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.

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.

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.

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.

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.

Intestinal and renal effects of low-volume phosphate and sulfate cathartic solutions designed for cleansing the colon: pathophysiological studies in five normal subjects.

OBJECTIVES: Ingestion of a concentrated low-volume phosphate solution produces copious diarrhea, which cleanses the colon, but it occasionally causes renal failure due to calcium phosphate precipitation in renal tubules. We hypothesized that a concentrated low-volume sulfate solution would be an equally effective cathartic, and that urine produced after sulfate would have less tendency to precipitate calcium salts than urine produced after phosphate. METHODS: Hydrated subjects ingested 75 ml of phosphosoda or an equimolar dose of sulfate salts in a small volume of solution. Four liters of PEG (polyethylene glycol) lavage solution was the control. All solutions were administered in split doses, 10 h apart. Propensity of urine to precipitate at pH 6.4 (the pH of renal tubular fluid) was assessed by determining the minimal calcium concentration that caused precipitation. RESULTS: Average diarrheal stool weight was 2,004 g after phosphate, 2,854 g after sulfate, and 3,021 g after PEG (P<0.001). Average calcium concentration (in mg/dl) required to induce urine precipitation at pH 6.4 was 43 after PEG, 10 after PO(4), and 187 after SO(4) (P=0.009). CONCLUSIONS: (i) In equimolar doses, sulfate produced 42% more diarrheal stool weight than phosphate. (ii) Phosphate increased the propensity for calcium salt precipitation in urine at pH 6.4, whereas sulfate did not. (iii) These results suggest that a hypertonic low-volume sulfate solution would be an effective cathartic for colon cleansing and that sulfate-induced catharsis would be less likely than phosphate catharsis to produce calcium salt deposition in renal tubules.

100 consecutive thyroidectomies performed by a single surgeon in an upstate South Carolina teaching hospital: an outcome analysis.

An experienced surgeon in a community hospital with surgical resident participation can perform thyroid surgery safely. An outcome analysis of 100 consecutive thyroidectomies showed a 1.2% incidence of permanent recurrent nerve injury and no cases of permanent hypo-parathyroidism. Temporary hypocalcemia was common (in total thyroidectomy patients) but was easily treated with oral calcium supplementation. Total thyroidectomy is an acceptable treatment for hyperthyroidism in those patients who are unable or unwilling to receive Radioiodine ablation.