Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic ß-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-ß1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma.

Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4+ T cells, and CD8+ T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.

Randomized Secondary Prevention Trials in Participants With Symptomatic Intracranial Atherosclerotic Stenosis.

Intracranial atherosclerotic stenosis is a prevalent cause of ischemic stroke worldwide. Its association with silent cerebral infarcts and its contribution to cognitive impairment and dementia emphasize the critical need for disease prevention and effective management strategies. Despite extensive research on secondary stroke prevention treatment over the past several decades, intracranial atherosclerotic stenosis continues to exhibit a notably higher recurrent stroke rate compared with other causes. This review focuses on randomized secondary prevention trials involving antithrombotic therapy, endovascular treatment, open surgical therapy, and remote ischemic conditioning. It aims to provide an insightful overview of the major findings from each trial and their implications for future research efforts.

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units.

BACKGROUND: Mobile stroke units (MSUs) are ambulances with staff and a computed tomographic scanner that may enable faster treatment with tissue plasminogen activator (t-PA) than standard management by emergency medical services (EMS). Whether and how much MSUs alter outcomes has not been extensively studied. METHODS: In an observational, prospective, multicenter, alternating-week trial, we assessed outcomes from MSU or EMS management within 4.5 hours after onset of acute stroke symptoms. The primary outcome was the score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes according to a patient value system, derived from scores on the modified Rankin scale of 0 to 6, with higher scores indicating more disability). The main analysis involved dichotomized scores on the utility-weighted modified Rankin scale (≥0.91 or <0.91, approximating scores on the modified Rankin scale of ≤1 or >1) at 90 days in patients eligible for t-PA. Analyses were also performed in all enrolled patients. RESULTS: We enrolled 1515 patients, of whom 1047 were eligible to receive t-PA; 617 received care by MSU and 430 by EMS. The median time from onset of stroke to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Of patients eligible for t-PA, 97.1% in the MSU group received t-PA, as compared with 79.5% in the EMS group. The mean score on the utility-weighted modified Rankin scale at 90 days in patients eligible for t-PA was 0.72 in the MSU group and 0.66 in the EMS group (adjusted odds ratio for a score of ≥0.91, 2.43; 95% confidence interval [CI], 1.75 to 3.36; P<0.001). Among the patients eligible for t-PA, 55.0% in the MSU group and 44.4% in the EMS group had a score of 0 or 1 on the modified Rankin scale at 90 days. Among all enrolled patients, the mean score on the utility-weighted modified Rankin scale at discharge was 0.57 in the MSU group and 0.51 in the EMS group (adjusted odds ratio for a score of ≥0.91, 1.82; 95% CI, 1.39 to 2.37; P<0.001). Secondary clinical outcomes generally favored MSUs. Mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group. CONCLUSIONS: In patients with acute stroke who were eligible for t-PA, utility-weighted disability outcomes at 90 days were better with MSUs than with EMS. (Funded by the Patient-Centered Outcomes Research Institute; BEST-MSU ClinicalTrials.gov number, NCT02190500.).

Polo-like kinase 4 inhibitor CFI-400945 suppresses liver cancer through cell cycle perturbation and eliciting antitumor immunity.

BACKGROUND AND AIMS: Prognosis of HCC remains poor due to lack of effective therapies. Immune checkpoint inhibitors (ICIs) have delayed response and are only effective in a subset of patients. Treatments that could effectively shrink the tumors within a short period of time are idealistic to be employed together with ICIs for durable tumor suppressive effects. HCC acquires increased tolerance to aneuploidy. The rapid division of HCC cells relies on centrosome duplication. In this study, we found that polo-like kinase 4 (PLK4), a centrosome duplication regulator, represents a therapeutic vulnerability in HCC. APPROACH AND RESULTS: An orally available PLK4 inhibitor, CFI-400945, potently suppressed proliferating HCC cells by perturbing centrosome duplication. CFI-400945 induced endoreplication without stopping DNA replication, causing severe aneuploidy, DNA damage, micronuclei formation, cytosolic DNA accumulation, and senescence. The cytosolic DNA accumulation elicited the DEAD box helicase 41-stimulator of interferon genes-interferon regulatory factor 3/7-NF-κß cytosolic DNA sensing pathway, thereby driving the transcription of senescence-associated secretory phenotypes, which recruit immune cells. CFI-400945 was evaluated in liver-specific p53/phosphatase and tensin homolog knockout mouse HCC models established by hydrodynamic tail vein injection. Tumor-infiltrated immune cells were analyzed. CFI-400945 significantly impeded HCC growth and increased infiltration of cluster of differentiation 4-positive (CD4 + ), CD8 + T cells, macrophages, and natural killer cells. Combination therapy of CFI-400945 with anti-programmed death-1 showed a tendency to improve HCC survival. CONCLUSIONS: We show that by targeting a centrosome regulator, PLK4, to activate the cytosolic DNA sensing-mediated immune response, CFI-400945 effectively restrained tumor progression through cell cycle inhibition and inducing antitumor immunity to achieve a durable suppressive effect even in late-stage mouse HCC.

The effect of increasing emergency department observation volumes on downstream admission rates.

Rising length of stay and inpatient boarding in emergency departments have directly affected patient satisfaction and nearly all provider-to-patient care metrics. Prior studies suggest that ED observation has significant clinical and financial benefits including decreasing hospitalization and length of stay. ED observation is one method long employed to shorten ED length of stay and to free up inpatient beds, yet many patients continue to be admitted to the hospital with an average hospital length of stay of only one day. The objectives of this study were to evaluate whether vigorous tracking and provider reviews of one day hospital admits affected the utilization of ED observation and whether this correlated with significant change in rates of admission from observation status. Between September 2020 and May 2021, in a tertiary care hospital with an annual ED volume of 55,0000, chart reviews of 24-h inpatient discharges were initiated by two senior EM faculty to determine perceived suitability for ED observation. Non-punitive email reviews were then initiated with ED attending providers in order to encourage evaluation of whether these patients would have benefitted from being placed into observation. We then analyzed ED observation patient volumes and subsequent admission rates to the hospital from ED observation and compared these numbers to baseline ED observation volume and admission rates between September 2018 and May 2019. A total of 1448 reviews were conducted on 24-h discharges which correlated with an increase in utilization of ED observation from 11.77% (95% CI [11.62, 12.31]) of total ED volume in our control period to 14.21% (95% CI [13.84, 14.58]) during the study period. We found that the overall admission rate from ED observation increased from 20.12% (95% CI [18.97, 21.26]) baseline to 23.80% (95% CI [22.60, 25.00]) during the same time periods. Our data suggest that increasing the total number of patients placed into observation by 21% correlated with a relative increase in admission rates from ED observation by 18%. This would suggest that our efforts to potentially include more patients into our observation program led to a significant increase in subsequent admission rates. There is likely a balance that must be struck between under- and over-utilization of ED observation, and expanding ED observation may be an effective solution to hospital boarding and ED overcrowding.

Operational outcomes of community-to-academic emergency department patient transfers.

BACKGROUND: Many patients require inter-hospital transfer (IHT) to tertiary Emergency Departments (EDs) to access specialty services. The purpose of this study is to determine operational outcomes for patients undergoing IHT to a tertiary academic ED, with an emphasis on timing and specialty consult utilization. METHODS: This study was a retrospective observational cohort study at a tertiary academic hospital from 10/1/21-9/30/22. Key operational metrics, including specialty consultations, were queried from the ED Information System (EDIS). Data were analyzed for temporal variation in operational metrics and consulting patterns between transferred and non-transferred patients, stratified by time of day and week. RESULTS: During the study period there were 50,589 ED patient encounters, of which 3196 (6.3 %) were identified as IHTs. Transferred patients made up a larger proportion of patient arrivals in off-hours compared to daytime hours (p < 0.001). Transferred patients were more likely to be admitted to the hospital (76 % vs 35 %, p < 0.001), go directly to a procedure (6 % vs 2 %, p < 0.001), or receive a specialty consult (90 % vs 42 %, p < 0.001), regardless of the day of week or time of day. Relative risk of consults amongst transferred patients varied by service, though was particularly increased amongst surgical sub-specialties. CONCLUSIONS: Transferred patients represented a larger proportion of ED volume during evening and overnight hours, received more consults, and had higher likelihood of admission. Consults for transfers were disproportionately surgical subspecialties, though few patients went directly to a procedure. These findings may have operational implications in optimizing availability of specialty services across regionalized health systems.

Practice as you Teach: Comparing Ordering Practices Between Shared and Physician-Only Visits in Academically Affiliated Community Emergency Departments.

BACKGROUND: Considerable variability exists in emergency physicians' (EPs) rates of resource utilization, which may cluster in distinct patterns. However, previous studies have focused on academic and tertiary care centers, and it is unclear whether similar patterns exist in community practice. OBJECTIVE: Our aim was to examine whether EPs practicing in community emergency departments (EDs) have practice patterns similar to those of academic EDs. Secondarily, we sought to investigate the effects of shared visits with advanced practice professionals and residents. METHODS: This was a retrospective study of two community EDs affiliated with an academic network. There were 62,860 visits among 50 EPs analyzed from October 1, 2018 through January 31, 2020 for rates of advanced imaging, admission, and shared visits. To classify practice patterns, we used a Gaussian Mixture Model (GMM), with groups and covariance determined by Bayesian Information Criteria. RESULTS: Our GMM revealed three groups. The largest had homogeneous patterns of resource use (n = 28; 50% were female; years of experience: 7; interquartile range [IQR] 2-11; advanced imaging: 28%; admission: 19%; shared: 34%), a small group with lower resource use (n = 4; 0% were female; years of experience: 6; IQR 4-10; advanced imaging: 28%; admission: 16%; shared: 8%), and a modest high-resource group (n = 18; 28% female; years of experience: 5; IQR 2-16; advanced imaging: 34%; admission: 23%; shared: 43%). Rates of shared visits had little direct correlation with imaging (r2 = 0.045) or admission (r2 = 0.093), and rates of imaging and admission were weakly correlated (r2 = 0.242). CONCLUSIONS: Our data suggest that community EPs may have multiple patterns of resource use, similar to those in academic EDs.

Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses.

BACKGROUND & AIMS: Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are the only two classes of FDA-approved drugs for individuals with advanced hepatocellular carcinoma (HCC). While TKIs confer only modest survival benefits, ICIs have been associated with remarkable outcomes but only in the minority of patients who respond. Understanding the mechanisms that determine the efficacy of ICIs in HCC will help to stratify patients likely to respond to ICIs. This study aims to elucidate how genetic composition and specific oncogenic pathways regulate the immune composition of HCC, which directly affects response to ICIs. METHODS: A collection of mouse HCCs with genotypes that closely simulate the genetic composition found in human HCCs were established using genome-editing approaches involving the delivery of transposon and CRISPR-Cas9 systems by hydrodynamic tail vein injection. Mouse HCC tumors were analyzed by RNA-sequencing while tumor-infiltrating T cells were analyzed by flow cytometry and single-cell RNA-sequencing. RESULTS: Based on the CD8+ T cell-infiltration level, we characterized tumors with different genotypes into cold and hot tumors. Anti-PD-1 treatment had no effect in cold tumors but was greatly effective in hot tumors. As proof-of-concept, a cold tumor (Trp53KO/MYCOE) and a hot tumor (Keap1KO/MYCOE) were further characterized. Tumor-infiltrating CD8+ T cells from Keap1KO/MYCOE HCCs expressed higher levels of proinflammatory chemokines and exhibited enrichment of a progenitor exhausted CD8+ T-cell phenotype compared to those in Trp53KO/MYCOE HCCs. The TKI sorafenib sensitized Trp53KO/MYCOE HCCs to anti-PD-1 treatment. CONCLUSION: Single anti-PD-1 treatment appears to be effective in HCCs with genetic mutations driving hot tumors, while combined anti-PD-1 and sorafenib treatment may be more appropriate in HCCs with genetic mutations driving cold tumors. IMPACT AND IMPLICATIONS: Genetic alterations of different driver genes in mouse liver cancers are associated with tumor-infiltrating CD8+ T cells and anti-PD-1 response. Mouse HCCs with different genetic compositions can be grouped into hot and cold tumors based on the level of tumor-infiltrating CD8+ T cells. This study provides proof-of-concept evidence to show that hot tumors are responsive to anti-PD-1 treatment while cold tumors are more suitable for combined treatment with anti-PD-1 and sorafenib. Our study might help to guide the design of patient stratification systems for single or combined treatments involving anti-PD-1.

The association between day of arrival, time of arrival, daily volume and the rate of patients that "left without being seen".

INTRODUCTION: Patients' left without being seen (LWBS) rate is used as an emergency department (ED) quality indicator. Prior research has investigated characteristics of these patients, but there are minimal studies assessing the impact of departmental variables. We evaluate the LWBS rate at a granular level, looking at its relationship to day of week, hour of arrival and total patient volume. METHODS: Retrospective cohort analysis of 109,983 cases from a single academic center. We captured patient disposition, day of week and hour of day of arrival, and total daily volume. Chi-squared test was performed to determine the difference in LWBS rates based on arrival variables. We ran a polynomial regression for LWBS rates by decile of daily patient volume. RESULTS: The overall LWBS rate was 1.82% over 2 years. This varied significantly by day of week and hour of day (p < 0.001). Day of week rates ranged from 0.73% on Sunday to 2.45% on Wednesday. Hour of day rates ranged from 0.26% between 8 AM-9 AM, to 3.71% between 10 PM-11 PM. As total daily patient volume increased, LWBS rates gradually increased until the 70th percentile, followed by significant exponential growth afterwards. DISCUSSION: LWBS rates are not static measurements, and vary greatly depending on ED circumstances. Weekdays and evenings have significantly higher rates. Additionally, LWBS rates climb above 2% as daily registrations reach the 70th percentile, increasing exponentially at each subsequent decile. Understanding these effects will allow for more effective, targeted interventions to minimize this rate and improve throughput.

Defining Key Features in Patient Perspectives of Hand Aesthetics.

BACKGROUND: The hand is highly visible and contributes to an individual's aesthetic image and perceived age. Current perspectives on hand aesthetics are primarily based on expert opinion rather than on lay population perspectives, which are less understood. Our study explores general population perceptions on the features that contribute most to an attractive hand. METHODS: Participants rated the attractiveness of 20 standardized hands as well as the appearance based on each characteristic: freckles, hair presence, skin tone, wrinkles, vein appearance, and soft tissue volume. The relative importance of each feature was assessed by comparison with overall attractiveness scores through multivariate analysis of variance. RESULTS: A total of 223 participants completed the survey. Soft tissue volume ( r = 0.73) was most strongly correlated with overall attractiveness, followed by wrinkles ( r = 0.71), skin tone consistency ( r = 0.69), veins ( r = 0.65), freckles ( r = 0.61), and hair ( r = 0.47). Female hands were perceived as more attractive, with a mean rating of 4.7 of 10, compared with 4.4 in males ( P < 0.001). Participants correctly identified the gender of 90.4% of male hands and 65.0% of female hands. Age was strongly inversely correlated with attractiveness ( r = -0.80). CONCLUSIONS: Soft tissue volume is the most important factor in lay perception of hand aesthetics. Female and younger hands were perceived as more attractive. Hand rejuvenation may be optimized by prioritizing soft tissue volume with filler or fat grafting, with secondary priority on resurfacing to address skin tone and wrinkling. An understanding of the factors most important to patients in aesthetic appearance is critical to achieving a pleasing result.

Adaptive and Constitutive Activations of Malic Enzymes Confer Liver Cancer Multilayered Protection Against Reactive Oxygen Species.

BACKGROUND AND AIMS: HCC undergoes active metabolic reprogramming. Reactive oxygen species (ROS) are excessively generated in cancer cells and are neutralized by NADPH. Malic enzymes (MEs) are the less studied NADPH producers in cancer. APPROACH AND RESULTS: We found that ME1, but not ME3, was regulated by the typical oxidative stress response pathway mediated by kelch-like ECH associated protein 1/nuclear factor erythroid 2-related factor (NRF2). Surprisingly, ME3 was constitutively induced by superenhancers. Disruption of any ME regulatory pathways decelerated HCC progression and sensitized HCC to sorafenib. Therapeutically, simultaneous blockade of NRF2 and a superenhancer complex completely impeded HCC growth. We show that superenhancers allow cancer cells to counteract the intrinsically high level of ROS through constitutively activating ME3 expression. When HCC cells encounter further episodes of ROS insult, NRF2 allows cancer cells to adapt by transcriptionally activating ME1. CONCLUSIONS: Our study reveals the complementary regulatory mechanisms which control MEs and provide cancer cells multiple layers of defense against oxidative stress. Targeting both regulatory mechanisms represents a potential therapeutic approach for HCC treatment.

Long-Term Disability Outcomes for Patients With Ischemic Stroke Presenting With Visual Deficits.

BACKGROUND: Ischemic strokes in both the anterior and posterior circulation can lead to visual deficits, which can affect functional ability. Thrombolytic therapies are often withheld to patients with visual deficits because of either being missed on initial evaluation or because of the misconception that their deficits are not as severe or as disabling. Alternatively, delays in patient arrival for emergent evaluation lead to missed opportunities for acute stroke treatment. This retrospective study aims to explore the differences in perceived long-term disability for patients with stroke who present with visual deficits vs those who do not as a manifestation of their acute stroke syndrome. In addition, we explore the differences in treatment effect with thrombolytics and further analyze if the region of ischemia causing the deficit leads to differences in disability outcomes. METHODS: We conducted a retrospective analysis of patients with visual deficits as evidenced by an abnormal score on NIHSS categories related to vision (gaze palsy, visual fields, or extinction/inattention). Patients with Acute Ischemic Stroke were reviewed from the Houston Methodist Hospital Outcomes-based Prospective Endpoints in Stroke (HOPES) Registry from 2016-2021 for visual deficits. In total, 155 patient charts with visual deficits and 155 patient charts without a documented visual deficit were reviewed for ischemic stroke location (anterior vs posterior circulation), NIHSS scores, and thrombolytic therapies. The outcome variable was categorized using mRS, as mRS between 0 and 3 while mRS 4 to 6 was considered as poor functional outcome at 90 days. The independent variable was the vision group. A multivariable logistic regression model was constructed adjusting for demographics and comorbidities on the binary outcome. RESULTS: Multivariable logistic model after adjusting for demographics and comorbidities showed that patients with acute ischemic stroke with vision defects were 4 times more likely to have poor functional outcomes at 90 days, with most of these patients (14% vs 6%; P < 0.05) suffering from severe disability compared with patients in the control group (i.e., patients with acute ischemic stroke without vision defects) (OR = 4.05; 95% CI [2.28-7.19]; P < 0.001). The application of thrombolytics and the location of ischemia (ACS vs PCS) did not result in a significant change in disability outcomes in patients with visual defects in this limited sample size. CONCLUSIONS: The results of this study indicated that a large population of patients with ischemic stroke experience visual deficits and are, therefore, at an increased likelihood of worse functional outcome. This reveals the necessity for rehabilitation techniques that specifically target visual deficits to speed up the recovery process of these patients. Further studies with larger sample size are needed to assess whether the location of ischemic event and the application of thrombolytic treatments plays a role in the disability outcomes of these patients.

Not All Testers are Admitters: An Analysis of Emergency Physician Resource Utilization and Consultation Rates.

BACKGROUND: Variability exists in emergency physician (EP) resource utilization as measured by ordering practices, rate of consultation, and propensity to admit patients. OBJECTIVE: To validate and expand upon previous data showing that resource utilization as measured by EP ordering patterns is positively correlated with admission rates. METHODS: This is a retrospective study of routinely gathered operational data from the ED of an urban academic tertiary care hospital. We collected individual EP data on advanced imaging, consultation, and admission rates per patient encounter. To investigate whether there might be distinct groups of practice patterns relating these 3 resources, we used a Gaussian mixture model, a classification method used to determine the likelihood of distinct subgroups within a larger population. RESULTS: Our Gaussian mixture model revealed 3 distinct groups of EPs based on their ordering practices. The largest group is characterized by a homogenous pattern of neither high or low resource utilization (n = 37, 27% female, median years' experience: 6 [interquartile ratio {IQR} 3-18]; rates of advanced imaging, 38.9%; consultation, 45.1%; and admission 39.3%), with a modest group of low-resource users (n = 15, 60% female, median years' experience: 6 [IQR 5-14]; rates of advanced imaging, 37%; consultation, 42.6%; and admission 37.3%), and far fewer members of a high-resource use group (n = 6, 0% female, median years' experience: 6 [IQR 4-16]; rates of advanced imaging, 42.2%; consultation, 45.8%; and admission 40.6%). This variation suggests that not "all testers are admitters," but that there exist wider practice variations among EPs. CONCLUSIONS: At our academic tertiary center, 3 distinct subgroups of EP ordering practices exist based on consultation rates, advanced imaging use, and propensity to admit a patient. These data validate previous work showing that resource utilization and admission rates are related, while demonstrating that more nuanced patterns of EP ordering practices exist. Further investigation is needed to understand the impact of EP characteristics and behavior on throughput and quality of care. © 2022 Elsevier Inc.

Hepatocellular Carcinoma Cells Up-regulate PVRL1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice.

BACKGROUND & AIMS: Immune checkpoint inhibitors are effective in the treatment of some hepatocellular carcinomas (HCCs), but these tumors do not always respond to inhibitors of programmed cell death 1 (PDCD1, also called PD1). We investigated mechanisms of resistance of liver tumors in mice to infiltrating T cells. METHODS: Mice were given hydrodynamic tail vein injections of clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-Cas9) and transposon vectors to disrupt Trp53 and overexpress C-Myc (Trp53KO/C-MycOE mice). Pvrl1 and Pvrl3 were knocked down in Hepa1-6 cells by using short hairpin RNAs. Hepa1-6 cells were injected into livers of C57BL/6 mice; some mice were given intraperitoneal injections of antibodies against PD1, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), or CD8 before the cancer cells were injected. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and quantitative real-time polymerase chain reaction; tumors were analyzed by mass cytometry using markers to detect T cells and other lymphocytes. We obtained HCC and nontumorous liver tissues and clinical data from patients who underwent surgery in Hong Kong and analyzed the tissues by immunohistochemistry. RESULTS: Trp53KO/C-MycOE mice developed liver tumors in 3-5 weeks; injections of anti-PD1 did not slow tumor development. Tumors from mice given anti-PD1 had larger numbers of memory CD8+ T cells (CD44+CD62L-KLRG1int) and T cells that expressed PD1, lymphocyte activating 3 (LAG3), and TIGIT compared with mice not given the antibody. HCC tissues from patients had higher levels of PVRL1 messenger RNA and protein than nontumorous tissues. Increased PVRL1 was associated with shorter times of disease-free survival. Knockdown of Pvrl1 in Hepa1-6 cells caused them to form smaller tumors in mice, infiltrated by higher numbers of CD8+ T cells that expressed the inhibitory protein TIGIT; these effects were not observed in mice with depletion of CD8+ T cells. In Hepa1-6 cells, PVRL1 stabilized cell surface PVR, which interacted with TIGIT on CD8+ T cells; knockdown of Pvrl1 reduced cell-surface levels of PVR but not levels of Pvr messenger RNA. In Trp53KO/C-MycOE mice and mice with tumors grown from Hepa1-6 cells, injection of the combination of anti-PD1 and anti-TIGIT significantly reduced tumor growth, increased the ratio of cytotoxic to regulatory T cells in tumors, and prolonged survival. CONCLUSIONS: PVRL1, which is up-regulated by HCC cells, stabilizes cell surface PVR, which interacts with TIGIT, an inhibitory molecule on CD8+ effector memory T cells. This suppresses the ant-tumor immune response. Inhibitors of PVRL1/TIGIT, along with anti-PD1 might be developed for treatment of HCC.

From metrics to practice: identifying preventable emergency department visits for patients with cancer.

BACKGROUND: Oncology patients disproportionately utilize the emergency department (ED) for symptom management. At our institution, approximately 1 in 4 visits to the ED by oncology patients led to discharge. We hypothesized that many of the visits leading to ED discharge would be potentially preventable (PP). METHODS: We retrospectively characterized ED discharges of oncology patients. Visits were classified by presenting symptom, type of cancer, and time of ED visit. Chart reviewers were additionally asked whether each case could have been safely managed as an outpatient. RESULTS: We analyzed 100 ED discharges in a 4-month period in 2016 and 2017. Gastrointestinal (GI) complaints, pain, and fever were the most common presenting symptoms for these visits. We rated 44 of 100 ED discharges as potentially preventable. Given we analyzed only ED discharges which comprise about 25% of ED visits for patients with cancer, overall about 10% of all ED visits by these patients may be preventable. We also found that ED visits without a clinic appointment or phone call to the clinic on the day of ED presentation were more likely to be preventable (51% vs 27%, OR 2.9, p = 0.026). CONCLUSIONS: Many ED visits by oncology patients may be preventable and occur for symptoms which can be managed as an outpatient. More of these visits also appear to occur in those who do not reach a clinic member prior to the visit. These findings suggest that improved access to clinics and standardized outpatient symptom management are next steps to consider in preventing ED visits in this vulnerable population.

Analysis of time-to-disposition intervals during early and late parts of an emergency department shift.

INTRODUCTION: Time-to-disposition is an important metric for emergency department throughput. We hypothesized that providers view the shift end as a key timepoint and attempt to leave as few dispositions as possible to the oncoming team, thereby making quicker decisions later in the shift. This study evaluates disposition distribution relative to when patients are assigned a provider during the course of a shift. METHODS: 50,802 cases were analyzed over the one-year study interval. 31,869 patients were seen in the early half of a shift (hours 1-4) and 18,933 were seen in the later half (hours 5+). We ran a linear mixed model that adjusted for age, gender, emergency severity index score, time of day, weekend arrivals, quarter of arrival and shift type. RESULTS: Median time-to-disposition for the early group was 3.25 h (IQR 1.90-5.04), and 2.62 h (IQR 1.51-4.31) for the late group. From our mixed model, we conclude that in the later parts of the shift, providers take on average 15.1% less time to make a disposition decision than in the earlier parts of the shift. CONCLUSION: Patients seen during the latter half of a shift were more likely to have a shorter time-to-disposition than similar patients seen in the first half of a shift. This may be influenced by many factors, such as providers spending the early hours of a shift seeing new patients which generate new tasks and delay dispositions, and viewing the end of shift as a landmark with a goal to maximize dispositions prior to sign-out.

Estimating maximum patient throughput at an ED scanner: Is three patients per hour the magic number?

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Early, awake proning in emergency department patients with COVID-19.

OBJECTIVE: Proning has been shown to improve oxygenation and mortality in certain populations of intubated patients with acute respiratory distress syndrome. Small observational analyses of COVID-19 patients suggest awake proning may lead to clinical improvement. Data on safety and efficacy is lacking. We sought to describe the effect of proning on oxygenation in nonintubated COVID-19 patients. We also evaluated feasibility, safety, and other physiological and clinical outcomes associated with this intervention. METHODS: We conducted a prospective, observational cohort study of nonintubated patients with COVID-19 who underwent proning per an Emergency Department (ED) clinical protocol. Patients with mild to moderate respiratory distress were included. We calculated change in oxygenation by comparing the oxygen saturation to fraction of inspired oxygen ratio (SpO2:FiO2) during the five minutes prior to proning and first 30 min of proning. We also captured data on respiratory rate, duration of proning, need for intubation, intensive care unit admission, survival to discharge. RESULTS: Fifty-two patients were enrolled. Thirty were excluded for not meeting protocol inclusion criteria or missing baseline oxygenation data, leaving 22 for analysis. The SpO2:FiO2 ratio increased by a median of 5 (IQR: 0-15) in the post-proning period compared to the pre-proning period (median: 298 (IQR: 263-352) vs 295 (IQR: 276-350), p = 0.01). Respiratory rate did not change significantly between time periods. No immediate adverse events occurred during proning. Five patients (23%) were intubated within 48 h of admission. CONCLUSION: Early, awake proning may be feasible in select COVID-19 patients and was associated with improved oxygenation.

Understanding Demand and Capacity Mismatch in an Academic Emergency Department Using a Staircase Model of Provider Capacity and Staggered Shift Start Times.

BACKGROUND: Staffing and provider capacity are essential components of emergency department (ED) throughput. Patient flow is dependent on matching patient arrivals with provider capacity. Current models assume a static rate of patients per hour for providers; however, this metric has been shown to decrease throughout a shift in a pattern we describe as a staircase. OBJECTIVE: We sought to analyze the demand capacity mismatch based on both a static and staircase model of resident productivity. We then suggest a new staggered staffing model that would improve flow in the ED. METHODS: This was a retrospective analysis of patient demand and productivity, analyzing both static and staircase models of provider capacity. An alternative staggered shift model was then suggested, and a 2-sample t test was performed to assess if a new model reduces the amount of demand/capacity mismatch. RESULTS: Seventeen thousand five hundred twenty data points were analyzed over the 2-year interval, comparing the difference between actual patients placed into a treatment space at each hour and projected resident capacity based on the staircase model, using both the existing schedule and a new staggered schedule. Mean absolute values for the disparity in coverage was 2.69 (95% confidence interval 2.65-2.72) for the staircase scheduling model, and 2.14 (95% confidence interval 2.12-2.17) when staggering provider start times. The mean difference between these data sets was 0.54 (95% confidence interval 0.52-0.57; p < 0.0001). CONCLUSIONS: Academic EDs may find value in using a staircase model to analyze provider capacity because it is more reflective of actual capacity. EDs may benefit from visualizing their capacity curves to identify mismatches and staggering resident shifts to improve throughput and flow.