Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced ...dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory “cytokine-storm”, a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
Display omitted
•Pro-inflammatory factors drive systolic and diastolic cardiac dysfunction•BRD4 activation drives diastolic dysfunction and is blocked by clinically relevant drugs•BET inhibition decreases ACE2 expression and decreases SARS-CoV2 infection
COVID-19 causes cardiac injury, although mechanisms and effective therapeutics are lacking. In this study, Mills et al., show that cytokines elevated in COVID-19 patients drive cardiac dysfunction. These responses are mapped using phosphoproteomics and single nuclei RNA sequencing, enabling a targeted drug screen to identify therapeutics for rapid repurposing. BET inhibitors were identified as leading candidates to block cardiac dysfunction and decrease SARS-CoV-2 cardiac infection.
Purpose
Many patients with cancer seek care for pain in the emergency department (ED). Prospective research on cancer pain in this setting has historically been insufficient. We conducted this study ...to describe the reported pain among cancer patients presenting to the ED, how pain is managed, and how pain may be associated with clinical outcomes.
Methods
We conducted a multicenter cohort study on adult patients with active cancer presenting to 18 EDs in the USA. We reported pain scores, response to medication, and analgesic utilization. We estimated the associations between pain severity, medication utilization, and the following outcomes: 30-day mortality, 30-day hospital readmission, and ED disposition.
Results
The study population included 1075 participants. Those who received an opioid in the ED were more likely to be admitted to the hospital and were more likely to be readmitted within 30 days (OR 1.4 (95% CI: 1.11, 1.88) and OR 1.56 (95% CI: 1.17, 2.07)), respectively. Severe pain at ED presentation was associated with increased 30-day mortality (OR 2.30, 95% CI: 1.05, 5.02), though this risk was attenuated when adjusting for clinical factors (most notably functional status).
Conclusions
Patients with severe pain had a higher risk of mortality, which was attenuated when correcting for clinical characteristics. Those patients who required opioid analgesics in the ED were more likely to require admission and were more at risk of 30-day hospital readmission. Future efforts should focus on these at-risk groups, who may benefit from additional services including palliative care, hospice, or home-health services.
Better understanding of the emergency care needs of patients with cancer will inform outpatient and emergency department (ED) management.
To provide a benchmark description of patients who present to ...the ED with active cancer.
This multicenter prospective cohort study included 18 EDs affiliated with the Comprehensive Oncologic Emergencies Research Network (CONCERN). Of 1564 eligible patients, 1075 adults with active cancer were included from February 1, 2016, through January 30, 2017. Data were analyzed from February 1 through August 1, 2018.
The proportion of patients reporting symptoms (eg, pain, nausea) before and during the ED visit, ED and outpatient medications, most common diagnoses, and suspected infection as indicated by ED antibiotic administration. The proportions observed, admitted, and with a hospital length of stay (LOS) of no more than 2 days were identified.
Of 1075 participants, mean (SD) age was 62 (14) years, and 51.8% were female. Seven hundred ninety-four participants (73.9%; 95% CI, 71.1%-76.5%) had undergone cancer treatment in the preceding 30 days; 674 (62.7%; 95% CI, 59.7%-65.6%) had advanced or metastatic cancer; and 505 (47.0%; 95% CI, 43.9%-50.0%) were 65 years or older. The 5 most common ED diagnoses were symptom related. Of all participants, 82 (7.6%; 95% CI, 6.1%-9.4%) were placed in observation and 615 (57.2%; 95% CI, 54.2%-60.2%) were admitted; 154 of 615 admissions (25.0%; 95% CI, 21.7%-28.7%) had an LOS of 2 days or less (median, 3 days; interquartile range, 2-6 days). Pain during the ED visit was present in 668 patients (62.1%; 95% CI, 59.2%-65.0%; mean SD pain score, 6.4 2.6 of 10.0) and in 776 (72.2%) during the prior week. Opioids were administered in the ED to 228 of 386 patients (59.1%; 95% CI, 18.8%-23.8%) with moderate to severe ED pain. Outpatient opioids were prescribed to 368 patients (47.4%; 95% CI, 3.14%-37.2%) of those with pre-ED pain, including 244 of 428 (57.0%; 95% CI, 52.2%-61.8%) who reported quite a bit or very much pain. Nausea in the ED was present in 336 (31.3%; 95% CI, 28.5%-34.1%); of these, 160 (47.6%; 95% CI, 12.8%-17.1%) received antiemetics in the ED. Antibiotics were administered in the ED to 285 patients (26.5%; 95% CI, 23.9%-29.2%). Of these, 209 patients (73.3%; 95% CI, 17.1%-21.9%) were admitted compared with 427 of 790 (54.1%; 95% CI, 50.5%-57.6%) not receiving antibiotics.
This initial prospective, multicenter study profiling patients with cancer who were treated in the ED identifies common characteristics in this patient population and suggests opportunities to optimize care before, during, and after the ED visit. Improvement requires collaboration between specialists and emergency physicians optimizing ED use, improving symptom control, avoiding unnecessary hospitalizations, and appropriately stratifying risk to ensure safe ED treatment and disposition of patients with cancer.
To verify the genome annotation and to create a resource to functionally characterize the proteome, we attempted to Gateway-clone all predicted protein-encoding open reading frames (ORFs), or the ...'ORFeome,' of Caenorhabditis elegans. We successfully cloned approximately 12,000 ORFs (ORFeome 1.1), of which roughly 4,000 correspond to genes that are untouched by any cDNA or expressed-sequence tag (EST). More than 50% of predicted genes needed corrections in their intron-exon structures. Notably, approximately 11,000 C. elegans proteins can now be expressed under many conditions and characterized using various high-throughput strategies, including large-scale interactome mapping. We suggest that similar ORFeome projects will be valuable for other organisms, including humans.
Older adults with cancer use the emergency department (ED) for acute concerns.
Characterize the palliative care needs and clinical outcomes of advanced cancer patients in the ED.
A planned secondary ...data analysis of the Comprehensive Oncologic Emergencies Research Network (CONCERN) data.
Cancer patients who presented to the 18 CONCERN affiliated EDs in the United States.
Survey included demographics, cancer type, functional status, symptom burden, palliative and hospice care enrollment, and advance directive code status.
Of the total (674/1075, 62.3%) patients had advanced cancer and most were White (78.6%) and female (50.3%); median age was 64 (interquartile range 54-71) years. A small proportion of them were receiving palliative (6.5% 95% confidence interval; CI 3.0-7.6;
= 0.005) and hospice (1.3% 95% CI 1.0-3.2;
= 0.52) care and had a higher 30-day mortality rate (8.3%, 95% CI 6.2-10.4).
Patients with advanced cancer continue to present to the ED despite recommendations for early delivery of palliative care.
Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, ...whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.
Purpose
Emergency department (ED) visits by patients with cancer frequently end in hospitalization. As concerns about ED and hospital crowding increase, observation unit care may be an important ...strategy to deliver safe and efficient treatment for eligible patients. In this investigation, we compared the prevalence and clinical characteristics of cancer patients who received observation unit care with those who were admitted to the hospital from the ED.
Methods
We performed a multicenter prospective cohort study of patients with cancer presenting to an ED affiliated with one of 18 hospitals of the Comprehensive Oncologic Emergency Research Network (CONCERN) between March 1, 2016 and January 30, 2017. We compared patient characteristics with the prevalence of observation unit care usage, hospital admission, and length of stay.
Results
Of 1051 enrolled patients, 596 (56.7%) were admitted as inpatients, and 72 (6.9%) were placed in an observation unit. For patients admitted as inpatients, 23.7% had a length of stay ≤2 days. The conversion rate from observation to inpatient was 17.1% (95% CI 14.6–19.4) among those receiving care in an observation unit. The average observation unit length of stay was 14.7 h. Patient factors associated ED disposition to observation unit care were female gender and low Charlson Comorbidity Index.
Conclusion
In this multicenter prospective cohort study, the discrepancy between observation unit care use and short inpatient hospitalization may represent underutilization of this resource and a target for process change.
PDF
