard of care (SC) protocol used conventional cTn testing at 0 and 3 h. The primary outcome was the total cost of treatment, and the secondary outcome was ED length of stay., Results: Among 32,450 included patients, an AP had no significant differences in cost (+$89, CI: -$714, $893 hospital cost, +$362, CI: -$414, $1138 health system cost) or ED length of stay (+46, CI: -28, 120 min) compared with the SC protocol. In lower acuity, free-standing EDs, patients under the AP experienced shorter length of stay (-37 min, CI: -62, 12 min) and reduced health system cost (-$112, CI: -$250, $25)., Conclusion: Overall, the implementation of AP using hs-cTn does not result in higher costs., Competing Interests: Joe Miller: Research support and consulting for Beckman Coulter; consulting for Siemens and AstraZeneca. Ben Cook: Research support for Abbott; research support and consulting for Beckman Coulter; research support for Roche. David Lanfear: Abbott Laboratories, Amgen, Astra Zeneca, Cytokinetics, DCRI (CONNECT‐HF), Illumina, Janssen, Lilly, Martin Pharmaceuticals, Ortho Diagnostics, Otsuka, Somalogic, Vicardia. Simon Mahler: funding/support from Roche Diagnostics, Abbott Laboratories, Ortho Clinical Diagnostics, Siemens, Grifols, Pathfast, Quidel, and HRSA (1H2ARH399760100). He is an advisor for Roche Diagnostics, Abbott Laboratories, Genetesis, Quidel, Inflammatix, Radiometer, and Amgen and the Chief Medical Officer for Impathiq Inc. Phil Levy: past chair of the American College of Cardiology (ACC) Accreditation Oversight Committee and a current member of the ACC NCDR Oversight Committee and the NCDR Chest Pain/MI Registry Publications Committee; he was also Vice Chair for the ACC/AHA Chest Pain Guidelines. Dr. Levy has served as a consultant for Quidel, Siemens, Roche Diagnostics, Ortho Diagnostics, Beckman Coulter, Pathfast, and the Baim Institute. James McCord: research support for Roche and Abbott; research support and consulting for Siemens and Beckman Coulter. Nicholas Mills has received honoraria or consultancy from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx, and the University of Edinburgh has received research grants from Abbott Diagnostics and Siemens Healthineers is supported by Chair, Programme and Research Excellence Awards (CH/F/21/90010, RG/20/10/34966, RE/18/5/34216) from the British Heart Foundation. Other coauthors have no disclosures to make., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Background: Uptake of lung cancer screening (LCS) has been slow with less than 20% of eligible people who currently or formerly smoked reported to have undergone a screening CT., Objective: To determine individual-, health system-, and neighborhood-level factors associated with LCS uptake after a provider order for screening., Design and Subjects: We conducted an observational cohort study of screening-eligible patients within the Population-based Research to Optimize the Screening Process (PROSPR)-Lung Consortium who received a radiology referral/order for a baseline low-dose screening CT (LDCT) from a healthcare provider between January 1, 2015, and June 30, 2019., Main Measures: The primary outcome is screening uptake, defined as LCS-LDCT completion within 90 days of the screening order date., Key Results: During the study period, 18,294 patients received their first order for LCS-LDCT. Orders more than doubled from the beginning to the end of the study period. Overall, 60% of patients completed screening after receiving their first LCS-LDCT order. Across health systems, uptake varied from 41 to 87%. In both univariate and multivariable analyses, older age, male sex, former smoking status, COPD, and receiving care in a centralized LCS program were positively associated with completing LCS-LDCT. Unknown insurance status, other or unknown race, and lower neighborhood socioeconomic status, as measured by the Yost Index, were negatively associated with screening uptake., Conclusions: Overall, 40% of patients referred for LCS did not complete a LDCT within 90 days, highlighting a substantial gap in the lung screening care pathway, particularly in decentralized screening programs., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Introduction: The objectives of this study are to develop a decision aid for orthopedic patients to decide between virtual or in-person care and assess patient preferences for these modalities in hand clinic. Methods: An orthopedic virtual care decision aid was developed alongside orthopedic surgeons and a virtual care expert. Subject participation involved 5 steps: Orientation, Memory, and Concentration Test (OMCT), knowledge pretest, decision aid, postdecision aid questionnaire, and Decisional Conflict Scale (DCS) assessment. Patients presenting to hand clinic were initially provided the OMCT to assess decision-making capacity, with those failing excluded. Subjects were then administered a pretest to assess their understanding of virtual and in-person care. Subsequently, the validated decision aid was provided to patients, after which a postdecision aid questionnaire and DCS assessment were administered. Results: This study enrolled 124 patients. Pre- to postdecision aid knowledge test scores increased by 15.3% ( p < 0.0001), and the average patient DCS score was 18.6. After reading the decision aid, 47.6% of patients believed that virtual and in-person care provided similar physician interaction, 46.0% felt little difference in effectiveness between the modalities, and 39.5% had no preference for either. Most patients understood their options (79.8%) and were ready to make a care modality decision (65.4%) following decision aid administration. Conclusion: Significant improvements in knowledge scores, strong DCS scores, and high levels of understanding and decision-making readiness support decision aid validity. Hand patients appear to have no consensus preferences for care modality, emphasizing the need for a decision aid to help determine individual care preferences.

Previous studies of esophagectomy outcomes by surgical specialty do not address malignancy or surgical approach. We sought to evaluate these cases using a national database. The National Surgical Quality Improvement Program (NSQIP)-targeted esophagectomy data set was queried for esophagectomies for malignancy and grouped by surgeon specialty: thoracic surgery (TS) or general surgery (GS). 1:1 propensity score matching was performed. Associations of surgical specialty with outcomes of interest (30-day mortality, anastomotic leak, Clavien-Dindo grade ≥ 3, and positive margin rate) were assessed overall and in surgical approach subsets. 1463 patients met inclusion criteria (512 GS and 951 TS). Propensity score matching yielded matched groups of 512, with similar demographics, preoperative stage, and neoadjuvant therapy rates. All outcomes of interest were similar between TS and GS groups, both overall and when stratified by surgical approach. Esophagectomy for malignancy has a similar perioperative safety profile and positive margin rate among general and thoracic surgeons, regardless of surgical approach., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models., Experimental Design: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response., Results: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression., Conclusions: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes., (©2023 American Association for Cancer Research.)

Background: The All of Us Research Program enrolls diverse US participants which provide a unique opportunity to better understand the problem of opioid use. This study aims to estimate the prevalence of opioid use and its association with sociodemographic characteristics from survey data and electronic health record (EHR)., Methods: A total of 214,206 participants were included in this study who competed survey modules and shared EHR data. Adjusted logistic regressions were used to explore the associations between sociodemographic characteristics and opioid use., Results: The lifetime prevalence of street opioids was 4%, and the nonmedical use of prescription opioids was 9%. Men had higher odds of lifetime opioid use (aOR: 1.4 to 3.1) but reduced odds of current nonmedical use of prescription opioids (aOR: 0.6). Participants from other racial and ethnic groups were at reduced odds of lifetime use (aOR: 0.2 to 0.9) but increased odds of current use (aOR: 1.9 to 9.9) compared with non-Hispanic White participants. Foreign-born participants were at reduced risks of opioid use and diagnosed with opioid use disorders (OUD) compared with US-born participants (aOR: 0.36 to 0.67). Men, Younger, White, and US-born participants are more likely to have OUD., Conclusions: All of Us research data can be used as an indicator of national trends for monitoring the prevalence of receiving prescription opioids, diagnosis of OUD, and non-medical use of opioids in the US. The program employs a longitudinal design for routinely collecting health-related data including EHR data, that will contribute to the literature by providing important clinical information related to opioids over time. Additionally, this data will enhance the estimates of the prevalence of OUD among diverse populations, including groups that are underrepresented in the national survey data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The programmable intermittent epidural bolus (PIEB) has been popularized as the optimal delivery technique for labor analgesia. Suggested advantages of this method are less local anesthetic consumption, improved maternal satisfaction, potentially shorter duration of labor, and decreased workload requirements for the anesthesia providers. However, a manual bolus is still routinely used for breakthrough pain when the PIEB is underperforming., Methods: We conducted a laboratory-based study to quantify the flow through a multiorifice epidural catheter using the PIEB setting on an epidural pump compared to the manual epidural bolus. Four syringe volumes, 3, 5, 10, and 20 mL, were selected for this experiment. The flow in a manual bolus was also studied with and without the presence of an epidural catheter filter. A generalized estimating equation analysis was done to compare data between the groups., Results: Regardless of the syringe size, there was a several-fold increase in flow when a manual bolus was used compared to a pump-administered dose, with the highest difference in the peak flow rate observed in 3-mL boluses with up to a 12-fold difference, while the difference was, at most, 7-fold in 5-mL and 10-mL boluses. Manual boluses without a filter achieve a mean peak flow rate higher than manual boluses with a filter., Conclusions: Our study found that manual boluses produced a higher flow rate compared to the CADD-Solis epidural pump (Smiths Medical). This study also found that the placement of a particulate filter reduces the flow rates generated while bolusing. Bulk flow rate is directly correlated with induced pressure and solution spread. Because higher bolus pressure has been shown to provide a more efficient distribution of local anesthetic and more efficient pain relief, these results may have impactful clinical significance and will pave the way for future studies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Background: While patient-reported outcome measures (PROMs) have benefit in cancer clinical trials, real-world applications are lacking. This study describes the method of implementation of a cancer enterprise-wide PROMs platform., Methods: After establishing a multispecialty stakeholder group within a large integrated health system, domain-specific instruments were selected from the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) instruments (pain interference, fatigue, physical function, and depression) and were administered at varying frequencies throughout each patient's cancer journey. All cancer patients with an oncologic visit were eligible to complete the PROMs prior to the visit using a patient portal, or at the time of the visit using a tablet. PROMs were integrated into clinical workflow. Clinical partnerships were essential for successful implementation. Descriptive preliminary data were compared using multivariable logistic regression to determine the factors associated with method of PROMs completion., Results: From September 16, 2020 to July 23, 2021, 23 of 38 clinical units (60.5%) implemented PROMs over 2392 encounters and 1666 patients. Approximately one third of patients (n = 629, 37.8%) used the patient portal. Black patients (aOR 0.70; 95% CI: 0.51-0.97) and patients residing in zip codes with higher percentage of unemployment (aOR: 0.07, 95% CI: 0.01-0.41) were among the least likely to complete PROMs using the patient portal., Conclusions: Successful system-wide implementation of PROMs among cancer patients requires engagement from multispecialty stakeholders and investment from clinical partners. Attention to the method of PROMs collection is required in order to reduce the potential for disparities, such as Black populations and those residing in areas with high levels of unemployment., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Comparing keloid treatment modalities and assessing response to treatments may be predicted by a better classification system. Objectives: To develop and validate the Detroit Keloid Scale (DKS), a standardized method of keloid assessment. Methods: Forty-seven physicians were polled to develop the DKS. The scale was validated in 52 patients against the Vancouver Scar Scale (VSS), Patient and Observer Scar Assessment Scale (POSAS), and Dermatology Life Quality Index (DLQI). Results: The inter-rater reliability was "substantial" for observer DKS and only "moderate" for VSS and observer POSAS (intraclass correlation coefficient were 0.80, 0.60, and 0.47, respectively). Pearson's correlation indicated "moderate" association between observer DKS with observer POSAS ( ρ  = 0.56, p  < 0.001) and "substantial" relationship between observer DKS and VSS ( ρ  = 0.63, p  < 0.001). Pearson's correlation indicated "moderate" association between patient portion of DKS and patient portion of POSAS and patient portion of the DKS and DLQI (0.61 and 0.60, respectively, p  < 0.05). DKS total score consistently showed significant "substantial" relationship with POSAS total score ( ρ  = 0.65, p  < 0.001). Conclusions: The DKS offers a validated keloid-specific outcome measure for comparing keloid treatments.

Cancer cells evade the immune system by expressing inhibitory immune checkpoint receptors such as ecto-5'-nucleotidase (NT5E), also known as CD73, which consequently suppress tumor neoantigen-specific immune response. Blockade of CD73 in mouse models of breast cancer showed a reduction in tumor growth and metastasis. CD73 expression is elevated in a variety of human tumors including breast cancer. While the regulation of CD73 expression at the transcriptional level has been well understood, the factors involved in regulating CD73 expression at the post-transcriptional level have not been identified. Herein, we discovered that the ubiquitin-specific peptidase 22 (USP22), a deubiquitinase associated with poor prognosis and overexpressed in breast cancers, is a positive regulator for CD73. Targeted USP22 deletion resulted in a statistically significant reduction in CD73 protein expression. In contrast, CD73 mRNA expression levels were not reduced, but even slightly increased by USP22 deletion. Further analysis demonstrated that USP22 is a deubiquitinase that specifically interacts with and inhibits CD73 ubiquitination. Consequently, USP22 protects CD73 from ubiquitin-mediated proteasomal degradation in breast cancer cells. Targeted USP22 deletion, inhibits syngeneic breast cancer growth. Collectively, our study reveals USP22 as a positive regulator to promote CD73 expression in breast cancer and provides a rationale to target USP22 in antitumor immune therapy., Competing Interests: None., (AJCR Copyright © 2022.)

Background: In our previous published study, we demonstrated that a qualitatively assessed elevation in deltoid muscle echogenicity on ultrasound was both sensitive for and a strong predictor of a type 2 diabetes (T2DM) diagnosis. This study aims to evaluate if a sonographic quantitative assessment of the deltoid muscle can be used to detect T2DM., Methods: Deltoid muscle ultrasound images from 124 patients were stored: 31 obese T2DM, 31 non-obese T2DM, 31 obese non-T2DM and 31 non-obese non-T2DM. Images were independently reviewed by 3 musculoskeletal radiologists, blinded to the patient's category. Each measured the grayscale pixel intensity of the deltoid muscle and humeral cortex to calculate a muscle/bone ratio for each patient. Following a 3-week delay, the 3 radiologists independently repeated measurements on a randomly selected 40 subjects. Ratios, age, gender, race, body mass index, insulin usage and hemoglobin A 1c were analyzed. The difference among the 4 groups was compared using analysis of variance or chi-square tests. Both univariate and multivariate linear mixed models were performed. Multivariate mixed-effects regression models were used, adjusting for demographic and clinical variables. Post hoc comparisons were done with Bonferroni adjustments to identify any differences between groups. The sample size achieved 90% power. Sensitivity and specificity were calculated based on set threshold ratios. Both intra- and inter-radiologist variability or agreement were assessed., Results: A statistically significant difference in muscle/bone ratios between the groups was identified with the average ratios as follows: obese T2DM, 0.54 (P < 0.001); non-obese T2DM, 0.48 (P < 0.001); obese non-T2DM, 0.42 (P = 0.03); and non-obese non-T2DM, 0.35. There was excellent inter-observer agreement (intraclass correlation coefficient 0.87) and excellent intra-observer agreements (intraclass correlation coefficient 0.92, 0.95 and 0.94). Using threshold ratios, the sensitivity for detecting T2DM was 80% (95% CI 67% to 88%) with a specificity of 63% (95% CI 50% to 75%)., Conclusions: The sonographic quantitative assessment of the deltoid muscle by ultrasound is sensitive and accurate for the detection of T2DM. Following further studies, this process could translate into a dedicated, simple and noninvasive screening method to detect T2DM with the prospects of identifying even a fraction of the undiagnosed persons worldwide. This could prove especially beneficial in screening of underserved and underrepresented communities., (© 2022. The Author(s).)

Objective: To determine the role of vaginal vault cytology as a surveillance tool for the detection of recurrence in patients with early stage cervical cancer treated with hysterectomy without adjuvant therapy., Methods: A retrospective cohort study was conducted of all women with cervical cancer treated with a hysterectomy from January 2000 to July 2016 at the Royal Brisbane & Women's Hospital, Australia. Women included were diagnosed with the equivalent of International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1A1 to 1B3 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, received either simple or radical hysterectomy with or without pelvic lymph node dissection, and did not receive adjuvant therapy. Age, stage, histology, surgical procedure, and details of individual surveillance regimens including examination findings and indications and results for all vault cytology tests performed in the first 5 years following surgical management were collected., Results: A total of 155 women met the inclusion criteria. Most cases were FIGO 2018 stage 1B1 (61.9%) and squamous cell carcinoma (64.5%). Included women underwent a median of 80 months of surveillance (range 25-200, IQR 64-108). In the first 5 years of surveillance, there were a total of 1001 vault cytology smears performed, with a median of 6 smears (IQR 5-9) per woman. A total of 19 smears were abnormal (1.9%). Of the cohort of 155 women, 19 (12.3%) had an abnormality detected; 1 (0.65%) had a high-grade intraepithelial abnormality and 2 (1.3%) had recurrences detected on cytology; however, a lesion was also seen and biopsied in all three women. A total of 16 of 1001 smears (1.6%) had low-grade abnormalities detected, all of which resolved with clinical observation only. All were alive and well at last review. There were in total 6 (3.9%) recurrences, 2 (33%) of which had abnormal cytology as above, and all of which had a lesion to biopsy and/or abnormal medical imaging., Conclusions: The routine use of vaginal vault cytology in surveillance following hysterectomy for early stage cervical cancer did not appear to alter the detection of recurrent malignancy., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We evaluated the safety of maximal cardiopulmonary exercise testing (CPET) in individuals with sickle cell disease (SCD). Maximal CPET using gas exchange analysis is the gold standard for measuring cardiopulmonary fitness in the laboratory, yet its safety in the SCD population is unclear., Design: Systematic review., Data Sources: Systematic search of Medline (PubMed), EMBASE, Cochrane, ClinicalTrials.gov and professional society websites for all published studies and abstracts through December 2020., Eligibility Criteria for Selecting Studies: Two reviewers independently extracted data of interest from studies that assessed safety outcomes of maximal CPET in children and adults with SCD. A modified version of the Newcastle-Ottawa Scale was used to assess for risk of bias in studies included., Results: In total, 24 studies met inclusion/exclusion criteria. Adverse events were reported separately or as part of study results in 36 (3.8%) of 939 participants with SCD undergoing maximal CPET in studies included. Most adverse events were related to transient ischaemic changes on ECG monitoring or oxygen desaturation during testing, which did not result in arrhythmias or other complications. Only 4 (0.43%) of 939 participants experienced pain events due to maximal CPET., Conclusion: Maximal CPET appears to be a safe testing modality in children and adults with SCD and can be used to better understand the physiological basis of reduced exercise capacity and guide exercise prescription in this population. Some studies did not focus on reporting adverse events related to exercise testing or failed to mention safety monitoring, which contributed to risk of bias., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Participant willingness to share electronic health record (EHR) information is central to success of the National Institutes of Health All of Us Research Program (AoURP). We describe the demographic characteristics of participants who decline access to their EHR data., Materials and Methods: We included participants enrolling in AoURP between June 6, 2017 and December 31, 2019 through the Trans-American Consortium for the Health Care Systems Research Network (TACH). TACH is a consortium of health care systems spanning 6 states, and an AoURP research partner., Results: We analyzed data for 25 852 participants (89.3% of those enrolled). Mean age = 52.0 years (SD 16.8), with 66.5% White, 18.7% Black/African American, 7.7% Hispanic, 32.5% female, and 76% with >a high school diploma. Overall, 2.3% of participants declined to share access to their EHR data (range across TACH sites = 1.3% to 3.5%). Younger age, female sex, and education >high school were significantly associated with decline to share EHR data, odds ratio (95% confidence interval) = 1.26 (1.19-1.33), 1.74 (1.42-2.14), and 2.44 (1.86-3.21), respectively. Results were similar when several sensitivity analyses were performed., Discussion: AoURP seeks a dataset reflecting our nation's diversity in all aspects of participation. Those under-represented in biomedical research may be reluctant to share access to their EHR data., Conclusion: In our data, race and ethnicity were not independently related to participant decision to decline access to their EHR information. Results suggest that the value of the AoURP dataset is unlikely to be constrained by the size or the racial/ethnic composition of this subgroup., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia., Methods: We queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared., Results: A total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p < 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068)., Conclusions: In contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia., (© 2022. The Author(s).)

Background: Use of pre-operative bowel preparation in colorectal resection has not been examined solely in patients who have had colorectal resection with primary colostomy (Hartmann procedure). We aimed to evaluate the association of bowel preparations with short-term outcomes after non-emergent Hartmann procedure. Patients and Methods: The National Surgical Quality Improvement Program Participant Use File colectomy database was queried for patients who had elective open or laparoscopic Hartmann operation. Patients were grouped by pre-operative bowel preparation: no bowel preparation, oral antibiotic agents, mechanical preparation, or both mechanical and oral antibiotic agent preparation (combined). Propensity analysis was performed, and outcomes were compared by type of pre-operative bowel preparation. The primary outcome was rate of any surgical site infection (SSI). Secondary outcomes included overall complication, re-operation, re-admission, Clostridioides difficile colitis, and length of stay. Results: Of the 4,331 records analyzed, 2,040 (47.1%) patients received no preparation, 251 (4.4%) received oral antibiotic preparation, 1,035 (23.9%) received mechanical bowel preparation, and 1,005 (23.2%) received combined oral antibiotic and mechanical bowel preparation. After propensity adjustment, rates of any SSI, overall complication, and length of hospital stay varied significantly between pre-operative bowel regimens (p < 0.005). The use of combined bowel preparation was associated with decreased rate of SSI, overall complication, and length of stay. No difference in rate of re-operation or post-operative Clostridioides difficile infection was observed based on bowel preparation. Conclusions: Compared with no pre-operative bowel preparation, any bowel preparation was associated with reduced rate of SSI, but not rate of re-operation or post-operative Clostridioides difficile infection.

Background: Recurrent laryngeal nerve (RLN) injury and postoperative hypocalcemia are potential complications of thyroidectomy, particularly in malignancy. Intraoperative nerve monitoring (IONM) remains controversial. We sought to evaluate the impact of IONM on these complications using a national data set., Methods: The American College of Surgeons National Surgical Quality Improvement Program thyroidectomy-targeted data set was queried for patients who underwent thyroidectomies from 2016 to 2017. Patients were grouped according to IONM use. Logistic regression models were constructed to evaluate associations of variables with 30-day hypocalcemic events (HCEs) and RLN injury. Associations were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). A subgroup analysis was performed of patients with malignancy., Results: A total of 9527 patients were identified; 5969 (62.7%) underwent thyroidectomy with IONM and 3558 (37.3%) without. By multivariable analysis, IONM had protective associations with HCE (OR = .81, 95% CI = .68-.96; P = .013) and RLN injury (OR = .83, 95% CI = .69-.98; P = .033). Malignancy increased risk of HCE (OR = 1.21, 95% CI=1.01-1.45; P = .038) and RLN injury (OR = 1.22, 95% CI = 1.02-1.46; P = .034). A large proportion (5943/9527, 62.4%) of patients had malignancy; 3646 (61.3%) underwent thyroidectomy with IONM and 2297 (38.7%) without. In the subgroup analysis, IONM had stronger protective associations with HCE (OR = .73, 95% CI = .60-.90; P = .003) and RLN injury (OR = .76, 95% CI = .62-.94; P = .012)., Discussion: Malignancy was associated with increased risk of HCE and RLN injury. Intraoperative nerve monitoring had a protective association with HCE and RLN injury, both overall, and in the malignant subgroup. Intraoperative nerve monitoring was correlated with improved thyroidectomy outcomes, especially if the indication was malignancy. This warrants further study to clarify cause and effect.

Background: Optimal management of anemia of chronic kidney disease (CKD) remains controversial. This retrospective study aimed to describe the epidemiology and selected clinical outcomes of anemia in patients with CKD in the US., Methods: Data were extracted from Henry Ford Health System databases. Adults with stages 3a-5 CKD not on dialysis (estimated glomerular filtration rate < 60 mL/min/1.73m 2 ) between January 1, 2013 and December 31, 2017 were identified. Patients on renal replacement therapy or with active cancer or bleeding were excluded. Patients were followed for ≥12 months until December 31, 2018. Outcomes included incidence rates per 100 person-years (PY) of anemia (hemoglobin < 10 g/dL), renal and major adverse cardiovascular events, and of bleeding and hospitalization outcomes. Adjusted Cox proportional hazards models identified factors associated with outcomes after 1 and 5 years., Results: Among the study cohort (N = 50,701), prevalence of anemia at baseline was 23.0%. Treatments used by these patients included erythropoiesis-stimulating agents (4.1%), iron replacement (24.2%), and red blood cell transfusions (11.0%). Anemia incidence rates per 100 PY in patients without baseline anemia were 7.4 and 9.7 after 1 and 5 years, respectively. Baseline anemia was associated with increased risk of renal and major cardiovascular events, hospitalizations (all-cause and for bleeding), and transfusion requirements. Increasing CKD stage was associated with increased risk of incident anemia, renal and major adverse cardiovascular events, and hospitalizations., Conclusions: Anemia was a prevalent condition associated with adverse renal, cardiovascular, and bleeding/hospitalization outcomes in US patients with CKD. Anemia treatment was infrequent., (© 2022. The Author(s).)

Evaluate the impact of an emergency department (ED)-based critical care consultation service, hypothesizing early consultation results in shorter hospital length of stay (LOS)., Design: Retrospective observational study from February 2018 to 2020., Setting: An urban academic quaternary referral center., Patients: Adult patients greater than or equal to 18 years admitted to the ICU from the ED. Exclusion criteria included age less than 18 years, do not resuscitate/do not intubate documented prior to arrival, advanced directives outlining limitations of care, and inability to calculate baseline modified Sequential Organ Failure Assessment (mSOFA) score., Interventions: ED-based critical care consultation by an early intervention team (EIT) initiated by the primary emergency medicine physician compared with usual practice., Measurements: The primary outcome was hospital LOS, and secondary outcomes were hospital mortality, ICU LOS, ventilator-free days, and change in the mSOFA., Main Results: A total 1,764 patients met inclusion criteria, of which 492 (27.9%) were evaluated by EIT. Final analysis, excluding those without baseline mSOFA score, limited to 1,699 patients, 476 in EIT consultation group, and 1,223 in usual care group. Baseline mSOFA scores (±sd) were higher in the EIT consultation group at 3.6 (±2.4) versus 2.6 (±2.0) in the usual care group. After propensity score matching, there was no difference in the primary outcome: EIT consultation group had a median (interquartile range [IQR]) LOS of 7.0 days (4.0-13.0 d) compared with the usual care group median (IQR) LOS of 7.0 days (4.0-13.0 d), p = 0.64. The median (IQR) boarding time was twice as long subjects in the EIT consultation group at 8.0 (5.0-15.0) compared with 4.0 (3.0-7.0) usual care, p < 0.001., Conclusions: An ED-based critical care consultation model did not impact hospital LOS. This model was used in the ED and the EIT cared for critically ill patients with higher severity of illness and longer ED boarding times., Competing Interests: The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Food insecurity (FI) is a significant public health problem. Possible sequelae of prolonged food insecurity include kidney disease, obesity, and diabetes. Our objective was to assess the feasibility of a partnership between Henry Ford Health System (HFHS) and Gleaners Community Foodbank of Southeastern Michigan to implement and evaluate a food supplementation intervention initiated in a hospital outpatient clinic setting., Methods: We established a protocol for using the Hunger Vital Signs to screen HFHS internal medicine patients for food insecurity and established the data sharing infrastructure and agreements necessary for an HFHS-Gleaners partnership that would allow home delivery of food to consenting patients. We evaluated the food supplementation program using a quasi-experimental design and constructing a historical comparison group using the electronic medical record. Patients identified as food insecure through screening were enrolled in the program and received food supplementation twice per month for a total of 12 months, mostly by home delivery. The feasibility outcomes included successful clinic-based screening and enrollment and successful food delivery to consenting patients. Our evaluation compared healthcare utilization between the intervention and historical comparison group during a 12-month observation period using a difference-in-differences (DID) analysis., Results: Of 1691 patients screened, 353 patients (20.9%) met the criteria for FI, of which 340/353 (96.3%) consented, and 256/340 (75.3%) were matched and had data sufficient for analysis. Food deliveries were successfully made to 89.9% of participant households. At follow-up, the intervention group showed greater reductions in emergency department visits than the comparison group, -41.5% and -25.3% reduction, respectively. Similar results were observed for hospitalizations, -55.9% and -17.6% reduction for intervention and control groups, respectively. DID regression analysis also showed lower trends in ED visits and hospitalizations for the intervention group compared to the comparison group., Conclusions: Results suggest that community-health system partnerships to address patient-reported food insecurity are feasible and potentially could reduce healthcare utilization in these patients. A larger, randomized trial may be the next step in fully evaluating this intervention, perhaps with more outcomes (e.g., medication adherence), and additional covariates (e.g., housing insecurity and financial strain)., (© 2022. The Author(s).)

Introduction: An outstanding question in kidney transplantation is how to prepare candidates and their social supports for optimal posttransplant outcomes. Project Aims: This program evaluation assessed whether a pretransplant quality improvement clinic improved clinical outcomes in the year posttransplant compared to recipients receiving standard of care. Design: The Countdown to Transplant Clinic was implemented with kidney transplant candidates expected to receive a transplant within the next few months. The clinic included an enhanced education session on posttransplant lifestyle management, confirmation of support (≥2 adults), and evaluations by transplant social work, psychology, and nephrology. Results: Seventy-five patients participated in the clinic and underwent a transplant. A retrospective chart review of posttransplant laboratory values, rehospitalizations (within 3-months posttransplant), biopsy-confirmed graft failure, and mortality (within 1-year posttransplant) were collected from both groups. Univariate and multivariate propensity score-weighted linear or logistic regression models were used to evaluate the association between clinic participation and outcomes. In models adjusting for relevant covariates, participation in The Countdown to Transplant Clinic (vs standard care) was associated with a lower coefficient of variation of serum tacrolimus (all values collected 3-12 months posttransplant), 30-day posttransplant white blood cell counts (but not 90-day), 90-day posttransplant potassium, and 30 and 31 to 90 days rehospitalizations. Clinic participation did not predict serum glucose levels at 30- or 90-days posttransplant. Due to low rates of rejection and mortality, meaningful comparisons were not possible. Conclusion: Participation in a pretransplant, multicomponent clinic may improve certain outcomes of interest posttransplantation. Pilot testing for feasibility for randomized controlled trials is a necessary next step.

Introduction: Granulocyte colony-stimulating factors are used in medical oncology for the prevention of neutropenia. On-body injectors (OBI) have an advantage over the traditional injection (TI) method of not requiring a second visit to the clinic, but these devices are subject to failure. The objective of this study was to assess the efficacy of OBIs in the real-world., Methods: Women with breast cancer diagnosed between June 2015 and June 2016 treated with cytotoxic chemotherapy and a granulocyte colony-stimulating factor were retrospectively identified from the medical records of Henry Ford Hospital. The primary outcome was the incidence of severe neutropenia (SN), defined as an absolute neutrophil count (ANC) ≤500. Secondary outcomes included incidence of neutropenia (ANC ≤ 1500), neutropenic fever, and mortality. A secondary analysis of the data was performed to identify predictors of SN., Results: A total of 837 cycles of chemotherapy were analyzed. The OBI was used in 395 cycles and the TI in 442. The OBI group had patients that were older, had higher baseline ANC, and were more often white. The incidences of SN, neutropenic fever and neutropenia were not different between groups. Patients with a lower baseline ANC and white ethnicity were at a higher risk for SN. AC (doxorubicin and cyclophosphamide) was the most commonly used chemotherapy regimen (38% of total cycles)., Conclusions: There was no difference in the efficacy of the OBI and TI methods for preventing SN, neutropenic fever and neutropenia.

Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX )., Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence., Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I 2  = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis., Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care., (© 2021. The Author(s).)

At the present time there are no consistently satisfactory treatment options for some challenging bone loss scenarios. We have previously reported on the properties of a novel 3D-printed hydroxyapatite-composite material in a pilot study, which demonstrated osteoconductive properties but was not tested in a rigorous, clinically relevant model. We therefore utilized a rat critical-sized femoral defect model with a scaffold designed to match the dimensions of the bone defect. The scaffolds were implanted in the bone defect after being loaded with cultured rat bone marrow cells (rBMC) transduced with a lentiviral vector carrying the cDNA for BMP-2. This experimental group was compared against 3 negative and positive control groups. The experimental group and positive control group loaded with rhBMP-2 demonstrated statistically equivalent radiographic and histologic healing of the defect site (p > 0.9), and significantly superior to all three negative control groups (p < 0.01). However, the healed defects remained biomechanically inferior to the unoperated, contralateral femurs (p < 0.01). When combined with osteoinductive signals, the scaffolds facilitate new bone formation in the defect. However, the scaffold alone was not sufficient to promote adequate healing, suggesting that it is not substantially osteoinductive as currently structured. The combination of gene therapy with 3D-printed scaffolds is quite promising, but additional work is required to optimize scaffold geometry, cell dosage and delivery., (© 2021 Wiley Periodicals LLC.)

Regional gene therapy using a lentiviral vector containing the BMP-2 complementary DNA (cDNA) has been shown to heal critical-sized bone defects in rodent models. An appropriate "cellular dose" needs to be defined for eventual translation into human trials. The purpose of this study was to evaluate bone defect healing potential and quality using three different doses of transduced human bone marrow cells (HBMCs). HBMCs were transduced with a lentiviral vector containing either BMP-2 or green fluorescent protein (GFP). All cells were loaded onto compression-resistant matrices and implanted in the bone defect of athymic rats. Treatment groups included femoral defects that were treated with a low-dose (1 × 10 6 cells), standard-dose (5 × 10 6 cells), and high-dose (1.5 × 10 7 cells) HBMCs transduced with lentiviral vector containing BMP-2 cDNA. The three control groups were bone defects treated with HBMCs that were either nontransduced or transduced with vector containing GFP. All animals were sacrificed at 12 weeks. The bone formed in each defect was evaluated with plain radiographs, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing. Bone defects treated with higher doses of BMP-2-producing cells were more likely to have healed (6/14 of the low-dose group; 12/14 of the standard-dose group; 14/14 of the high-dose group; χ 2 (2) = 15.501, p  < 0.001). None of the bone defects in the control groups had healed. Bone defects treated with high dose and standard dose of BMP-2-producing cells consistently outperformed those treated with a low dose in terms of bone formation, as assessed by microCT and histomorphometry, and biomechanical parameters. However, statistical significance was only seen between defects treated with high dose and low dose. Larger doses of BMP-2-producing cells were associated with a higher likelihood of forming heterotopic ossification. Femurs treated with a standard- and high-dose BMP-2-producing cells demonstrated similar healing and biomechanical properties. Increased doses of BMP-2 delivered through higher cell doses have the potential to heal large bone defects. Adapting regional gene therapy for use in humans will require a balance between promoting bone repair and limiting heterotopic ossification. Impact statement Critical bone loss may result from complex traumatic bone injury (i.e., open fracture or blast injury), revision total joint arthroplasty, and spine pseudoarthrosis. This is a challenging clinical problem to treat and regional gene therapy is an innovative means of addressing it. This study provides information regarding the quantity of cells or "cell dose" of transduced cells needed to treat a critical-sized bone defect in a rat model. This information may be extrapolated for use in humans in future trials.

Objective: Immature CD11b  +  Gr1 + myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study's objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b + Gr1 + myeloid cells., Methods: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti-PD1 mAb. The treatment effect was assessed by a survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess the protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies., Results: The depletion of Gr1 + immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. In addition to the adoptive transfer studies, these findings validate the role of immunosuppressive CD11b + Gr1 + myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironments produced recruitment and regulatory factors for immunosuppressive CD11b + Gr1 + myeloid cells. CD11b + Gr1 + myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted primarily by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers' expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found to be the most significantly elevated gene in tumor-primed myeloid cells. The inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression and function in myeloid cells., Conclusion: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b  +  Gr1 + myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in immunosuppressive myeloid cells decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Recent reports have questioned the efficacy of intraosseous (IO) drug administration for out-of-hospital cardiac arrest (OHCA) resuscitation. Our aim was to determine whether prehospital administration of resuscitative medications via the IO route was associated with lower rates of return of spontaneous circulation (ROSC) and survival to hospital discharge than peripheral intravenous (IV) infusion in the setting of OHCA., Methods: We obtained data on all OHCA patients receiving prehospital IV or IO drug administration from the three most populous counties in Michigan over three years. Data was from the Michigan Cardiac Arrest Registry to Enhance Survival (CARES) database. The association between route of drug administration and outcomes was tested using a matched propensity score analysis., Results: From a total of 10,626 OHCA patients, 6869 received parenteral drugs during their prehospital resuscitation (37.8% by IO) and were included in analysis. Unadjusted outcomes were lower in patients with IO vs. IV access: 18.3% vs. 23.8% for ROSC (p < 0.001), 3.2% vs. 7.6% for survival to hospital discharge (p < 0.001), and 2.0% vs. 5.8% for favorable neurological function (p < 0.001). After adjustment, IO route remained associated with lower odds of sustained ROSC (OR 0.72, 95% CI 0.63-0.81, p < 0.001), hospital survival (OR 0.48, 95% CI 0.37-0.62, p < 0.001), and favorable neurological outcomes (OR 0.42, 95% CI 0.30-0.57, p < 0.001)., Conclusion: In this cohort of OHCA patients, the use of prehospital IO drug administration was associated with unfavorable clinical outcomes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Cervical cancer is the third most common malignancy affecting women. Screening with Papanicolaou (Pap) tests effectively identifies precancerous lesions and early-stage cervical cancer. While the nationwide rate of cervical cancer screening (CCS) is 84%, our urban general internal medicine (GIM) clinic population had a CCS rate of 70% in 2016., Objective: To improve our clinic's CCS rate to match or exceed the national average within 18 months by identifying barriers and testing solutions., Design: A quality improvement project led by a multidisciplinary group of healthcare providers., Participants: Our GIM clinic includes 16 attending physicians, 116 resident physicians, and 20 medical assistants (MAs) with an insured and underserved patient population., Intervention: Phase 1 lasted 9 months and implemented CCS patient outreach, patient financial incentives, and clinic staff education. Phase 2 lasted 9 months and involved a workflow change in which MAs identified candidates for CCS during patient check-in. Feedback spanned the entire study period., Main Measures: Our primary outcome was the number of Pap tests completed per month during the 2 study phases. Our secondary outcome was the clinic population's CCS rate for all eligible clinic patients., Key Results: After interventions, the average number of monthly Pap tests increased from 35 to 56 in phase 1 and to 75 in phase 2. Of 385 patients contacted in phase 1, 283 scheduled a Pap test and 115 (41%) completed it. Compared to baseline, both interventions improved cervical cancer screening (phase 1 relative risk, 1.86; 95% CI, 1.64-2.10; P < 0.001; phase 2 relative risk, 2.70; 95% CI, 2.40-3.02; P < 0.001). Our clinic's CCS rate improved from 70% to 75% after the 18-month intervention., Conclusions: The rate of CCS increased by 5% after a systematic 2-phase organizational intervention that empowered MAs to remind, identify, and prepare candidates during check-in for CCS., (© 2021. Society of General Internal Medicine.)

Background: The relationship of health disparities and comorbidities in coronavirus disease 2019 (COVID-19)-related outcomes are an ongoing area of interest. This report assesses risk factors associated with mortality in patients presenting with COVID-19 infection and healthcare disparities., Methods: We conducted a retrospective cohort study of consecutive patients presenting to emergency departments within an integrated health system who tested positive for COVID-19 between 7 March and 30 April 2020 in metropolitan Detroit. The primary outcomes were hospitalization and 30-day mortality., Results: A total of 3633 patients with a mean age of 58 years were included. The majority were female and Black non-Hispanic. Hospitalization was required for 64% of patients, 56% of whom were Black. Hospitalized patients were older, more likely to reside in a low-income area, and had a higher burden of comorbidities. By 30 days, 433 (18.7%) hospitalized patients died. In adjusted analyses, the presence of comorbidities, an age >60 years, and more severe physiological disturbance were associated with 30-day mortality. Residence in low-income areas (odds ratio [OR], 1.02; 95% confidence interval [CI], .76-1.36) and public insurance (OR, 1.24; 95% CI, .76-2.01) were not independently associated with a higher risk of mortality. Black female patients had a lower adjusted risk of mortality (OR, 0.46; 95% CI, .27-.78)., Conclusions: In this large cohort of COVID-19 patients, those with comorbidities, advanced age, and physiological abnormalities on presentation had higher odds of death. Disparities in income or source of health insurance were not associated with outcomes. Black women had a lower risk of dying., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Protocols utilizing high-sensitivity cardiac troponin (hs-cTn) assays for the evaluation of suspected acute coronary syndrome (ACS) in the emergency department (ED) have been gaining popularity across the US and the world. These protocols more rapidly rule-out ACS and more accurately identify the presence of acute myocardial injury. At this time, few randomized trials have evaluated the safety and operational impact of these assays, resulting in limited evidence to guide the use and implementation of hs-cTn in the ED., Objective: The main study objective is to test the effectiveness of a rapid ACS rule-out pathway using hs-cTnI in safely discharging patients from the ED for whom clinical suspicion for ACS exists., Design: This prospective, implementation trial (n = 11,070) will utilize a stepped wedge cluster randomized trial design. The design will allow for all participating sites to capture benefit from the implementation of the hs-cTnI pathway while providing data evaluating the effectiveness in providing safe and rapid evaluation of patients with clinical suspicion for ACS., Summary: Demonstrating that clinical pathways using hs-cTnI can be effectively implemented to rapidly rule-out ACS while conserving costly hospital resources has significant implications for the care of patients with possible acute cardiac conditions in EDs across the US., Clinicaltrialsgov Identifier: NCT04488913., (© 2021 The Authors.)

Background: Enhanced recovery protocols optimize pain control via multimodal approaches that include transversus abdominis plane (TAP) block. The aim of this study was to evaluate the effect of preoperative vs. postoperative plain 0.25 % bupivacaine TAP block on postoperative opioid use after colorectal surgery., Methods: A retrospective cohort study comparing postoperative opioid use in patients who received preoperative (n = 240) vs. postoperative (n = 22) plain 0.25 % bupivacaine TAP blocks. The study was conducted in a single tertiary care institution and included patients who underwent colorectal resections between August 2018 and January 2020. The primary outcome of the study was postoperative opioid use. Secondary outcomes included operative details, length of stay, reoperation, and readmission rates., Results: Patients who received postoperative plain 0.25 % bupivacaine TAP blocks were less likely to require postoperative patient-controlled analgesia (PCA) (59.1 % vs. 83.3 %; p = 0.012) and opioid medications on discharge (6.4 % vs. 16.9 %; p = 0.004) relative to patients who received preoperative TAP. When needed, a significantly smaller amount of opioid was prescribed to the postoperative group (84.5 vs. 32.0 mg, p = 0.047). No significant differences were noted in the duration of postoperative PCA use, amount of oral opioid use, and length of stay., Conclusions: Plain 0.25 % bupivacaine TAP block administered postoperatively was associated with significantly lower need for postoperative PCA and discharge opioid medications. The overall hospital length of stay was not affected by the timing of TAP block. Because of the limited sample size in this study, conclusions cannot be generalized, and more research will be required.

Purpose: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA., Patients and Methods: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months., Results: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m 2 . Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively., Conclusion: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups., Trial Registration: U.S. National Library of Medicine, NCT01686126., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Interval cytoreduction following neoadjuvant chemotherapy is a well-recognized treatment alternative to primary debulking surgery in the treatment of advanced epithelial ovarian cancer where patient and/or disease factors prevent complete macroscopic disease resection to be achieved. More recently, the strain of the global COVID-19 pandemic on hospital resources has forced many units to alter the timing of interval surgery and extend the number of neoadjuvant chemotherapy cycles. In order to support this paradigm shift and provide more accurate counseling during these unprecedented times, we investigated the survival outcomes in advanced epithelial ovarian cancer patients with the intent of maximal cytoreduction following neoadjuvant chemotherapy with respect to timing of surgery and degree of cytoreduction., Methods: A retrospective review of all patients aged 18 years and above with FIGO (2014) stage III/IV epithelial ovarian cancer treated with neoadjuvant chemotherapy and the intention of interval cytoreduction surgery between January 2008 and December 2017 was conducted. Overall and progression-free survival outcomes were analyzed and compared with patients who only received chemotherapy. Outcome measures were correlated with the number of neoadjuvant chemotherapy cycles and amount of residual disease following surgery., Results: Six hundred and seventy-one patients (median age 67 (range 20-91) years) were included in the study with 572 patients treated with neoadjuvant chemotherapy and surgery and 99 patients with chemotherapy only. There was no difference in the proportion of patients in whom complete cytoreduction was achieved based on number of cycles of neoadjuvant chemotherapy (2-4 cycles: 67.7%, n=337/498); ≥5 cycles: 62.2%, n=46/74). Patients undergoing cytoreduction surgery after neoadjuvant chemotherapy had a median 5-year progression-free and overall survival of 24 and 38 months, respectively. No significant difference in overall survival between surgical groups was observed (interval cytoreduction: 41 months vs delayed cytoreduction: 43 months, p=0.52). Those who achieved complete cytoreduction to R0 (no macroscopic disease) had a significant median overall survival advantage compared with those with any macroscopic residual disease (R0: 49-51 months vs R<1: 22-39 months, p<0.001 vs R≥1: 23-26 months, p<0.001)., Conclusions: Survival outcomes do not appear to be worse for patients treated with neoadjuvant chemotherapy if cytoreduction surgery is delayed beyond three cycles. In advanced epithelial ovarian cancer patients the imperative to achieve complete surgical cytoreduction remains gold standard, irrespective of surgical timing, for best survival benefit., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Respiratory failure is the most common cause of death in patients with corona virus disease 2019 (COVID-19). There have been many investigations to determine predictors of bad outcomes in patients with this illness. Liver enzyme elevation has been described in hospitalized patients with severe COVID-19; however, little is known about the significance of liver injury regarding outcomes. We conducted a retrospective chart review of 348 patients admitted with COVID-19 in our quaternary care center. Liver injury on admission was defined based on the laboratory cutoff of aspartate aminotransferase >35 IU/L and/or alanine aminotransferase >52 IU/L. Patients were divided into two cohorts based on the presence or absence of liver injury. These cohorts were compared to assess differences in presentation, complications, and outcomes. The primary outcome was respiratory failure requiring intubation, and the secondary outcome was in-hospital mortality. The presence of new onset liver enzyme elevation on presentation was associated with increased severity of illness, need for mechanical ventilation, and mortality. Presence of liver injury increased the chance of acute hypoxic respiratory failure requiring mechanical ventilation by 1.79 times. The degree and timeline of liver enzyme elevation during hospitalization corresponded with elevations of other inflammatory markers. Conclusion : Liver injury appears to correlate with the inflammatory syndrome caused by COVID-19, with the degree of liver injury corresponding with severity of inflammation. We suggest early and continued monitoring of liver enzymes as they can be useful to identify patients who may need early escalation of care., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

In the past few decades, major initiatives have been launched around the world to address chemical safety testing. These efforts aim to innovate and improve the efficacy of existing methods with the long-term goal of developing new risk assessment paradigms. The transcriptomic and toxicological profiling of mammalian cells has resulted in the creation of multiple toxicogenomic datasets and corresponding tools for analysis. To enable easy access and analysis of these valuable toxicogenomic data, we have developed ToxicoDB (toxicodb.ca), a free and open cloud-based platform integrating data from large in vitro toxicogenomic studies, including gene expression profiles of primary human and rat hepatocytes treated with 231 potential toxicants. To efficiently mine these complex toxicogenomic data, ToxicoDB provides users with harmonized chemical annotations, time- and dose-dependent plots of compounds across datasets, as well as the toxicity-related pathway analysis. The data in ToxicoDB have been generated using our open-source R package, ToxicoGx (github.com/bhklab/ToxicoGx). Altogether, ToxicoDB provides a streamlined process for mining highly organized, curated, and accessible toxicogenomic data that can be ultimately applied to preclinical toxicity studies and further our understanding of adverse outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)