Acute Myocardial Infarction-Related Hospitalizations in Non-elderly Patients with Pneumonia: a Population-Based Study.

The objective is to study factors that increase the likelihood of acute myocardial infarction (AMI) in hospitalized adult non-elderly patients with pneumonia compared to other medical inpatients and to understand the utilization rate of percutaneous coronary intervention (PCI) for AMI in inpatients with pneumonia and its related impact on hospitalization stay and cost. A population-based study was conducted using the Nationwide Inpatient Sample (NIS, 2019) with adult non-elderly inpatients (age 18-65 years) with a medical condition as their primary diagnosis and a co-diagnosis of pneumonia during hospitalization stay. This study sample was divided by the primary diagnosis of AMI versus other medical conditions (non-AMI). A logistic regression model was used to evaluate the odds ratio (OR) of predictors associated with AMI in patients with pneumonia. The results showed a direct relationship between increasing age and the likelihood of AMI in pneumonia inpatients with three times higher odds seen in 51-65 years of age (OR 2.95, 95% CI 2.82-3.09). The comorbidities included complicated hypertension (OR 2.84, 95% CI 2.78-2.89), diabetes with complications (OR 1.27, 95% CI 1.24-1.29), and drug abuse (OR 1.27, 95% CI 1.22-1.31) that increased the likelihood of AMI-related hospitalization. The utilization rate of surgical treatment (PCI) was 14.37% for the management of AMI in inpatients with pneumonia. Inpatients co-diagnosed with pneumonia and comorbidities such as hypertension and diabetes were more likely to be hospitalized for AMI. These at-risk patients should be considered for early risk stratification. Utilization of PCI was associated with a lower in-hospital mortality rate.

Rising Burden of Cardiovascular Disease Risk Factors and Acute Cardiac Events in Young Adults With Comorbid Depression: A Comparison Nationwide US Cohorts Hospitalized 10-years Apart.

Depression and coronary artery disease are leading causes of mortality in adults in high-income countries. Due to the paucity of data on the young, we aimed to investigate the prevalence of cardiovascular disease (CVD) risk factors and associated major adverse cardiac and cerebrovascular events (MACCE) in young adults hospitalized with comorbid depression a decade apart. We conducted a retrospective analysis of the National Inpatient Sample Database for the years 2007 and 2017. Young adults (18-44 years) hospitalized with comorbid depression were identified using ICD-9 CM/ICD-10 codes. Frequency and trends in demographics, comorbidities including CVD risk factors, and MACCE have been compared between the 2017 vs 2007 cohorts. A total of 1,274,118 admissions with a median age of 34 years and 68.7% of females were recorded with comorbid depression. When the 2007 cohort was compared with the 2017 cohort, a rising trend in depression was observed (5.5% vs 8.2%, P < 0.001). The 2017 cohort of young adults with depression more often consisted of male, non-white patients. The burden of CVD risk factors such as hypertension, diabetes with chronic complications, smoking, and obesity was also greater in the 2017 cohort. Although the all-cause mortality remained comparable (0.3%) in both cohorts, there was a significantly higher rate and risk of MACCE including acute myocardial infarction (aOR 1.18, 95%CI:1.10-1.26), atrial fibrillation or flutter (aOR 1.47, 95%CI:1.40-1.54) and stroke (aOR 1.33, 95%CI: 1.26-1.40) (P < 0.001) in the 2017 cohort. In conclusion, this nationwide study reveals an alarmingly increased prevalence of CVD risk factors and an increase in the rate and risk of MACCE in 2 cohorts of young adults with comorbid depression studied a decade apart. The burden of mental disorders in young adults has been rising in the last decade and warrants extra vigilance by clinicians to recognize and manage depression to curtail CVD risk and improve MACE-associated outcomes.

Predictors of Acute Myocardial Infraction in Patients With Vasculitis: A Nationwide Inpatient Cross-Sectional Study.

Objectives The primary goal of this study is to explore demographic and comorbid factors that increase the hospitalization risk of acute myocardial infarction (AMI) in patients with vasculitis along with the utilization rate of percutaneous coronary intervention (PCI)/angioplasty. Additionally, we aim to study the prevalence of AMI in vasculitis inpatients based on geographical distribution. Methods We conducted a retrospective cohort study using the Nationwide Inpatient Sample (NIS) in 2019 involving 33,210 inpatients hospitalized on emergency-based admissions with a co-diagnosis of vasculitis, subdivided into cohorts without AMI (N = 31,790) and with AMI (N = 1,420) as the primary diagnosis. A binomial logistic regression model was used to evaluate the odds ratio (OR) of predictors associated with AMI in patients with vasculitis compared to the non-AMI cohort. Results The prevalence of AMI in the total inpatient population with vasculitis was 4.28%, with a majority of patients being in the older age group of 51-65 years (63%), males (59.2%), and white (59%). Inpatients with vasculitis having pre-existing co-morbid conditions were at greater risk for AMI, such as obesity (OR 2.84, 95%CI 2.78-2.89), metastatic cancer (OR 1.73, 95%CI 1.26-2.37), complicated hypertension (OR 1.64, 95%CI 1.46-1.85), and arthropathies (OR 1.48, 95%CI 1.30-1.68). The in-hospital mortality rate was significantly higher in the AMI cohort compared to the non-AMI cohort (13% vs 2.9%). The utilization rate of PCI/endovascular angioplasty was 13.02% (185 out of 1,420) and had a lower in-hospital mortality rate compared to those managed by medical treatment (8.1% vs 13.8%). Conclusion AMI is an important differential diagnosis to consider in vasculitis patients admitted into the hospital with chest pain. Due to the low prevalence of vasculitis and diagnostic challenges, these primary conditions can be often missed. There is a greater risk of inpatient mortality among vasculitis patients with AMI. Therefore, a higher index of suspicion should be exercised, especially in elderly males with risk factors. Vasculitis patients with chronic comorbidities such as arthropathies, obesity and hypertension are at a greater risk for suffering from AMI. Careful screening and management of cardiovascular risk factors is mandatory in vasculitis patients.

Hospitalization Outcomes Related to Acute Kidney Injury in Inpatients With Acute Myocardial Infarction: A Cross-Sectional Nationwide Study.

Objective To delineate the differences in demographic characteristics and hospitalization outcomes in patients with acute myocardial infarction by comorbid acute kidney injury (AKI) and to explore the risk factors for in-hospital mortality due to AKI in acute myocardial infarction (AMI) inpatients. Methods We conducted a retrospective cross-sectional study using a nationwide inpatient sample and included 77,585 adult inpatients with AMI and further divided by the presence of a co-diagnosis of AKI. A logistic regression model was used to evaluate the odds ratio (OR) of the association between in-hospital mortality and AKI and other comorbidities. Results The prevalence of AKI in AMI inpatients during hospitalization was 11.69%. Among AMI inpatients with AKI, it was prevalent in males (73.9%) and whites (48.8%). Patients with AKI had a higher prevalence of complicated comorbid hypertension (58.7%), diabetes with complications (34.8%), cardiogenic shock (17.4%), and drug abuse (12.3%). Male patients had lower odds of in-hospital mortality (OR 0.69; 95% Cl 0.61-0.79) compared to females. Hispanics had a higher association with mortality (OR 1.45; 95% Cl 1.21-1.74) than whites and other races/ethnicities. Patients who developed cardiogenic shock were at 17 times higher odds of in-hospital mortality (OR 17.25; 95% CI 15.14-19.67), followed by AKI (OR 4.64; 95% CI 4.06-5.31), and alcohol abuse (OR 1.29; 95% CI 1.03-1.64). The in-hospital mortality rate among AMI inpatients with AKI (7.6%) was significantly higher compared to that seen in the non-AKI cohort (0.9%). Conclusion AMI inpatients with AKI during hospitalization was prevalent in males and whites. Among the demographic risk factors, females and Hispanics had a higher likelihood of in-hospital mortality during the inpatient management of AMI. Cardiogenic shock and AKI increased the odds of in-hospital mortality compared to other comorbidities in AMI inpatients.

Risk Factors for Colorectal Cancer in Inpatients With Ulcerative Colitis: A Nationwide Cross-Sectional Analysis.

Objectives The objective is to study the demographic and geographical factors that increase the risk of colorectal cancer (CRC) in inpatients with ulcerative colitis (UC) and evaluate the mortality risk and hospitalization outcomes in terms of length of stay (LOS) and cost of care in patients with CRC in UC. Methods We conducted a cross-sectional study using the nationwide inpatient sample (NIS, 2019). We included 78,835 inpatients (age 15-65 years) hospitalized on emergency-based admissions with a primary diagnosis of UC. The study sample was divided by the presence of CRC. Categorical and continuous data were analyzed using Pearson's chi-square test and independent-sample t-test respectively. Independent binomial logistic regression models were used to evaluate the odds ratio (OR) of predictors associated with CRC in patients with UC compared to non-CRC. Results The prevalence of CRC in inpatients with UC was 0.2%, and the mean age for admission of patients with UC with CRC was 49.6 years (SD ± 10.29). A directly proportionate relationship exists between increasing age and the risk of CRC in UC inpatients with 10 times higher odds seen in 51-65 years of age (OR 10.0, 95% CI 5.11-19.61). Males (OR 2.15, 95% CI 1.49-3.08) and Hispanics (OR 1.69, 95% CI 1.04-2.74) are at higher odds for CRC compared to their counterparts. Acquired immunodeficiency syndrome (AIDS) was associated with increased odds (OR 6.23, 95% CI 2.48-15.68) for CRC in UC inpatients. There existed an increased association for CRC in UC inpatients with complicated hypertension, and alcohol and drug abuse but was statistically non-significant. As per the adjusted regression model, CRC in UC inpatients increased the risk of in-hospital mortality (OR 41.09, 95% CI 19.49-86.58). Conclusions CRC was more prevalent in middle-aged Caucasian males with UC and those with chronic comorbidities including complicated diabetes and hypertension, alcohol abuse, and AIDS. Patients with UC and AIDS were found to have greater odds of developing CRC. A high index of clinical suspicion is needed in the management of these patient groups as the inpatient mortality risk was higher in UC inpatients with CRC.

Utilization of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia and Related Hospital Outcomes: A Cross-Sectional Study of US Hospitals.

Background In this study, we aimed to provide a descriptive overview of the utilization of hematopoietic stem cell transplantation (HSCT) for the treatment of acute myeloid leukemia (AML), determine the rates of HSCT use stratified by patients' demographic characteristics, and measure the hospitalization outcomes. Methodology We conducted a cross-sectional study using the Nationwide Inpatient Sample (NIS) obtained from hospitals in the United States. Our sample included 21,385 adult patients (aged ≥18 years) with a primary discharge diagnosis of AML. The sample was further grouped by inpatients who were managed with HSCT and chemotherapy as the primary procedure. We compared the demographic characteristics and hospital outcomes in AML inpatients across treatment cohorts by performing descriptive statistics and Pearson's chi-square test. Next, we measured the differences in continuous variables (length of stay and cost) using the analysis of variance (ANOVA). All analyses were conducted using SPSS version 26 (IBM Corp., Armonk, NY, USA). Results The hospital-based utilization rate of HSCT was 0.4% in AML inpatients. The utilization rate of HSCT was higher in females (0.5%), African Americans (0.6%), those with median household incomes above the 50th percentile (0.5%), and those covered by private insurance (0.8%). A significantly higher proportion of AML inpatients with HSCT had depression (22.2% vs. 11.4% in total). AML inpatients receiving HSCT had significantly longer hospitalization stays and higher treatment costs than those receiving chemotherapy. The all-cause inpatient mortality was 11.6% in AML inpatients. Statistically, there were no significant differences by treatment. Conclusions HSCT appears to be underutilized for the treatment of AML. This treatment had a higher utilization rate in females and those from high-income families and was covered by private insurance. The utilization of chemotherapy and HSCT did not significantly differ in the presence of comorbidities, except for depression and hypertension having a higher utilization of HSCT.

Extensional Rheological Measurements of Surfactant-Polymer Mixtures.

Polymer solutions flowing in the porous media during enhanced oil recovery (EOR) processes are subjected to both shear and extensional rheological deformation. However, the previous rheological studies conducted on a surfactant-polymer (SP) system or polymer systems were only shear-based. In this paper, the extensional rheological performance of hydrolyzed polyacrylamide (HPAM) in the presence of an anionic surfactant at various concentrations (0, 0.01, 0.05, 0.1, 0.2, and 0.3%) is studied with deionized water and 1% NaCl. Further, the extensional rheological behavior of HPAM in the presence of NaCl and CaCl2 is studied at varying ionic strengths (1-10%). A capillary break-up extensional rheometer is used for performing extensional rheological characterization. Results revealed that the extensional resistance of HPAM is enhanced in the presence of a surfactant. Particularly, around the critical micelle concentration value of the surfactant (0.1%), HPAM showed higher extensional resistance. Higher extensional resistance for the SP system is observed with deionized water when compared to 1% NaCl. HPAM showed improved performance at 1% NaCl salinity when compared to the higher concentration of NaCl salinity. However, the presence of even 1% of calcium ions is detrimental to the extensional properties of HPAM.

Coagulopathy and Hospital Outcomes in Patients With Spontaneous Bacterial Peritonitis: A Call for Action to Improve Care of Inpatients.

Objectives To assess the risk of in-hospital mortality in spontaneous bacterial peritonitis (SBP) with coagulopathy, and to understand the impact of comorbid coagulopathy on length of stay (LOS) and total charges for SBP inpatients. Methods We included adult patients (age, 18-50 years) with a principal diagnosis of SBP using the Nationwide Inpatient Sample (NIS, 2012 to 2014). These patients were further subgrouped by comorbid coagulopathy. The independent sample t-test was used to measure the mean difference in LOS and total charges between subgroups. The logistic regression model was used to measure the odds ratio (OR) of association of coagulopathy and in-hospital mortality after adjusting for demographic confounders and other comorbid risk factors. Results SBP with comorbid coagulopathy was prevalent in males (68.7%) and white (58.1%). When compared with the non-coagulopathy cohort, males had 1.6 times (95% CI 1.46-1.84), and hispanics had 1.4 times (95% CI 1.19-1.58) high odds for coagulopathy. In-hospital mortality was statistically significant in SBP inpatients with coagulopathy (6.5% vs. 2.8% in non-coagulopathy), and with two times higher odds of association (95% CI 1.47-2.51) compared with non-coagulopathy cohort. SBP inpatients with comorbid coagulopathy had a statistically significantly higher LOS by 1.1 days and higher total charges by $14,123 per hospitalization compared with the non-coagulopathy cohort. Conclusions Coagulopathy is a significant risk factor that increases the risk of in-hospital mortality in SBP inpatients by 92%. Comorbid coagulopathy is also associated with extended LOS and higher hospitalization costs, thereby increasing the healthcare burden. Clinicians need to effectively manage coagulopathy in SBP patients to improve patient outcomes and reduce the healthcare burden with better health-related quality of life.

Arrhythmia-related Hospitalization and Comorbid Cannabis Use Disorder: Trend Analysis in US Hospitals (2010-2014).

Objective To study the trends of arrhythmia hospitalizations with cannabis use disorders (CUDs) in terms of demographic characteristics and inpatient outcomes. Methods We used the nationwide inpatient sample (NIS) data during the post-legalization period (2010-2014) and included 570,556 arrhythmia inpatients (age, 15-54 years), and 14,426 inpatients had comorbid CUD (2.53%). We used the linear-by-linear association test and independent-sample T-test for assessing the change in hospital outcomes in inpatients with CUD. Results Arrhythmia hospitalizations with CUD increased by 31% (2010-2014). This increasing trend was seen in adults (45-54 years, P < 0.001) and was predominant in males (77.6%). Hypertension (40.6%), hyperlipidemia (17.6%), and obesity (15%) were prevalent medical comorbidities with variable trends over the five years. Among substance use disorders, tobacco (50.9%), and alcohol (31.4%) were major comorbidities with a variable trend (P = 0.003 for each). There was a 71.4% increase in the inpatient mortality rate between 2010 (0.7%) and 2014 (1.2%). The mean length of stay was three days, and the total hospitalization charges have been increasing (P < 0.001), averaging $35,812 per hospital admission. Conclusion Chronic cannabis use or abuse worsens hospitalization outcomes in arrhythmic patients, and more clinical studies are needed to study the causal association between these conditions due to the rising mortality risk.

Problematic Cannabis Use and Risk of Complications in Patients with Chronic Hepatitis C.

Objectives To evaluate the risk of complication in hospitalized chronic hepatitis C (CHC), patients with cannabis use disorder (CUD). Methods We conducted a retrospective study using the nationwide inpatient sample (NIS), and included 31,623 patients (age 15-54) with a primary international classification of diseases, ninth revision (ICD-9) diagnosis for CHC and grouped by co-diagnosis of CUD (1101, 3.5%). Logistic regression model adjusted for confounders was used to evaluate the odds ratio (OR) of CUD and complications during CHC hospitalization. Results Comorbid CUD was prevalent in males (73.2%), Caucasians (59.9%), and from low-income families (65.7%). The most prevalent complications in patients with CUD were ascites (44.9%), alcoholic cirrhosis (42.8%) and non-alcoholic cirrhosis (41.1%). The odds of association for hepatic encephalopathy was 2.2 times higher (95% CI 1.477-3.350) in 2.8% CHC inpatients with CUD compared to 1.2% non-CUD inpatients. Hepatic encephalopathy had higher odds of association with a male by 1.4 times (95% CI 1.094-1.760), and African American by 1.7 times (95% CI 1.293-2.259). Conclusion CUD is significantly associated with 122% increased likelihood for hepatic encephalopathy that may worsen overall hospitalization outcomes in CHC patients. Hence, we need to consider the complex relationship between CUD and CHC and manage them optimally to improve the health-related quality of life.

Comorbidities and Consequences in Hospitalized Heart Failure Patients with Depression.

Objective To evaluate the demographic predictors of major depressive disorder (MDD) in hospitalized congestive heart failure (CHF) patients and measure the differences in hospital stay and cost per comorbidities and the associated risk of in-hospital mortality. Methods This retrospective cross-sectional study used nationwide inpatient data from the healthcare cost and utilization project (HCUP). We identified patients with CHF as the primary diagnosis and MDD as the secondary diagnosis using ICD-9-CM codes and compared with the CHF patient without MDD. The differences in comorbidities were quantified using chi-square tests and the logistic regression model was used to evaluate mortality risk among comorbidities using odds ratio (OR). Results Elder CHF patients, 36-50-year-old (OR: 1.324) and whites (OR: 1.673), have a higher likelihood of a co-diagnosis of MDD. Females with heart failure have two-fold higher odds of MDD (OR: 2.332). Majority of the medical comorbidities were seen in a higher proportion of CHF patients without MDD. Hypothyroidism (10.2%) and drug abuse (15.2%) were seen more in depressed patients comparatively. Among substance use disorder, patients with drug abuse stayed longer and had a higher hospitalization total cost ($51,828). And, hypothyroidism was associated with longer inpatient stay (5.6 days) and cost ($64,726), and four-fold higher odds of in-hospital mortality (OR: 4.405). Though alcohol abuse was seen only in 7.4% of CHF patients with MDD, it was associated with the three-fold higher likelihood of deaths during hospitalization (OR: 3.195). Conclusion A middle-aged, white female with comorbid depression has a higher risk of hospitalization for heart failure. Depressed CHF patients with comorbid hypothyroidism were hospitalized for a longer duration with higher inpatient cost and four times higher risk of mortality during hospitalization stay. Further studies are required to evaluate the underlying cause of worse hospital outcomes in depressed CHF patients with alcohol abuse and hypothyroidism. An integrated healthcare model is required for early diagnosis and treatment of depression and associated comorbidities in CHF patients to reduce mortality and improve post-CHF outcomes.

Cannabis Use Disorder in Young Adults with Acute Myocardial Infarction: Trend Inpatient Study from 2010 to 2014 in the United States.

Objective This study determines the trend of acute myocardial infarction (AMI) in cannabis users. Demographic characteristics, hospitalization outcomes, and utilization of primary treatment modalities were evaluated in AMI inpatient population. Methods The study used data from the nationwide inpatient sample (NIS) for the years 2010-2014. We identified patients with AMI as the primary diagnosis (N = 379,843) and patients with cannabis use disorder as the secondary diagnosis. We used Pearson's chi-square (χ2) test and independent sample t-test for measuring the categorical and continuous data, respectively. Results Inpatient admissions for AMI among cannabis users increased by 32% (P = 0.001). The overall mean age of cannabis users with AMI (41 years) remained stable with no significant differences observed across age groups. AMI was predominant in male cannabis users (79.1%), and there was a 38.3% increase in the prevalence in female cannabis users over five years (P < 0.001). About one-third of the cannabis users with AMI were covered by medicaid with a 70.5% pike (21% in 2010 to 37.5% in 2014; P < 0.001). There was a strong linear trend in nonelective admissions for AMI in cannabis users (P = 0.003) along with a moderate-to-severe morbidity (P = 0.001). Mean length of inpatient stay had a decreasing linear trend (P = 0.003), whereas hospitalization costs were increasing (P = 0.024), averaging $65,879 per admission for AMI. Cannabis users had a strong linear increasing trend (P = 0.007), with a 60% increase in in-hospital mortality (1.0% in 2010 to 1.6% in 2014). Conclusion Due to the risk of AMI, as seen in numerous case reports, the trend of emergency admission and severe morbidity due to AMI in cannabis users is also increasing. Also, cannabis users have a higher healthcare cost to manage AMI, yet the in-hospital mortality has risen tremendously over the last few years. It is imperative to know that chronic cannabis worsens the outcomes in AMI patients, and more clinical studies are needed to show the association of episodic use in cannabis abusers and AMI.

Etiologies, Trends, and Predictors of 30-Day Readmissions in Patients With Diastolic Heart Failure.

An estimated half of all heart failure (HF) populations has been categorized to have diastolic HF (DHF), but sparse data are available describing etiologies and predictors of 30-day readmission in DHF population. The study cohort was derived from the National Readmission Database 2013 to 2014, a subset of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality. DHF was identified using International Classification of Diseases, 9th Revision code 428.3x in primary diagnosis field. Readmission etiologies were identified by International Classification of Diseases, 9th Revision code in primary diagnosis field. The primary outcome was 30-day readmission. Hierarchical multivariable logistic regression was used to adjust for confounders. In total, 192,394 patients with DHF were included, of which 40,927 (21.27%) patients were readmitted with total readmissions of 47,056 within 30 days. Predictors of increased readmissions were age (odds ratio [OR] 1.002, 95% confidence interval [CI] 1.001 to 1.0003, p <0.001), diabetes (OR 1.08, 95% CI 1.05 to 1.11, p <0.001), chronic pulmonary disease (OR 1.18, 95% CI 1.15 to 1.21, p <0.001), renal failure (OR 1.21, 95% CI 1.17 to 1.25, p <0.001), peripheral vascular disease (OR 1.05, 95% CI 1.02 to 1.09, p = 0.002), anemia (OR 1.12, 95% CI 1.10 to 1.15, p <0.001), transfusion during index admission (OR 1.18, 95% CI 1.13 to 1.23, p <0.001), discharge to the facility (OR 1.13, 95% CI 1.10 to 1.16, p <0.001), length of stay >2 days, and Charlson comorbidity index ≥3, whereas obesity (OR 0.82, 95% CI 0.80 to 0.85, p <0.001), elective admissions (OR 0.88, 95% CI 0.83 to 0.94, p <0.001), and non-Medicare/Medicaid primary payer were predictors of lower readmission rate. Most common etiologies of readmission were acute HF (28.01%), infections (9.54%), acute kidney injury (5.35%), acute respiratory failure (4.86%), and pneumonia (3.92%). In conclusion, DHF population with higher comorbidity burden, longer length of stay, and discharge to facility were prone to increased readmissions, with most common etiologies of readmission being HF, infections, and acute kidney injury.

Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells.

Purpose: Ibrutinib inhibits Bruton tyrosine kinase (BTK) by irreversibly binding to the Cys-481 residue in the enzyme. However, ibrutinib also inhibits several other enzymes that contain cysteine residues homologous to Cys-481 in BTK. Patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) demonstrate a high overall response rate to ibrutinib with prolonged survival. Acalabrutinib, a selective BTK inhibitor developed to minimize off-target activity, has shown promising overall response rates in patients with relapsed/refractory CLL. A head-to-head comparison of ibrutinib and acalabrutinib in CLL cell cultures and healthy T cells is needed to understand preclinical biologic and molecular effects.Experimental Design: Using samples from patients with CLL, we compared the effects of both BTK inhibitors on biologic activity, chemokine production, cell migration, BTK phosphorylation, and downstream signaling in primary CLL lymphocytes and on normal T-cell signaling to determine the effects on other kinases.Results: Both BTK inhibitors induced modest cell death accompanied by cleavage of PARP and caspase-3. Production of CCL3 and CCL4 chemokines and pseudoemperipolesis were inhibited by both drugs to a similar degree. These drugs also showed similar inhibitory effects on the phosphorylation of BTK and downstream S6 and ERK kinases. In contrast, off-target effects on SRC-family kinases were more pronounced with ibrutinib than acalabrutinib in healthy T lymphocytes.Conclusions: Both BTK inhibitors show similar biological and molecular profile in primary CLL cells but appear different on their effect on normal T cells. Clin Cancer Res; 23(14); 3734-43. ©2016 AACR.

Etiologies and Predictors of 30-Day Readmission and In-Hospital Mortality During Primary and Readmission After Transcatheter Aortic Valve Implantation.

There are sparse data on the etiologies and predictors of readmission after transcatheter aortic valve implantation (TAVI). The study cohort was derived from the National Readmission Data 2013, a subset of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality. TAVI was identified using appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes. The coprimary outcomes were 30-day readmissions and in-hospital mortality during primary admission and readmission. Hierarchical 2-level logistic models were used to evaluate study outcomes. Our analysis included 5,702 (weighted n = 12,703) TAVI procedures. About 1,215 patients were readmitted (weighted n = 2,757) within 30 days during the study year. Significant predictors of readmission included transapical access (OR, 95% CI, p value) (1.23, 1.10 to 1.38, <0.01), diabetes (1.18, 1.06 to 1.32, p 0.004), chronic lung disease (1.32, 1.18 to 1.47, <0.01), renal failure (1.43, 1.24 to 1.65, <0.01), patients discharged to facilities (1.28, 1.14 to 1.43, <0.01), and those who had lengthier hospital stays during primary admission (length of stay >10 days: 3.06, 2.22 to 4.22, <0.01). Female gender (1.39, 1.16 to 1.68, <0.01), blood transfusion (1.88, 1.55 to 2.29, <0.01), use of vasopressors (3.63, 2.50 to 5.28, <0.01), hemodynamic support (6.39, 5.20 to 7.85, <0.01) and percutaneous coronary intervention (1.89, 1.30 to 2.74, 0.01) during primary admission were significant predictors of in-hospital mortality. Age and transapical access were significant predictors of in-hospital mortality during readmission. In conclusion, heart failure, pneumonia, and bleeding complications are among important etiologies of readmission in patients after TAVI. Patients who underwent transapical TAVI and those with slower in-hospital recovery and co-morbidities such as chronic lung disease and renal failure are more likely to be readmitted to the hospital.

Molecular evidence of Zn chelation of the procaspase activating compound B-PAC-1 in B cell lymphoma.

The resistance of apoptosis in cancer cells is pivotal for their survival and is typically ruled by mutations or dysregulation of core apoptotic cascade. Mantle cell lymphoma (MCL) is a non-Hodgkin's B-cell malignancy expressing higher anti-apoptotic proteins providing survival advantage. B-PAC-1, a procaspase activating compound, induces apoptosis by sequestering Zn bound to procaspase-3, but the amino acids holding Zn in Caspase-3 is not known. Here we show that reintroduction of WT caspase-3 or 7 in Caspase3-7 double knock-out (DKO) mouse embryonic fibroblasts (MEF) promoted B-PAC-1 to induce apoptosis (27-43%), but not in DKO MEFs or MEFs expressing respective Casp3-7 catalytic mutants (12-13%). Using caspase-6 and -9 exosite analysis, we identified and mutated predicted Zn-ligands in caspase-3 (H108A, C148S and E272A) and overexpressed into DKO MEFs. Mutants carrying E272A abrogated Zn-reversal of apoptosis induced by B-PAC-1 via higher XIAP and smac expressions but not in H108A or C148S mutants. Co-immunoprecipitation analysis revealed stronger XIAP-caspase-3 interaction suggesting a novel mechanism of impulsive apoptosis resistance by disrupting predicted Zn-ligands in caspase-3. B-PAC-1 sponsored apoptosis in MCL cell lines (30-73%) via caspase-3 and PARP cleavages accompanied by loss of Mcl-1 and IAPs including XIAP while Zn substantially abrogated B-PAC-1-driven apoptosis (18-36%). In contrary, Zn is dispensable to inhibit staurosporin, bendamustine, ABT199 or MK206-induced apoptosis. Consistent to cell lines, B-PAC-1 stimulated cell death in primary B-lymphoma cells via caspase-3 cleavage with decline in both Mcl-1 and XIAP. This study underscores the first genetic evidence that B-PAC-1 driven apoptosis is mediated via Zn chelation.

Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells.

Intrinsic and extrinsic apoptotic pathways converge to activate common downstream executioner caspases (caspase-3, -6, and -7), resulting in cell death. In chronic lymphocytic leukemia (CLL), neoplastic B cells evade apoptosis owing to the overexpression of survival proteins. We hypothesized that direct activation of procaspases could bypass the apoptosis resistance induced by the upstream prosurvival proteins. The procaspase-activating compounds (PAC-1), including B-PAC-1 (L14R8), convert inactive executioner procaspases to their active cleaved forms by chelation of labile zinc ions. Both at transcript and protein levels, primary CLL cells express high levels of latent procaspases (3, -7, and -9). B-PAC-1 treatment induced CLL lymphocyte death which was higher than that in normal peripheral blood mononuclear cells or B cells, and was independent of prognostic markers and microenvironmental factors. Mechanistically, B-PAC-1 treatment activated executioner procaspases and not other Zn-dependent enzymes. Exogenous zinc completely, and pancaspase inhibitors partially, reversed B-PAC-1-induced apoptosis, elucidating the zinc-mediated mechanism of action. The cell demise relied on the presence of caspase-3/7 but not caspase-8 or Bax/Bak proteins. B-PAC-1 in combination with an inhibitor of apoptosis protein antagonist (Smac066) synergistically induced apoptosis in CLL samples. Our investigations demonstrated that direct activation of executioner procaspases via B-PAC-1 treatment bypasses apoptosis resistance and is a novel approach for CLL therapeutics.

Impact of bone marrow stromal cells on Bcl-2 family members in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world. High levels of Bcl-2 family anti-apoptotic proteins are responsible for apoptosis resistance. Besides anti-apoptotic proteins, the microenvironment provides substantial survival signals to CLL leukemic cells. However, in-depth knowledge on the role of individual Bcl-2 family members in the context of the microenvironment is still limited. We performed a comprehensive analysis of transcripts and proteins of 18 Bcl-2 family members using an "apoptosis array microfluidic card" in primary cells before and after stromal co-cultures. Our data showed that five of six anti-apoptotic members (excluding Bcl-b), two of three pro-apoptotic members (excluding Bok) and six of nine BH3-only members were present at detectable mRNA levels in CLL cells. Importantly, stromal-mediated extended survival of CLL cells was strongly associated with elevated global transcription. Upon co-culturing with stromal cells, there was an early response of an increase in anti- (2/5) and pro-apoptotic protein (3/8) transcripts on day 1, while an increase in anti-apoptotic proteins was observed on day 3, with no significant change in pro-apoptotic proteins. Our study revealed a differential pattern of expression of both transcripts and proteins following stromal co-cultures, proposing a significance of Bcl-2 family members in the stromal microenvironment.