Cell-programmed nutrient partitioning in the tumour microenvironment.

Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.

Should Transport Ventilators Be Used in Times of Crisis? The Use of Emergency Authorized Nonconventional Ventilators Is Associated With Mortality Among Patients With COVID-19 Acute Respiratory Distress Syndrome.

OBJECTIVES: Nonconventional ventilators (NCVs), defined here as transport ventilators and certain noninvasive positive pressure devices, were used extensively as crisis-time ventilators for intubated patients with COVID-19. We assessed whether there was an association between the use of NCV and higher mortality, independent of other factors. DESIGN: This is a multicenter retrospective observational study. SETTING: The sample was recruited from a single healthcare system in New York. The recruitment period spanned from March 1, 2020, to April 30, 2020. PATIENTS: The sample includes patients who were intubated for COVID-19 acute respiratory distress syndrome (ARDS). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day in-hospital mortality. Multivariable logistic regression was used to derive the odds of mortality among patients managed exclusively with NCV throughout their ventilation period compared with the remainder of the sample while adjusting for other factors. A secondary analysis was also done, in which the mortality of a subset of the sample exclusively ventilated with NCV was compared with that of a propensity score-matched subset of the control group. Exclusive use of NCV was associated with a higher 28-day in-hospital mortality while adjusting for confounders in the regression analysis (odds ratio, 1.41; 95% CI [1.07-1.86]). In the propensity score matching analysis, the mortality of patients exclusively ventilated with NCV was 68.9%, and that of the control was 60.7% ( p = 0.02). CONCLUSIONS: Use of NCV was associated with increased mortality among patients with COVID-19 ARDS. More lives may be saved during future ventilator shortages if more full-feature ICU ventilators, rather than NCVs, are reserved in national and local stockpiles.

Genome-scale CRISPR screening reveals that C3aR signaling is critical for rapid capture of fungi by macrophages.

The fungal pathogen Histoplasma capsulatum (Hc) invades, replicates within, and destroys macrophages. To interrogate the molecular mechanisms underlying this interaction, we conducted a host-directed CRISPR-Cas9 screen and identified 361 genes that modify macrophage susceptibility to Hc infection, greatly expanding our understanding of host gene networks targeted by Hc. We identified pathways that have not been previously implicated in Hc interaction with macrophages, including the ragulator complex (involved in nutrient stress sensing), glycosylation enzymes, protein degradation machinery, mitochondrial respiration genes, solute transporters, and the ER membrane complex (EMC). The highest scoring protective hits included the complement C3a receptor (C3aR), a G-protein coupled receptor (GPCR) that recognizes the complement fragment C3a. Although it is known that complement components react with the fungal surface, leading to opsonization and release of small peptide fragments such as C3a, a role for C3aR in macrophage interactions with fungi has not been elucidated. We demonstrated that whereas C3aR is dispensable for macrophage phagocytosis of bacteria and latex beads, it is critical for optimal macrophage capture of pathogenic fungi, including Hc, the ubiquitous fungal pathogen Candida albicans, and the causative agent of Valley Fever Coccidioides posadasii. We showed that C3aR localizes to the early phagosome during Hc infection where it coordinates the formation of actin-rich membrane protrusions that promote Hc capture. We also showed that the EMC promotes surface expression of C3aR, likely explaining its identification in our screen. Taken together, our results provide new insight into host processes that affect Hc-macrophage interactions and uncover a novel and specific role for C3aR in macrophage recognition of fungi.

Right Ventricular "Bubble Time" to Identify Patients With Right Ventricular Dysfunction.

STUDY OBJECTIVE: We propose a novel method of evaluating right ventricular (RV) dysfunction in the emergency department (ED) using RV "bubble time"-the duration of time bubbles from a saline solution flush are visualized in the RV on echocardiography. The objective was to identify the optimal cutoff value for RV bubble time that differentiates patients with RV dysfunction and report on its diagnostic test characteristics. METHODS: This prospective diagnostic accuracy study enrolled a convenience sample of hemodynamically stable patients in the ED. A sonographer administered a 10-mL saline solution flush into the patient's intravenous catheter, performed a bedside echocardiogram, and measured RV bubble time. Subsequently, the patient underwent a comprehensive cardiologist-interpreted echocardiogram within 36 hours, which served as the gold standard. Patients with RV strain or enlargement of the latter found on an echocardiogram were considered to have RV dysfunction. Bubble time was evaluated by a second provider, blinded to the initial results, who reviewed the ultrasound clips. The primary outcome measure was the optimal cutoff value of RV bubble time that identifies patients with and without RV dysfunction. RESULTS: Of 196 patients, median age was 67 year, and half were women, with 69 (35.2%) having RV dysfunction. Median RV bubble time among patients with RV dysfunction was 62 seconds (interquartile range [IQR]: 52, 93) compared with 21 seconds (IQR: 12, 32) among patients without (P<.0001). The optimal cutoff value of RV bubble time for identifying patients with RV dysfunction was 40 or more seconds, with a sensitivity of 0.97 (95% CI 0.93 to 1.00) and specificity of 0.87 (95% CI 0.82 to 0.93). CONCLUSION: In patients in the ED, an RV bubble time of 40 or more seconds had high sensitivity in identifying patients with RV dysfunction, whereas an RV bubble time of less than 40 seconds had good specificity in identifying patients without RV dysfunction. These findings warrant further investigation in undifferentiated patient populations and by emergency physicians without advanced ultrasound training.

The proper connection between shelterin components is required for telomeric heterochromatin assembly.

Telomeric regions contain prominent sites of heterochromatin, which is associated with unique histone modification profiles such as the methylation of histone H3 at Lys9 (H3K9me). In fission yeast, the conserved telomeric shelterin complex recruits the histone H3K9 methyltransferase complex CLRC to establish subtelomeric heterochromatin. Although many shelterin mutations affect subtelomeric heterochromatin assembly, the mechanism remains elusive due to the diverse functions of shelterin. Through affinity purification, we found that shelterin directly associates with CLRC through the Ccq1 subunit. Surprisingly, mutations that disrupt interactions between shelterin subunits compromise subtelomeric heterochromatin without affecting CLRC interaction with shelterin component Pot1, located at chromosome ends. We further discovered that telomeric repeats are refractory to heterochromatin spreading and that artificial restoration of shelterin connections or increased heterochromatin spreading rescued heterochromatin defects in these shelterin mutants. Thus, subtelomeric heterochromatin assembly requires both the recruitment of CLRC by shelterin to chromosome ends and the proper connection of shelterin components, which allows CLRC to skip telomeric repeats to internal regions.

Hip effusions or iliopsoas hematomas on ultrasound in identifying hip fractures in the emergency department.

OBJECTIVE: We evaluated the sensitivity, specificity, predictive values, and likelihood ratios of hip effusion and/or iliopsoas hematoma on point-of-care ultrasound (POCUS) performed by ultrasound fellows and fellowship trained emergency providers to identify hip fractures in emergency department (ED) patients with a high suspicion of hip fracture. METHODS: This was a prospective observational study of a convenience sample of patients with high suspicion of hip fracture at two academic EDs between 2018 and 2021. Patients with negative x-rays who did not receive further imaging with magnetic resonance imaging (MRI) or computed tomography (CT) were excluded. Sonographers were blinded to clinical data and ED imaging results. At the primary site, 8 ultrasound fellows and 4 emergency ultrasound fellowship-trained emergency providers performed the ultrasonographic examinations. At the secondary site, 2 ultrasound fellows, 4 emergency ultrasound-fellowship trained physicians, and 1 sports medicine fellowship-trained emergency provider performed the ultrasonographic examinations. A positive ultrasound was defined as either the presence of a hip effusion or iliopsoas hematoma on the affected extremity. The primary outcome measures were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) of POCUS findings for identification of a hip fracture compared with a ranked composite reference standard consisting of x-ray, CT, or magnetic resonance imaging (MRI); the highest-level test performed for each patient was used for comparison. RESULTS: Among 213 patients analyzed, all 213 received an x-ray, 116 received a CT scan, and 14 received an MRI; 113/213 x-rays (53.1%), 35/116 CT scans (30.2%), and 7/14 MRIs (50.0%) were positive for a hip fracture. A total of 123 patients were diagnosed with a hip fracture (57.7%). There were 13 false negative x-ray results. Overall, compared with the reference standard of x-ray, CT, or MRI, POCUS had a sensitivity of 97% (95% CI: 94%, 100%), specificity of 70% (95% CI: 61%, 79%), PPV of 82% (95% CI: 75%, 88%), and NPV of 94% (95% CI: 88%, 100%) in the identification of hip fractures; with a positive likelihood ratio of 3.22 (95% CI: 2.35, 4.43) and negative likelihood ratio of 0.05 (95% CI: 0.02, 0.12). CONCLUSION: In a convenience sample of ED patients with high clinical suspicion for hip fracture, the presence of a hip effusion and/or iliopsoas hematoma on POCUS performed by expert emergency ultrasonographers showed high sensitivity in diagnosing patients with a hip fracture.

Pulmonary Congestion on Lung Ultrasound Predicts Increased Risk of 30-Day Readmission in Heart Failure Patients.

OBJECTIVES: Heart failure exacerbations are a common cause of hospitalizations with a high readmission rate. There are few validated predictors of readmission after treatment for acute decompensated heart failure (ADHF). Lung ultrasound (LUS) is sensitive and specific in the assessment of pulmonary congestion; however, it is not frequently utilized to assess for congestion before discharge. This study assessed the association between number of B-lines, on LUS, at patient discharge and risk of 30-day readmission in patients hospitalized for acute decompensated heart failure (ADHF). METHODS: This was a single-center prospective study of adults admitted to a quaternary care center with a diagnosis of ADHF. At the time of discharge, the patient received an 8-zone LUS exam to evaluate for the presence of B-lines. A zone was considered positive if ≥3 B-lines was present. We assessed the risk of 30-day readmission associated with the number of lung zones positive for B-lines using a log-binomial regression model. RESULTS: Based on data from 200 patients, the risk of 30-day readmission in patients with 2-3 positive lung zones was 1.25 times higher (95% CI: 1.08-1.45), and in patients with 4-8 positive lung zones was 1.50 times higher (95% CI: 1.23-1.82, compared with patients with 0-1 positive zones, after adjusting for discharge blood urea nitrogen, creatinine, and hemoglobin. CONCLUSION: Among patients admitted with ADHF, the presence of B-lines at discharge was associated with a significantly increased risk of 30-day readmission, with greater number of lung zones positive for B-lines corresponding to higher risk.

PET Oncological Radiopharmaceuticals: Current Status and Perspectives.

Molecular imaging is the visual representation of biological processes that take place at the cellular or molecular level in living organisms. To date, molecular imaging plays an important role in the transition from conventional medical practice to precision medicine. Among all imaging modalities, positron emission tomography (PET) has great advantages in sensitivity and the ability to obtain absolute imaging quantification after corrections for photon attenuation and scattering. Due to the ability to label a host of unique molecules of biological interest, including endogenous, naturally occurring substrates and drug-like compounds, the role of PET has been well established in the field of molecular imaging. In this article, we provide an overview of the recent advances in the development of PET radiopharmaceuticals and their clinical applications in oncology.

Changing resuscitation strategies during a pandemic: lessons from the consecutive surges in New York and global challenges.

PURPOSE OF REVIEW: To provide a framework for resuscitation of COVID-19 critical illness for emergency and intensive care clinicians with the most up to date evidence and recommendations in the care of COVID-19 patients in cardiac arrest or in extremis. RECENT FINDINGS: Performing cardiopulmonary resuscitation (CPR) on COVID-19 patients requires the clinicians to adopt infection mitigation strategies such as full personal protective equipment, mechanical chest compression devices, and restricting the number of people present during the resuscitation. The time of intubation is a subject of ongoing research and clinicians should use their best judgment for each patient. Clinicians should prepare for CPR in prone position. Particular attention should be given to the psychological well-being of the staff. Point of care ultrasound has proved to be an invaluable diagnostic tool in assessing ventricular dysfunction and parenchymal lung disease. Although novel therapies to supplant the function of diseased lungs have shown promise in select patients the evidence is still being collected. The end-of-life discussions have been negatively impacted by prognostic uncertainty as well as barriers to in person meetings with families. SUMMARY: The resuscitation of critically ill COVID-19 patients poses new challenges, but the principles remain largely unchanged.

A Prospective Evaluation of Point-of-Care Ultrasonographic Diagnosis of Diverticulitis in the Emergency Department.

STUDY OBJECTIVE: We evaluate the sensitivity and specificity of point-of-care ultrasonography, performed by ultrasonographic fellowship-trained emergency physicians and physician assistants, compared with computed tomography (CT) scan in diagnosing acute diverticulitis in the emergency department (ED). METHODS: This was a prospective observational study of a convenience sample of patients with suspected diverticulitis who were treated at an academic ED between 2017 and 2020. Sonographers were blinded to clinical data, laboratory results, and CT scan findings. A total of 19 ultrasonographic fellowship-trained emergency physicians and physician assistants performed the ultrasonographic examinations. Point-of-care ultrasonographic diagnosis of acute diverticulitis was defined as the presence of bowel wall thickening, greater than 5 mm, surrounding a diverticulum, enhancement of the surrounding pericolonic fat, and sonographic tenderness to palpation. The primary outcome measures were sensitivity, specificity, positive predictive value, and negative predictive value of point-of-care ultrasonography in the diagnosis of diverticulitis compared with CT, which was considered the criterion standard. RESULTS: Data from 452 patients were analyzed. Median age was 60 years, 54% were women, and 36% had a diagnosis of diverticulitis based on CT scan. Of the 452 patients, there were 13 false-positive (3%) and 10 false-negative (2%) point-of-care ultrasonographic examinations. Overall, compared with CT, point-of-care ultrasonography had a sensitivity of 92% (95% confidence interval 88% to 96%), specificity of 97% (95% confidence interval 94% to 99%), positive predictive value of 94% (95% confidence interval 90% to 97%), and negative predictive value of 96% (93% to 98%) in the diagnosis of diverticulitis. CONCLUSION: In a convenience sample of ED patients with suspected diverticulitis, point-of-care ultrasonography performed by ultrasonographic fellowship-trained emergency physicians and physician assistants could be used as an imaging modality for diagnosing acute diverticulitis, with high sensitivity and specificity compared with CT scan.

Use of Point-of-Care Ultrasound to Facilitate Guidance and Intrauterine Placement of a Foley Urinary Catheter to Tamponade Life-Threatening Postprocedure Hemorrhage Caused by Disseminated Intravascular Coagulation.

BACKGROUND: Severe vaginal hemorrhage caused by disseminated intravascular coagulation (DIC) after dilation and evacuation is a rare but life-threatening situation that can be difficult to manage. Obtaining hemostasis in such a patient with heavy vaginal bleeding secondary to DIC can be difficult. One technique involves the use of a urinary bladder catheter inserted into the uterus that is inflated to apply pressure on the endometrium, allowing for tamponade of the bleeding. CASE REPORT: A 36-year-old female gravida 2 para 0 at 21 weeks' gestation presented to the emergency department after being transferred from another facility for a higher level of care available at our facility, after a dilation and evacuation procedure that was indicated because of intrauterine fetal demise. The physical examination was significant for an ill-appearing female with active heavy vaginal bleeding. Resuscitation was initiated with packed red blood cells, cryoprecipitate, and platelets. Because of her thrombocytopenia, the development of DIC was suspected. Point-of-care ultrasound (POCUS) was performed and showed a thickened endometrial stripe with evidence of multiple anechoic foci, which were thought to represent intrauterine clots. To tamponade the bleeding, a 30-cc standard Foley urinary bladder catheter was placed into the uterus, using POCUS for guidance, to attempt to induce hemostasis via tamponade of the bleeding after inflation of the catheter balloon. Placement of an intrauterine urinary catheter to enable tamponade can be useful for the management of uncontrolled hemorrhage, but can be difficult to accomplish without use of POCUS for guidance. POCUS enabled us to accomplish accurate intrauterine placement of the urinary catheter and confirmation of a properly placed catheter balloon within the uterus. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Menorrhagia in the emergency department can be difficult to manage, especially in the setting of DIC. Placement of an intrauterine urinary catheter can be useful in management but may be difficult for the inexperienced provider. POCUS can be used to guide the catheter into place and confirm the location once the balloon is inflated.

Pyomyositis Diagnosed by Point-of-Care Ultrasound in the Emergency Department.

BACKGROUND: Currently, the role of ultrasound in diagnosing superficial abscesses is well validated, however, its role for deep space infections and intramuscular pathology is limited. Distinguishing between simple cellulitis and abscess is critical for emergency physicians (EP), as the treatment is very different. Management of cellulitis relies on antibiotic therapy, whereas abscess treatment requires incision and drainage. It is important that EPs can accurately distinguish between the two entities. CASE REPORT: We report a case of a 41-year-old man with a history of high blood pressure and poorly controlled diabetes who presented with right lateral thigh redness, warmth, and tenderness. A point-of-care ultrasound (POCUS) of the patient's right lateral thigh with a high-frequency linear (8 MHz) ultrasound probe showed a 2.93 × 3.38 × 6.0-cm complex fluid collection deep to the fascial plane, approximately 3.0 cm from the skin surface, that contained mixed echogenicities with posterior acoustic enhancement consistent with an intramuscular abscess of the vastus lateralis. The patient was diagnosed with pyomyositis of his vastus lateralis. He was started on vancomycin and admitted to the surgical service for antibiotic treatment and surgical drainage. WHY SHOULD EMERGENCY PHYSICIANS BE AWARE OF THIS?: This case demonstrates that the use of POCUS by EPs can facilitate the rapid recognition and treatment of a disease that is challenging to diagnose on physical examination and can be potentially life-threatening if missed. EPs can consider performing a POCUS when evaluating skin infections to ensure rapid diagnosis and appropriate medical care for a potentially severe condition.

Delta-Opioid Receptor (δOR) Targeted Near-Infrared Fluorescent Agent for Imaging of Lung Cancer: Synthesis and Evaluation In Vitro and In Vivo.

In the United States, lung cancer is the leading cause of cancer death and ranks second in the number of new cases annually among all types of cancers. Better methods or tools for diagnosing and treating this disease are needed to improve patient outcomes. The delta-opioid receptor (δOR) is reported to be overexpressed in lung cancers and not expressed in normal lung. Thus, we decided to develop a lung cancer-specific imaging agent targeting this receptor. We have previously developed a δOR-targeted fluorescent imaging agent based on a synthetic peptide antagonist (Dmt-Tic) conjugated to a Cy5 fluorescent dye. In this work, we describe the synthesis of Dmt-Tic conjugated to a longer wavelength near-infrared fluorescent (NIRF) dye, Li-cor IR800CW. Binding affinity of Dmt-Tic-IR800 for the δOR was studied using lanthanide time-resolved fluorescence (LTRF) competitive binding assays in cells engineered to overexpress the δOR. In addition, we identified lung cancer cell lines with high and low endogenous expression of the δOR. We confirmed protein expression in these cell lines using confocal fluorescence microscopy imaging and used this technique to estimate the cell-surface receptor number in the endogenously expressing lung cancer cell lines. The selectivity of Dmt-Tic-IR800 for imaging of the δOR in vivo was shown using both engineered cell lines and endogenously expressing lung cancer cells in subcutaneous xenograft models in mice. In conclusion, the δOR-specific fluorescent probe developed in this study displays excellent potential for imaging of lung cancer.

Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5.

Fluorescence molecular imaging can be employed for the development of novel cancer targeting agents. Herein, we investigated the pharmacokinetics (PK) and cellular uptake of Dmt-Tic-Cy5, a delta-opioid receptor (δOR) antagonist-fluorescent dye conjugate, as a tumor-targeting molecular imaging agent. δOR expression is observed normally in the CNS, and pathologically in some tumors, including lung liver and breast cancers. In vitro, in vivo, and ex vivo experiments were conducted to image and quantify the fluorescence signal associated with Dmt-Tic-Cy5 over time using in vitro and intravital fluorescence microscopy and small animal fluorescence imaging of tumor-bearing mice. We observed specific retention of Dmt-Tic-Cy5 in tumors with maximum uptake in δOR-expressing positive tumors at 3 h and observable persistence for >96 h; clearance from δOR nonexpressing negative tumors by 6 h; and systemic clearance from normal organs by 24 h. Live-cell and intravital fluorescence microscopy demonstrated that Dmt-Tic-Cy5 had sustained cell-surface binding lasting at least 24 h with gradual internalization over the initial 6 h following administration. Dmt-Tic-Cy5 is a δOR-targeted agent that exhibits long-lasting and specific signal in δOR-expressing tumors, is rapidly cleared from systemic circulation, and is not retained in non-δOR-expressing tissues. Hence, Dmt-Tic-Cy5 has potential as a fluorescent tumor imaging agent.

Chromosome boundary elements and regulation of heterochromatin spreading.

Chromatin is generally classified as euchromatin or heterochromatin, each with distinct histone modifications, compaction levels, and gene expression patterns. Although the proper formation of heterochromatin is essential for maintaining genome integrity and regulating gene expression, heterochromatin can also spread into neighboring regions in a sequence-independent manner, leading to the inactivation of genes. Because the distance of heterochromatin spreading is stochastic, the formation of boundaries, which block the spreading of heterochromatin, is critical for maintaining stable gene expression patterns. Here we review the current understanding of the mechanisms underlying heterochromatin spreading and boundary formation.

Return of the Living Dead Gut - A Case Report of Ischemic Colitis Identified on Point of Care Ultrasound.

Ischemic colitis is the most common form of gastrointestinal ischemia 1. The diagnosis of ischemic colitis is made by clinical data and computed tomography (CT) imaging of the abdomen and pelvis 1. While colonoscopy is considered the gold standard for diagnosis, this is not performed in the emergency department (ED) 2. Few studies have been performed to describe the sonographic findings of ischemic colitis using point of care ultrasound (POCUS). We report a case that highlights the sonographic findings of ischemic colitis in a patient who had two separate visits to the ED, showcasing the utility of POCUS in making this diagnosis. POCUS can be used as a diagnostic tool for early detection of ischemic colitis leading to prompt treatment with antibiotics, CT imaging, and surgical consultation.

A Case Report of a LVAD Driveline Infection Diagnosed by Point-of-care Ultrasound.

INTRODUCTION: As the prevalence of patients with left ventricular assist devices (LVAD) presenting to the emergency department (ED) increases, clinicians must be aware of LVAD-associated infections. CASE REPORT: A well-appearing, 41-year-old male with history of heart failure status post prior-LVAD placement presented to the ED for swelling of his chest. What appeared initially as a superficial infection was further assessed with point-of-care ultrasound and found to represent a chest wall abscess involving the driveline, ultimately resulting in sternal osteomyelitis and bacteremia. CONCLUSION: Point-of-care ultrasound should be considered an important tool in the initial assessment of potential LVAD-associated infection.

Doppler ultrasound peak systolic velocity versus end tidal carbon dioxide during pulse checks in cardiac arrest.

BACKGROUND: An accurate, non-invasive measure of return of spontaneous circulation (ROSC) is needed to improve management of cardiac arrest patients. OBJECTIVES: During a pulse check in Emergency Department (ED) cardiac arrest patients, we compared the correlation between 1) end tidal carbon dioxide (ETCO2) and systolic blood pressure (SBP), and 2) Doppler ultrasound peak systolic velocity (PSV) and SBP. Additionally, we assessed the accuracy of PSV ≥ 20 cm/sec in comparison to previously suggested ETCO2 ≥ 20 or ≥ 25 mmHg thresholds to predict ROSC with SBP ≥ 60 mmHg. METHODS: This was a secondary analysis of a previously published prospective observational study of ED cardiac arrest patients with an advanced airway and femoral arterial line in place. During each pulse check, highest SBP, highest PSV, and ETCO2 at the end of the pulse check were recorded. Spearman correlation coefficients were calculated and compared using a Fisher Z-transformation. Accuracy of previously determined PSV and ETCO2 thresholds for detecting ROSC with SBP ≥ 60 mmHg were compared using McNemar's tests. RESULTS: Based on data from 35 patients with 111 pulse checks, we found a higher correlation between PSV and SBP than ETCO2 and SBP (0.71 vs 0.31; p < 0.001). Diagnostic accuracy of PSV ≥ 20 cm/sec for detecting ROSC with SBP ≥ 60 mmHg was 89% (95% CI: 82%-94%) versus 59% (95% CI: 49%-68%) and 58% (95% CI: 48%-67%) for ETCO2 ≥ 20 and ≥ 25 mmHg, respectively. CONCLUSIONS: During a pulse check, Doppler ultrasound PSV outperformed ETCO2 for correlation with SBP and accuracy in detecting ROSC with SBP ≥ 60 mmHg.

Feasibility of [18F]FSPG PET for Early Response Assessment to Combined Blockade of EGFR and Glutamine Metabolism in Wild-Type KRAS Colorectal Cancer.

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX that responded to therapy, [18F]FSPG PET was significantly decreased from baseline at 1-week post-therapy, prior to changes in tumor volume. In contrast, [18F]FSPG PET was not decreased in non-responding PDX. These data suggest that [18F]FSPG PET may serve as an early metric of response to EGFR and glutaminase inhibition in the WT KRAS CRC setting.