Death In Patients Research Articles

Case-control study on risk factors for in-hospital mortality in patients with severe COVID-19.

The purpose of this study was to identify independent risk factors affecting patient survival and explore predictors of severe cases of coronavirus disease 2019 (COVID-19). We conducted a retrospective, observational, case-control study on adult patients with severe COVID-19 who were admitted to affiliated hospitals in Tianjin between December 18, 2022, and January 31, 2023. We used univariate and multifactorial logistic regression analyses to analyze demographic indicators, comorbidity profiles, and laboratory parameters in two groups of patients (deceased and surviving) to identify independent risk factors for death in patients with severe COVID-19. Patients in the deceased group were older than those in the survival group (p = 0.018), and there were more cases of coexisting respiratory insufficiency in the deceased group (p = 0.002). Additionally, laboratory test results for white blood cell count (WBC) and creatine kinase (CK) showed significantly higher values in the deceased group (p = 0.047 and p = 0.029, respectively), while arterial oxygen partial pressure (PAO2) showed significantly lower values compared to the survival group (p = 0.021). Age, respiratory insufficiency, WBCH (highest WBC value), CKH (highest CK value), and PAO2F (first PAO2 value) had area under curve (AUC) values of 0.698, 0.838, 0.721, 0.744, and 0.633, respectively. The main risk factors for mortality in patients with severe COVID-19 that we identified in this study were the advanced age of patients, coexisting respiratory insufficiency, elevated levels of WBC and CK, and decreased levels of PAO2. Elevated WBC and CK laboratory parameters, in particular, demonstrated good predictive value for in-hospital mortality risk.

Impact of the fibrosis-4 index in patients with ST-elevated myocardial infarction.

The fibrosis-4 (FIB4) index, a simple, noninvasive marker used for hepatic diseases, represents adverse outcomes. The aim of the present study was to evaluate whether the FIB4 index can predict adverse outcomes in patients with ST-elevation myocardial infarction (STEMI). We investigated patients with STEMI who underwent primary percutaneous coronary intervention (PCI) and were alive at discharge. The cut-off FIB4 index at discharge was investigated using the survival classification and regression tree (CART) model to predict adverse outcomes. The primary outcome was all-cause mortality. Between January 2006 and December 2018, 1354 patients with STEMI (median age, 68 years; men, 76.1%) were investigated. The median value of the FIB4 index was 1.21 (0.84-1.78). The CART model divided the study population into low (FIB4 index <0.945; n = 435), intermediate (0.945 ≤ FIB4 index < 2.185; n = 692), and high (FIB4 index ≥2.185; n = 227) groups based on the significant predictive values for all-cause death. During a median follow-up period of 4.3 years, all-cause death occurred in 208 patients (15.4%). The Kaplan-Meier analysis showed a significant increase in mortality with higher FIB4 index values (log-rank, P < 0.001). The multivariate Cox regression model revealed that the FIB4 index was an independent risk predictor for all-cause death in patients with STEMI [low group as reference vs. intermediate group, hazard ratio: 1.975; 95% confidence interval (CI): 1.166-3.346; P = 0.011 and vs. high group, hazard ratio: 4.633; 95% CI: 2.549-8.418; P < 0.001]. The FIB4 index was associated with the risk of all-cause mortality in patients with STEMI who underwent primary PCI.

Bioinformatics-based analysis of EMT-related genes in cervical cancer patients

Background: In most cases, patients who are not screened canonically have advanced disease by the time they are first diagnosed. Therefore, invasive metastasis is the main feature and cause of death in patients with advanced cervical cancer. Methods: The GEO database was searched for analytical data on cervical cancer. The GSE9750 dataset was employed to identify differentially expressed genes (DEGs) in tumor samples compared to normal samples, carry out enrichment analysis, build protein-protein interaction (PPI) networks to identify key genes (Hub gene), and perform between diagnostic genes and immune infiltrated cells. Results: A total of 1440 DEGs and 46 differential genes linked to EMT were screened. GO enrichment produced 455 results, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment （KEGG ）yielded a total of 18 pathways. A PPI network was built using 46 differential genes related to EMT, and 9 Hub genes were also validated. Nine hub genes had exactly the same up- and down-regulation trend as before in the external verification set, but only six hub genes were ultimately determined to be diagnostic genes after further validation by the external verification set. The results of the KM (Kaplan-Meier) survival study also revealed five prognostic genes related to survival, namely MMP1, CXCL8, SSP1, MMP3, and VCAM1. Conclusion: The genes MMP1, CXCL8, SSP1, MMP3, and VCAM1are crucial in the development of EMT in patients with cervical cancer and can be employed as both diagnostic and therapeutic targets during the progression of EMT in cervical cancer patients.

Increased access to pediatric specialist healthcare using eConsult: A retrospective observational cohort and case–control study

ABSTRACT Objectives Primary care practitioners (PCPs) report that using the Champlain BASE™ eConsult service (eConsult) averts one-third of face-to-face (FTF) specialist referrals, however, there are concerns about duplication of services and adverse patient outcomes. Following an eConsult, we evaluated patient healthcare utilization and associated treatment costs. Methods Retrospective cohort study (2014 to 2018) of patients (&amp;lt;18 years old) for whom an eConsult visit averted a FTF specialist referral. Patients were linked to provincial health administrative databases and hospital electronic medical records for healthcare use for the same diagnosis and specialty for the 18 months following the eConsult. Concurrently, a retrospective case–control study compared utilization and costs between an eConsult versus a matched FTF visit for the same diagnosis. We also assessed PCP satisfaction. Results In follow-up, &amp;lt;5% of the study cohort of eConsult patients (n = 242) later accessed the healthcare system for the identical diagnosis and specialty type. FTF visits generate more frequent outpatient visits (12.6 times more [95% CI: 2.28 to 69.66, P = 0.002]) and higher costs compared to eConsult visits. There were no hospital admissions or deaths in patients with eConsult. PCPs (98%) described eConsult as an excellent service. Conclusions Using eConsult is associated with &amp;lt;5% of patients subsequently having a FTF visit for the same reason. Matched FTF visits generated more healthcare utilization and higher costs compared with eConsult. eConsult in pediatrics is safe and can minimize FTF specialist visits in elective cases and increase capacity, towards a more efficient and cost-effective healthcare system.

Ultra-Small Copper-Based Multienzyme-Like Nanoparticles Protect Against Hepatic Ischemia-Reperfusion Injury Through Scavenging Reactive Oxygen Species in Mice.

Hepatic ischemia-reperfusion injury (IRI) is a severe complication that occurs in the process of liver transplantation, hepatectomy, and other end-stage liver disease surgery, often resulting in the failure of surgery operation and even patient death. Currently, there is no effective way to prevent hepatic IRI clinically. Here, it is reported that the ultra-small copper-based multienzyme-like nanoparticles with catalase-like (CAT-like) and superoxide dismutase-like (SOD-like) catalytic activities significantly scavenge the surge-generated endogenous reactive oxygen species (ROS) and effectively protects hepatic IRI. Density functional theory calculations confirm that the nanoparticles efficiently scavenge ROS through their synergistic effects of the ultra-small copper SOD-like activity and manganese dioxides CAT-like activity. Furthermore, the results show that the biocompatible CMP NPs significantly protected hepatocytes from IRI in vitro and in vivo. Importantly, their therapeutic effect is much stronger than that of N-acetylcysteamine acid (NAC), an FDA-approved antioxidative drug. Finally, it is demonstrated that the protective effects of CMP NPs on hepatic IRI are related to suppressing inflammation and hepatocytic apoptosis and maintaining endothelial functions through scavenging ROS in liver tissues. The study can provide insight into the development of next-generation nanomedicines for scavenging ROS.

Changes in the Treatment and Prevention of Heart Failure Based on the 2023 Focused Update of the 2021 European Society of Cardiology Guidelines

Introduction and Objective:The 2023 update to the 2021 ESC Guidelines for diagnosing and treating acute and chronic heart failure introduces significant changes in pharmacotherapy and prevention. Staying informed about these updates is crucial given the evolving landscape of heart failure management. This review provides an overview of the latest recommendations and supporting evidence. Review Methods:A comprehensive review of scientific publications and guidelines from PubMed, Google Scholar, Clinical Key, Via Medica Journals, and relevant clinical guidelines was conducted to ensure the most recent evidence is considered. Brief Description of the State of Knowledge:Heart failure is a growing global concern. The 2023 update highlights key management changes. Recent trials, including EMPEROR-Preserved and DELIVER, show empagliflozin and dapagliflozin reduce heart failure hospitalization and cardiovascular death in patients with mildly reduced and preserved ejection fraction. The guidelines now recommend intravenous iron for patients with reduced or mildly reduced ejection fraction and iron deficiency. For those with type 2 diabetes and chronic kidney disease, SGLT2 inhibitors and finerenone, a non-steroidal mineralocorticoid antagonist, are recommended to reduce heart failure hospitalization and prevent renal function decline. Summary:The 2023 ESC Guidelines update offers revised recommendations for heart failure management and prevention, integrating the latest clinical trial data and meta-analyses. Key areas include the use of SGLT2 inhibitors, iron deficiency management, and preventive strategies for high-risk populations. Implementing these guidelines can significantly improve preventive and therapeutic outcomes for heart failure patients.

Free Fatty Acids and Biochemical Changes in Iraqi patients with Chronic Renal Failure

Chronic renal failure (CRF) is progressive irreversible destruction of kidney tissue by disease which, if not treated by dialysis or transplant, will result in patient's death. This study was carried out on 30 patients (17 male and 13 female) with chronic renal failure. The aim of this research was studied the changes in the level of total protein ,albumin, calcium ,ionized calcium, phosphorous , iron ,ALP, LDH ,CK and FFA in patients with CRF before and after hemodialysis .The obtained results have been compared with 30 healthy subjects as control group (18male and 12 female). The results showed that there was significant increase in the level of calcium ,ionized calcium, phosphorous ,iron ,ALP,LDH,CK and FFA ,while there was a significant decrease in the level of total protein ,albumin before hemodialysis comparison to control group . Non significant changes was observed in the level of total protein ,albumin, calcium ,ionized calcium, phosphorous and significant increase in the level of iron ,ALP,LDH,CK and FFA after hemodialysis as compared to control group. This study shows significant positive correlation between FFA and each of albumin and total protein in pre and post-dialysis patients ,and a significant positive correlation with calcium and non significant with ionized calcium in pre-dialysis patients where as there were non significant correlation with calcium and a significant negative correlation with ionized calcium in post-dialysis patients. The conclusion of this study is hemodialysate composition (concentration of electrolytes, free –ionized calcium and some other plasma constituents), the increase concentration of other biochemical changes after renal dialysis because of amissibility a much of amounts of body fluids, and the change in acidosis status may be affect on the correlation between FFA and other parameters used in this study.

Single-cell RNA sequencing identifies a subtype of FN1 + tumor-associated macrophages associated with glioma recurrence and as a biomarker for immunotherapy

BackgroundGlioma is the most common primary malignant tumor in the brain, and even with standard treatments including surgical resection, radiotherapy, and chemotherapy, the long-term survival rate of patients remains unsatisfactory. Recurrence is one of the leading causes of death in glioma patients. The molecular mechanisms underlying glioma recurrence remain unclear.MethodsOur study utilized single-cell sequencing, spatial transcriptomics, and RNA-seq data to identify a subtype of FN1 + tumor-associated macrophages (FN1 + TAMs) associated with glioma recurrence.ResultsThis study revealed an increased abundance of FN1 + TAMs in recurrent gliomas, indicating their potential involvement as a critical factor in glioma recurrence. A negative correlation was observed between the abundance of FN1 + TAMs in primary gliomas and the interval time to recurrence, suggesting poor prognosis for glioma patients with high levels of FN1 + TAMs. Further investigation showed that FN1 + TAMs were enriched in hypoxic tumor regions, implying that metabolic changes in tumors drive the production and recruitment of FN1 + TAMs. Additionally, FN1 + TAMs were found to contribute to the regulation of an immunosuppressive microenvironment in gliomas, and their abundance might serve as an indicator of patients’ sensitivity to immunotherapy. Finally, we developed a user-friendly website, PRIMEG (http://www.szflab.site/PRIMEG/), for exploring the immune microenvironment of primary and recurrent gliomas.ConclusionOur findings highlight a subtype of FN1 + TAMs associated with glioma recurrence, providing new insights into potential therapeutic targets. Moreover, the abundance of FN1 + TAMs hold promise for predicting immune therapy response and aiding in more precise risk stratification of recurrent glioma patients.

The relationship of short-term exposure to meteorological factors on diabetes mellitus mortality risk in Hefei, China: a time series analysis.

The study aims to explore whether short-term exposure to meteorological factors has a potential association with the risk of diabetes mellitus (DM) mortality. During the period 2015-2018, we collected daily data on meteorological factors and deaths of diabetic patients in Hefei. A total of 1101 diabetic deaths were recorded. We used structural equation modeling to initially explore the relationships among air pollutants, meteorological variables, and mortality, and generalized additive modeling (GAM) and distributional lag nonlinear modeling (DLNM) to explore the relationship between meteorological factors and the mortality risk of DM patients. We also stratified by age and gender. The mortality risk in diabetic patients was expressed by relative risks (RR) and 95% confidence intervals (CI) for both single and cumulative days. Single-day lagged results showed a high relative humidity (RH) (75th percentile, 83.71%), a fairly high average temperature (T mean) (95th percentile, 30.32°C), and an extremely low diurnal temperature range (DTR) (5th percentile, 3.13°C) were positively related to the mortality risk of DM. Stratified results showed that high and very high levels of T mean were significantly positively linked to the mortality risk of DM among females and the elderly, while very high levels of DTR were linked to the mortality risk in men and younger populations. In conclusion, this study found that short-duration exposure to quite high T mean, high RH, and very low DTR were significantly positively related to the mortality risk of DM patients. For women and older individuals, exposure to high and very high T mean environments should be minimized. Men and young adults should be aware of daily temperature changes.

12351 Real World Performance of the Afirma Xpression Atlas in Bethesda V and Vi Thyroid Nodules: A Private Practice Experience

Abstract Disclosure: M.S. Tkach: None. E. Coughlin: None. A. Pinero-Pilona: None. Fine Needle Aspiration (FNA) is a cornerstone of the diagnosis of thyroid cancer. The Bethesda System for Reporting Thyroid Cytopathology (BS-TCP), developed in 2010, and genomic sequencing classifiers (GSC) now allow clinicians to objectively identify the risk of malignancy of thyroid nodules (“TN”) prior to surgical interventions. For further characterization, the Afirma Xpression Atlas (XA) was created and launched in May 2018, utilizing RNA sequencing to evaluate fusions and variants. As of 2023, the Afirma XA panel includes 905 genomic variants and 235 fusions from 593 genes. Post-validation studies for the Afirma XA have focused on large academic centers, but applicability or extrapolation to smaller endocrinology practices is less clear, potentially due to different patient population and thyroid cancer prevalence. This study was designed to analyze and measure the performance of the Afirma XA in BS-TCP V and VI TN classified as GSC suspicious for malignancy in a small endocrinology practice. We conducted a retrospective cohort analysis comparing all BS-TCP V and VI TN with their respective final surgical pathology results between June 2018 and December 2023. 76 TN meeting the criteria for BS-TCP V or VI classification were identified. We excluded any TN (12 total) for which pathology data was unavailable; reasons ranged from lack of patient follow-up to patient's death with no autopsy available. Forty-seven thyroid TN were therefore included, and the BS-TCP VI category was the predominant cytopathology discovered, representing 78.7% of the TN in this group. Afirma XA was able to identify genomic alterations in 78.7% of all included TN (thus 78.7% is its sensitivity). Sensitivity of XA was found to be 70% in BS-TCP V (n=10) and 81.1% in BS-TCP VI (n=37). 83% of the analyzed TN were from female patients and 17% were from male patients; there was no statistically significant difference between XA frequency in TN from male vs. female patients. 100% of all BS-TCP V and VI TN (n=47) as determined by the cytopathologist were associated with cancer on pathology; thus, the sensitivity of the cytopathology itself is 100%, and positive predictive value of XA in both groups was 100%. Age and nodule size were not significantly associated with XA presence or absence overall. XA was overwhelmingly comprised of BRAF :p:V600E c.1799T&amp;gt;A mutations: 70.2% of of XA findings showed this mutation (50% in V and 75.6% in VI). Our percentage of XA on BS-TCP V and VI nodules reflects similarity to prior large studies in academic centers. Based on this data, we conclude that XA is a valuable tool for high-risk TN classification and treatment guidance; it can both aid in surgical planning and determine options for potential pharmacotherapy. We conclude that in our study, the relation between XA and cytopathology in BS-TCP V and VI nodules correlates well with data from large academic center studies, even in a small private practice. Presentation: 6/3/2024

Robotic kidney transplant has superior outcomes compared to open kidney transplant: results of a propensity match analysis.

Several studies have demonstrated the feasibility of robotic kidney transplant (RKT) as a safe alternative to open kidney transplant (OKT). However, significant selection bias in RKT patient selection limits meaningful comparison between the two techniques. This is a single-center retrospective review of a prospectively maintained kidney transplant database (2021-2024). Outcomes after the first 50 "non-selected" RKTs are compared with a contemporary cohort of 100 OKTs after propensity score matching for age, gender, BMI and type of donation (living vs deceased). Data pertinent to recipient demographics, intraoperative parameters, and short-term post-operative outcomes were collected and compared. Both groups were well-matched for recipient age, gender, BMI, and donation type. RKT group had significantly longer total operative time (RKT 258min vs. OKT 183min; p < 0.0001) and warm ischemia time (RKT 37min vs. OKT 31min; p < 0.0001) but significantly less blood loss (OKT 155ml vs. RKT 93ml). Average length of hospital stay for both groups was 5days, with OKT group demonstrating significantly higher rates of post-operative complications (OKT 31% vs. RKT 14%; p = 0.028), return to OR (OKT 15% vs. RKT 2%; p = 0.021), hematoma (OKT 13% vs. RKT 2%; p = 0.0355), and lymphocele (OKT 25% vs. RKT 6%; p = 0.0039). OKT group also had higher 30-day readmission rate (OKT 31% vs. RKT 14%) and post-operative opioid requirement (OKT 93 MME vs. RKT 65; p = 0.0254). There were no differences in rates of wound infection, urine leaks, delayed graft function, acute rejection, graft loss, and patient death between the two groups. RKT is a safe and viable alternative to OKT as a first-choice procedure for all patients with ESRD. RKT offers many advantages over OKT which can lead to its wider adoption in the coming years as the new standard of care for ESRD patients.

7076 Inhibiting Oxidosqualene Cyclase, An Enzyme In The Cholesterol Biosynthetic Pathway, Suppresses Lung Metastasis Of Triple-Negative Breast Cancer Cells

Abstract Disclosure: Y. Liang: None. S.M. Hyder: None. Triple-negative breast cancers (TNBC) lack ER, PR and Her2neu proteins that are commonly targeted in breast cancer therapies. As a consequence, women who suffer from TNBC have poor prognosis and limited treatment options, and are usually administered toxic, non-specific chemotherapeutic agents. Drug-resistance almost always occurs, leading to tumor metastasis, the main cause of patient death. New non-toxic therapeutic strategies to control metastasis of TNBC are urgently needed. Cholesterol is an essential structural and functional component of cell membranes that is necessary for the growth of both primary tumors and metastatic colonies that reside in distant organs. Therefore, inhibiting cholesterol production is an attractive therapeutic strategy. Treatment with statins, a class of cholesterol biosynthesis inhibitors that target HMGCoA-reductase, is associated with certain undesirable side effects; consequently, we targeted oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway, to disrupt tumor metastasis. Potent small molecule inhibitors of OSC have been identified. RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for treating several forms of primary tumors. We developed a mouse model for studying lung metastasis using a MDA-MB-231 variant (LM2) TNBC cell line obtained from Dr. Massagué (Memorial Sloan-Kettering Cancer Center). These are aggressive cells, and injection of only 2 X 105 cells produces detectable lung metastatic colonies in approximately 4-6 weeks. We inoculated female nu/nu mice, 5-6 weeks old, with 2 X 105 MDA-MB-231/LM2 cells in 0.1 ml DMEM/F12 medium without serum via tail vein. Five days after tumor cell inoculation animals received 20 mg/kg (n=6), 40 mg/kg (n=7) RO (ip) or vehicle alone (n=7) every other day for two weeks. Animals were then sacrificed, and both lungs harvested and immediately fixed in Bouin’s fixative. Metastatic colonies on the lung surface were identified and counted under a dissecting microscope. Our study showed that RO effectively reduced lung metastasis without affecting animal weight. Compared with 56 + 7 colonies (Mean ± SEM) in controls given vehicle alone, RO significantly reduced lung metastatic colonies to 28 ± 5 in animals exposed to 20 mg/kg and 6 ± 1 in 40 mg/kg treated animals (p&amp;lt;0.05, ANOVA). Reduction in number of colonies in 40 mg/kg group was also significantly different from colonies counted in 20 mg/kg treated animals. Our study is the first to demonstrate that disruption of cholesterol biosynthesis in a model of human TNBC leads to reduced metastasis in lungs. Further studies will determine mechanisms through which RO suppresses TNBC metastasis to the lungs. Supported by Zalk Missouri Professor Endowment Funds. Presentation: 6/3/2024

8091 Clinical Features Associated with ICU Admission and Mortality in Thyroid Storm and Impending Thyroid Storm

Abstract Disclosure: E.D. Zhang: None. I. Hussain: None. Introduction: Thyroid storm is a rare, life-threatening manifestation of thyrotoxicosis characterized by a clinical syndrome of acute multi-organ failure, which can result in significant morbidity and mortality. Impending thyroid storm is a stage of thyrotoxicosis that may progress to thyroid storm if untreated. The aim of this study was to evaluate the demographics and outcomes of patients with thyroid storm at our institution and determine the clinical features associated with severe complications and mortality. We also evaluated the differences in clinical features and outcomes in patients diagnosed with impending thyroid storm versus thyroid storm. Methods: This was a retrospective single-center cohort study evaluating patients aged 18 years or older who were clinically diagnosed with thyroid storm or impending storm at two affiliated tertiary academic centers from 2008-2021. A search of the electronic medical record system using ICD-10 codes for thyroid storm identified patient charts which were reviewed for eligibility. Results: This study included 121 admissions, with 75 (62.0%) patients with thyroid storm and 46 (38.0%) patients with impending thyroid storm. Our study cohort was notably more racially and ethnically diverse than prior U.S. studies with 5.0% non-Hispanic White, 52.9% Black, 33.9% Hispanic, and 8.3% Asian patients. The mortality rate was 4.7%, with all patient deaths occurring in the thyroid storm group. Multivariable logistic regression analysis showed atrial fibrillation (OR 4.09, 95% CI 1.21, 13.85, p=0.02) and acute respiratory failure (OR 22.18, 95% CI 2.29, 215.19, p=0.008) to be significantly associated with a composite outcome of intensive care unit (ICU) admission or death. Comparison of impending storm and thyroid storm groups showed fever (p=0.02), acute respiratory failure (p=0.03), and ICU admission (p=0.02) to be significantly different between groups. Conclusions: This study describes the largest published single-center cohort of patients treated for thyroid storm in the United States. Furthermore, our study contributes importantly to the data for racial/ethnic minorities who are under-represented in prior studies. The mortality rate in this study is lower than most recent studies. The presence of atrial fibrillation and acute respiratory failure were noted to be significantly associated with a composite outcome of ICU admission or death, and the five fatal cases had high rates of cardiac arrest and shock. These findings suggest that complications involving cardiopulmonary compromise are clinically important in predicting severe disease and poor outcomes. Acute respiratory failure was also noted to be significantly different between impending storm and thyroid storm groups indicating that while not currently included in existing diagnostic systems, it is an important complication of thyroid storm that may have prognostic value. Presentation: 6/2/2024

7993 Thienopyrimidine-Based Estrogen Receptor Modulators Adopt Unique Ligand Binding Poses to Elicit Anti-Proliferative Activities in ER+ Breast Cancer Cells

Abstract Disclosure: E.C. Fink: None. S.L. Mateus: None. N. Meganathan: None. V.K. Sammeta: None. J.D. Norris: None. D.P. McDonnell: None. T. Willson: None. S.W. Fanning: None. One in eight women will be diagnosed with breast cancer in their lifetimes. Estrogen receptor alpha (ER) drives breast cancer pathology and is expressed in approximately seventy percent of tumors. Hormone therapies are used to treat and prevent the metastasis of ER+ breast cancers and these patients have favorable 5-year survivals. However, most breast cancer patient deaths are ER+. While the next generation of antiestrogens have shown promise in the advanced setting, more work needs to be done to fully address these mortalities. ER is a ligand-dependent master transcriptional regulator, whereby ligand-specific ER conformational ensembles redirect multiple programs to produce oncogenic or therapeutic endpoints. To better understand ER structure-activity relationships, we have developed new antiestrogenic small molecules based on a thienopyrimidine scaffold. Comprehensive structural, ER activity, and cancer endpoint profiling shows that these new molecules adopt a unique ligand binding pose, which perturbs new structural elements within the orthosteric hormone binding pocket. These molecules downregulate ER target genes and halt the proliferation of ER+ breast cancer cells. Presentation: 6/3/2024

7076 Inhibiting Oxidosqualene Cyclase, an Enzyme in the Cholesterol Biosynthetic Pathway, Suppresses Lung Metastasis of Triple-negative Breast Cancer Cells

Abstract Disclosure: Y. Liang: None. S.M. Hyder: None. Triple-negative breast cancers (TNBC) lack ER, PR and Her2neu proteins that are commonly targeted in breast cancer therapies. As a consequence, women who suffer from TNBC have poor prognosis and limited treatment options, and are usually administered toxic, non-specific chemotherapeutic agents. Drug-resistance almost always occurs, leading to tumor metastasis, the main cause of patient death. New non-toxic therapeutic strategies to control metastasis of TNBC are urgently needed. Cholesterol is an essential structural and functional component of cell membranes that is necessary for the growth of both primary tumors and metastatic colonies that reside in distant organs. Therefore, inhibiting cholesterol production is an attractive therapeutic strategy. Treatment with statins, a class of cholesterol biosynthesis inhibitors that target HMGCoA-reductase, is associated with certain undesirable side effects; consequently, we targeted oxidosqualene cyclase (OSC), an enzyme that occurs downstream of HMGCoA-reductase in the cholesterol biosynthetic pathway, to disrupt tumor metastasis. Potent small molecule inhibitors of OSC have been identified. RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for treating several forms of primary tumors. We developed a mouse model for studying lung metastasis using a MDA-MB-231 variant (LM2) TNBC cell line obtained from Dr. Massagué (Memorial Sloan-Kettering Cancer Center). These are aggressive cells, and injection of only 2 X 10[5] cells produces detectable lung metastatic colonies in approximately 4-6 weeks. We inoculated female nu/nu mice, 5-6 weeks old, with 2 X 10[5] MDA-MB-231/LM2 cells in 0.1 ml DMEM/F12 medium without serum via tail vein. Five days after tumor cell inoculation animals received 20 mg/kg (n=6), 40 mg/kg (n=7) RO (ip) or vehicle alone (n=7) every other day for two weeks. Animals were then sacrificed, and both lungs harvested and immediately fixed in Bouin’s fixative. Metastatic colonies on the lung surface were identified and counted under a dissecting microscope. Our study showed that RO effectively reduced lung metastasis without affecting animal weight. Compared with 56 + 7 colonies (Mean ± SEM) in controls given vehicle alone, RO significantly reduced lung metastatic colonies to 28 ± 5 in animals exposed to 20 mg/kg and 6 ± 1 in 40 mg/kg treated animals (p&amp;lt;0.05, ANOVA). Reduction in number of colonies in 40 mg/kg group was also significantly different from colonies counted in 20 mg/kg treated animals. Our study is the first to demonstrate that disruption of cholesterol biosynthesis in a model of human TNBC leads to reduced metastasis in lungs. Further studies will determine mechanisms through which RO suppresses TNBC metastasis to the lungs. Supported by Zalk Missouri Professor Endowment Funds. Presentation: 6/3/2024

Causes of death in Japanese patients with diabetes based on the results of a survey of 68,555 cases during 2011-2020: Committee report on causes of death in diabetes mellitus, Japan Diabetes Society (English version).

The principal causes of death among 68,555 patients with diabetes and 164,621 patients without diabetes who died in 208 hospitals throughout Japan between 2011 and 2020 were determined based on a survey of hospital records. The most frequent cause of death in patients with diabetes was malignant neoplasms (38.9%) (lung 7.8%, pancreas 6.5%, liver 4.1%), followed, in order of descending frequency, by infectious diseases (17.0%) and then vascular diseases (10.9%) (cerebrovascular diseases 5.2%, ischemic heart diseases 3.5%, renal failure 2.3%). The proportion of deaths from malignant neoplasms and vascular diseases has trended upward and downward, respectively. Almost all deaths from ischemic heart diseases were due to myocardial infarction, and the proportion of deaths from heart diseases other than ischemic heart diseases was relatively high (9.0%), with most cases due to heart failure. Diabetic coma associated with hyperglycemia accounted for only 0.3% of deaths. The proportion of deaths from malignant neoplasms, infectious diseases, renal failure, ischemic heart diseases, and heart failure was significantly higher in patients with diabetes than in those without diabetes, and the proportion of deaths from cerebrovascular diseases was significantly lower in patients with diabetes. With regard to the relationship between the age and cause of death in patients with diabetes, malignant neoplasms were the most frequent cause of death in all age groups, and the incidence was around 50% for those in their 50s and 60s. The incidence of death due to infectious diseases was highest in patients older than their 70s. The incidence of death due to vascular diseases for patients in their 40s and 50s was higher than that due to infectious diseases. The highest incidence of death due to ischemic heart diseases was observed for patients in their 40s, and that due to renal failure and heart failure in patients older than their 70s. Compared with patients without diabetes, patients with diabetes demonstrated a higher incidence of death due to pancreatic cancer, infectious diseases, renal failure, ischemic heart diseases, and heart failure, and a lower incidence of death due to cerebrovascular diseases in all age groups. The average age at death of patients with diabetes was 74.4 years old in men and 77.4 years old in women, which were lower than the average lifespan of the Japanese general population in 2020 by 7.2 and 10.3 years, respectively. However, these differences were smaller than in previous surveys. The average age at death due to all causes, especially due to ischemic heart diseases, cerebrovascular diseases, heart failure, infectious diseases, and diabetic coma, was lower in patients with 'poorer' glycemic control than in those with 'better' glycemic control. In the total survey population, the average age at death of patients with diabetes was significantly higher than that of patients without diabetes. The average age at death due to malignant neoplasms and cerebrovascular diseases was higher in patients with diabetes than in those without diabetes and that due to renal failure, ischemic heart diseases, and infectious diseases was lower in patients with diabetes than in those without diabetes.

The benefit of reduced serum phosphate levels depends on patient characteristics: a nationwide prospective cohort study.

In cohort studies of hyperphosphatemic hemodialysis patients, reduced serum phosphate levels have been linked to a lower mortality risk. To investigate whether this benefit is influenced by patient characteristics, we calculated the number needed to be exposed (NNE), stratified by patient characteristics. In this 9-year prospective cohort study using the nationwide Japanese registry, we enrolled 78256 hemodialysis patients aged 18years or older. We investigated the relationship between time-averaged (TA) phosphate levels and mortality due to cardiovascular disease (CVD) using Cox proportional models. We estimated the 1-year NNE for CVD death in patients with baseline serum phosphate levels ≥6.0mg/dL and exposure to TA phosphate levels decreasing to 3.5-<5.0mg/dL using mixed-effects Poisson models. The hazard ratio of CVD mortality decreased linearly with lower serum TA phosphate levels in those with prior atherosclerotic CVD (ACVD) or diabetic nephropathy (DN) but plateaued with serum phosphate <5.0mg/dL in those without. The hazard ratios (95% confidence interval) for phosphate ≥7.0mg/dL compared with 3.5-<3.9mg/dL were 1.58 (1.38-1.81) in those with prior ACVD, 1.91 (1.68-2.17) in those without, 1.87 (1.63-2.16) in those with DN and 1.65 (1.46-1.87) in those without. However, the NNE for one more person to benefit (NNEB) for CVD death was lower in patients with a history of ACVD than in those without (61 vs 118). Patients with DN had lower NNEB than those without (69 vs 113). In patients with TA albumin ≥3.8g/dL, older patients had lower NNEB, while patients with TA albumin <3.45g/dL showed no benefit in some groups, including the elderly. The benefit of intensive phosphate management may be pronounced in patients with a history of ACVD or DN. A comprehensive approach that considers both age and nutritional status may be necessary when managing serum phosphate levels.

A Quality Improvement Initiative for Inpatient Advance Care Planning

The Centers for Medicare & Medicaid Services (CMS) implemented advance care planning (ACP) billing codes in 2016 to encourage practitioners to conduct and document ACP conversations, and included ACP as a quality metric in the CMS Bundled Payments for Care Improvement Initiative in 2018. Use of this billing code in the inpatient setting has not been studied. To determine whether a quality improvement intervention to increase inpatient ACP is effective in increasing ACP billing rates or changing hospital treatment plans or patient outcomes. This nationwide cohort study and difference-in-differences analyses compared changes in ACP billing, treatment, and outcomes in Medicare fee-for-service beneficiaries aged 65 years and older who were hospitalized and cared for by 3 different groups: practitioners employed by a national acute care staffing organization who underwent an ACP quality improvement intervention, nonintervention practitioners at the same hospital, and control group practitioners from other hospitals. Using data from the Master Beneficiary Summary File, acute care hospital stays for nonsurgical conditions were linked to Medicare enrollment, claims, and vital status data from 1-year preadmission to 1-year postadmission from 2015 to 2019. The ACP billing rates for each group were assessed for associations with 6 inpatient treatments and 4 outcomes. Data analyses were performed from January 2022 to December 2024. Billed ACP conversations, receipt of intensive care and life support (intensive care unit admission, gastrostomy tube placement, mechanical ventilation, tracheostomy), treatment limitations (newly initiated do-not-resuscitate orders) and outcomes (discharge to hospice, inpatient death, 30-day postadmission death, and 1-year postadmission death). The total study sample included 109 intervention hospitals, 1691 control hospitals, nearly 12 million Medicare fee-for-service beneficiaries aged 65 years and older, and 738 309 practitioners associated with admissions from 2016 to 2018. ACP billing rates increased more for the intervention (1.3% in preintervention to 14.0% in postintervention; P < .001) than for the nonintervention (same hospitals) and control groups (odds ratio [OR], 2.6; 95% CI, 1.7-4.1 intervention vs control). Increased ACP billing rates were significantly associated with decreased rates of inpatient death in the intervention group (OR, 0.95; 95% CI, 0.90-1.00) compared to the nonintervention (OR, 1.10; 95% CI, 1.04-1.17) and control groups (reference). All other associations were nonsignificant. This nationwide cohort study suggests that while the ACP quality initiative increased ACP billing, changes in clinical outcomes were inconsistent with the hypotheses. Further study is needed to address questions regarding confounding by unobserved measures of care quality.

Activities of daily living limitation and functional decline during hospitalization predict 180-day readmission and mortality in older patients with pneumonia: A single-center, retrospective cohort study

BackgroundThe role of activities of daily living (ADL) as a predictor of adverse outcomes in patients with pneumonia is unclear. This study aimed to assess the association between ADL, including physical and cognitive function, and death or readmission in older inpatients with pneumonia. MethodsThis retrospective, single-center, observational study included consecutive older inpatients with pneumonia between October 2018 and December 2019. ADL was assessed using the Functional Independence Measure (FIM). Functional decline during hospitalization was defined as a decrease of at least 1 point in FIM at discharge from admission. The primary outcome was the time to composite 180-day mortality and readmission from any cause after discharge. ResultsIn total, 363 patients (median [interquartile range] age: 80 [73–86] years, male: 68 %) were divided according to the median FIM scores (≥100, n = 183 and < 100, n = 180). Among the patients, 25 experienced functional decline during hospitalization, 69 were readmitted, and 17 died. In the Kaplan–Meier analysis, both the lower FIM group and the functional decline group had significantly lower event-free rates than the higher FIM groups and the non-functional decline groups (log-rank test, p < 0.001), respectively. After multivariate analysis, both the lower FIM (adjusted HR, 2.11; 95 % CI, 1.24–3.58; p = 0.006) and functional decline (adjusted HR, 3.18; 95 % CI, 1.44–7.05; p = 0.005) were significantly associated with the primary outcome. ConclusionsIn older patients hospitalized with pneumonia, ADL limitations at discharge and a decline in ADL were associated with poor outcomes.

Mitotic spindle positioning protein serves as prognostic biomarker in patients with colorectal cancer

Background Colorectal cancer (CRC) ranks among the most aggressive types of cancer globally. Currently, clinical tumor prognostic biomarkers still lack accuracy. Mitotic spindle positioning (MISP) protein connects microtubules to the actin cytoskeleton and adhesive plaques, playing a critical role in spindle positioning, orientation, and the process of cell division. MISP can regulate the malignant biological functions of pancreatic cancer and intrahepatic cholangiocarcinoma and it acts as biomarker for prognosis, but its role in CRC remains unclear. Methods This study has collected 37 CRC tissue samples and 37 corresponding adjacent nontumor tissue samples, and 57 additional CRC tissues samples. Clinical data were obtained from the patients with CRC. MISP mRNA and protein expression levels were analyzed in normal control and CRC tissues using the GEPIA and Human Protein Atlas website. MISP protein levels in the collected tissues were analyzed using immunohistochemistry. Results MISP mRNA and protein expression levels were significantly increased in CRC tissues compared to adjacent nontumor tissues. Higher MISP protein levels were associated with distant metastasis, recurrence, and lower survival rates. Kaplan–Meier analysis showed that high expression levels of MISP protein were associated with recurrence and death in CRC patients. In addition, a high expression level of MISP protein, lymph node metastasis, and distance metastasis were risk factors for recurrence and a poor prognosis in patients with CRC. Conclusion Elevated MISP protein correlated with tumor metastasis, recurrence, and lower survival rates in patients with CRC, and thus, MISP has the potential to become a prognostic marker for CRC.