SATB2 is a novel biomarker and therapeutic target for cancer.

Several studies have confirmed the involvement of cancer stem cells (CSC) in tumour progression, metastasis, drug resistance and cancer relapse. SATB2 (special AT-rich binding protein-2) acts as a transcriptional co-factor and modulates chromatin architecture to regulate gene expression. The purpose of this review was to discuss the pathophysiological roles of SATB2 and assess whether it could be used as a therapeutic target for cancer. SATB2 modulated the expression of those genes which regulated pluripotency and self-renewal. Overexpression of SATB2 gene in normal epithelial cells was shown to induce transformation, as a result transformed cells gained CSC's characteristics by expressing stem cell markers and pluripotency maintaining factors, suggesting its role as an oncogene. In addition, SATB2 induced epithelial-mesenchymal transition (EMT) and metastasis. Interestingly, the expression of SATB2 was positively correlated with the activation of ß-catenin/TCF-LEF pathway. Furthermore, SATB2 silencing inhibited EMT and their positive regulators, and tumour growth, and suppressed the expression of stem cell markers, pluripotency maintaining factors, cell cycle and cell survival genes, and TCF/LEF targets. Based on the cancer genome atlas (TCGA) expression data and published papers, SATB2 alone or in combination with other proteins could be used a diagnostic biomarker for cancer. Although there is no pharmacological inhibitor of SATB2, studies using genetic approaches suggest that SATB2 could be a potential target for cancer treatment and prevention.

α-Mangostin-encapsulated PLGA nanoparticles inhibit colorectal cancer growth by inhibiting Notch pathway.

Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality. Recent studies have stated that Notch signalling is highly activated in cancer stem cells (CSCs) and plays an important role in the development and progression of CRC. Like normal colorectal epithelium, CRCs are organized hierarchically and include populations of CSCs. In order to enhance the biological activity of α-mangostin, we formulated α-mangostin-encapsulated PLGA nanoparticles (Mang-NPs) and examined the molecular mechanisms by which Mang-NPs inhibit CRC cell viability, colony formation, epithelial-mesenchymal transition (EMT) and induce apoptosis. Mang-NPs inhibited cell viability, colony formation and induced apoptosis. Mang-NPs also inhibited EMT by up-regulating E-cadherin and inhibiting N-cadherin and transcription factors Snail, Slug and Zeb1. As dysregulated signalling through the Notch receptors promotes oncogenesis, we measured the effects of Mang-NPs on Notch pathway. Mang-NPs inhibited Notch signalling by suppressing the expression of Notch receptors (Notch1 and Notch2), their ligands (Jagged 1 and DLL4), γ-secretase complex protein (Nicastrin) and downstream target (Hes-1). Notch receptor signalling regulates cell fate determination in stem cell population. Finally, Mang-NPs inhibited the self-renewal capacity of CSCs, stem cell markers (CD133, CD44, Musashi and LGR5) and pluripotency maintaining factors (Oct4, Sox-2, KLF-4, c-Myc and Nanog). Overall, our data suggest that Mang-NPs can inhibit CRC growth, EMT and CSCs' population by suppressing Notch pathway and its target. Therefore, Mang-NPs can be used for the treatment and prevention of CRC.

Did the Affordable Care Act Reach Penetrating Trauma Patients?

BACKGROUND: The benefits of the Affordable Care Act (ACA) for trauma patients have been well established. However, the ACA's impact on penetrating trauma patients (PTPs), a population that is historically young and uninsured, has not been defined. We hypothesized that PTPs in the post-ACA era would have better outcomes. MATERIAL AND METHODS: The National Trauma Data Bank (NTDB) was queried for all PTPs from 2009 (pre-ACA) and 2011-2014 (post-ACA). Subset analysis was performed in patients aged 19-25 y, as this group was eligible for the ACA's dependent care provision (DCP). RESULTS: There were 9,714,471 patients in the study, with 2,053,501 (21.1%) pre-ACA and 7,660,970 (78.9%) post-ACA. When compared to pre-ACA, patients in the post-ACA cohort were more likely to have commercial/private insurance, less likely to have Medicaid, and more likely to be uninsured. On logistic regression, the pre-ACA era was associated with mortality (HR: 1.02, 95% CI: 1.01-1.04, P = 0.004). Being uninsured was associated with mortality (HR: 1.89, 95% CI: 1.87-1.92, P < 0.001). On subset analysis of the DCP age group, post-ACA patients were more likely to be uninsured (24.1% versus 17.6%; P < 0.001). In addition, for the DCP age group, pre-ACA era was not associated with mortality (HR: 1.03, 95% CI: 0.99-1.06, P = 0.20). CONCLUSIONS: Although the ACA provided a survival benefit to PTPs overall, it did not increase insurance coverage for this population. In addition, the DCP of the ACA did not improve insurance access for PTP in the eligible age group. Further efforts are needed to extend insurance access to this population.

Lack of T-cell-mediated IL-2 and TNFα production is linked to decreased CD58 expression in intestinal tissue during acute simian immunodeficiency virus infection.

For an effective T-cell activation and response, co-stimulation is required in addition to the antigen-specific signal from their antigen receptors. The CD2/CD58 interaction is considered as one of the most important T-cell co-stimulatory pathways for T-cell activation and proliferation, and its role in regulating intestinal T-cell function in acute and chronic SIV -infected macaques is poorly documented. Here, we demonstrated a significant reduction of CD58 expression in both T- and B-cell populations during acute SIV infection along with high plasma viral load and a loss of intestinal CD4+ T cells compared to SIV-uninfected control macaques. The reduction of CD58 expression in T cells was correlated with the reduced expression of T-cell-mediated IL-2 and TNFα production. Together, these results indicate that reduction in the CD2/CD58 interaction pathway in mucosal lymphocytes might play a crucial role in mucosal T-cell dysfunction during acute SIV/HIV infection.

A comprehensive approach to expression of L1 loci.

L1 elements represent the only currently active, autonomous retrotransposon in the human genome, and they make major contributions to human genetic instability. The vast majority of the 500 000 L1 elements in the genome are defective, and only a relatively few can contribute to the retrotransposition process. However, there is currently no comprehensive approach to identify the specific loci that are actively transcribed separate from the excess of L1-related sequences that are co-transcribed within genes. We have developed RNA-Seq procedures, as well as a 1200 bp 5΄ RACE product coupled with PACBio sequencing that can identify the specific L1 loci that contribute most of the L1-related RNA reads. At least 99% of L1-related sequences found in RNA do not arise from the L1 promoter, instead representing pieces of L1 incorporated in other cellular RNAs. In any given cell type a relatively few active L1 loci contribute to the 'authentic' L1 transcripts that arise from the L1 promoter, with significantly different loci seen expressed in different tissues.

Disparities in the Presentation and Management of Cutaneous Melanoma That Required Admission.

OBJECTIVE: In this study, we aimed to examine the association of demographic and socioeconomic factors with cutaneous melanoma that required admission. METHODS: A cross-sectional study utilizing the Nationwide Inpatient Sample database, 2003-2009, was merged with County Health Rankings Data. RESULTS: A total of 2,765 discharge -records were included. Men were more likely to have melanoma in the head, neck, and trunk regions (p < 0.001), while extremities melanoma was more common in women (p < 0.001). Males had a higher risk of lymph node metastasis on presentation (OR 1.54, 95% CI [1.27-1.89]). Blacks and Hispanics were more likely to present with extremities melanoma. Patients with low annual income were more likely to be treated by low-volume surgeons and in hospitals located in high-risk communities (p < 0.05 each). Patients with Medicaid coverage were twice as likely to present with distant metastasis and were more likely to be managed by low-volume surgeons (p < 0.05 each). CONCLUSIONS: The presentation and outcomes of cutaneous melanoma have a distinct pattern of distribution based on patients' characteristics.

Financial Implication of Radioactive Iodine Therapy for Early-Stage Papillary Thyroid Cancer.

OBJECTIVE: The aim of this study was to evaluate disease-specific survival and cost related to radioactive iodine therapy (RAI) utilization in patients with early-stage papillary thyroid carcinoma (PTC). METHODS: This was a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2012. RESULTS: A total of 38,374 patients with PTC were identified. Of those, 56.3% had adjuvant RAI. RAI administration was not associated with a survival advantage in patients with PTC stage I (hazard ratio [HR] 1.26, 95% confidence interval [CI] 0.11, 14.54; p = 0.85) or stage II (HR 0.50, 95% CI 0.05, 4.88; p = 0.55). Patients with PTC stage III who underwent adjuvant RAI had an improved survival (HR 0.30, 95% CI 0.10, 0.91; p = 0.033). In 2012, RAI was used in 45.5% of patients with stage I and in 71.4% of patients with stage II. The total expenditure on adjuvant RAI for PTC stage I throughout the study period was estimated to be USD 82.3 million with an annual average of USD 9.1 (±2.0) million/year. If the decline rate in the utilization of RAI continued, the model projected that the annual expenditure would decrease by USD 0.14 million/year. CONCLUSION: There is a high prevalence of adjuvant RAI utilization for early-stage PTC that is causing financial burden on the health system with no evidence of survival benefit.

Risk and Survival of Patients with Head and Neck Cutaneous Melanoma: National Perspective.

OBJECTIVE: Head and neck cutaneous melanoma represents a distinct entity of skin cancer. We aim to examine management and survival of patients with head and neck cutaneous melanoma. METHODS: A retrospective cohort study utilizing the National Cancer Database, 2004-2012. RESULTS: A total of 20,322 (21.2%) head and neck melanomas and 75,547 (78.8%) melanomas of other sites were included. The median follow-up time of head and neck melanoma was 41.6 months (interquartile range: 22.9-68.2 months). Patients with melanoma of the head and neck were more likely to be ≥65 years old, male, and/or white (p < 0.001 each). Positive surgical margin was more prevalent in head and neck melanoma [OR: 2.19, 95% CI: (2.03, 2.37)], and was associated with a lower survival [HR: 1.41, 95% CI: (1.28, 1.57)]. High positive lymph node ratio was associated with a lower survival [HR: 2.00, 95% CI: (1.13, 3.57)]. Adjuvant immunotherapy was associated with an improved survival [HR: 0.67, 95% CI: (0.57, 0.80)]. CONCLUSION: Head and neck cutaneous melanoma is associated with certain demographics. Surgical margin status, lymph node ratio, and immunotherapy are independently associated with overall survival.

Breadth and magnitude of antigen-specific antibody responses in the control of plasma viremia in simian immunodeficiency virus infected macaques.

BACKGROUND: Increasing evidence suggests an unexpected potential for non-neutralizing antibodies to prevent HIV infection. Consequently, identification of functional linear B-cell epitopes for HIV are important for developing preventative and therapeutic strategies. We therefore explored the role of antigen-specific immune responses in controlling plasma viremia in SIV infected rhesus macaques. METHODS: Thirteen rhesus macaques were inoculated either intravaginally or intrarectally with SIVMAC251. Peripheral blood CD4+ T-cells were quantified. Plasma was examined for viremia, antigen specific IgG, IgA and IgM binding responses and neutralizing antibodies. Regions containing binding epitopes for antigen-specific IgG, IgM and IgA responses were determined, and the minimum size of linear Envelope epitope responsible for binding antibodies was identified. RESULTS: The presence of neutralizing antibodies did not correlate the outcome of the disease. In a few SIV-infected macaques, antigen-specific IgG and IgM responses in plasma correlated with decreased plasma viremia. Early induction and the breadth of antigen-specific IgG responses were found to be significantly correlated with the control of plasma viral load. Immunoglobulin classes share similar functional linear B-cell epitopes. SIV-specific linear envelope B-cell epitopes were found to be 12 amino-acids in length. CONCLUSIONS: Early induction of combination of peptide-specific IgG responses were found to be responsible for the control of plasma viral load and indicative of disease outcome in SIV-infected rhesus macaques and might be important for the development of therapeutic strategies for control or prevention of HIV/AIDS.

Risk and outcomes of 24-h delayed and weekend appendectomies.

BACKGROUND: Time interval from hospital admission to operative intervention has been suggested as a crucial risk factor for a number of surgical procedures. In this study, we aim to compare postappendectomy outcomes for operations performed 24 h after admission or on the weekend to within 24 h and weekday operations, respectively. MATERIAL AND METHODS: A cross-sectional study using the Nationwide Inpatient Sample database, 2004-2009. The study population included patients who underwent appendectomy for acute appendicitis. RESULTS: A total of 265,972 records were identified, of which 221,745 (83.4%) patients had appendectomy on the same day of admission, whereas 16.6% had the procedure the following day. Next day operations were more likely to be associated with postoperative complications (OR = 1.26, 95% CI = [1.19-1.33], P < 0.001). A hospital stay of >3 d was also more common for next day interventions (P < 0.001). Appendectomies performed on weekends had a higher risk of complications compared to other days (OR = 1.08, 95% CI = [1.02-1.14], P = 0.005). Teaching and urban hospitals were more likely to perform appendectomies on the day after admission (P < 0.05). Older patients (≥35 years), females, Blacks and Hispanics, and those on Medicaid or Medicare were all at higher risk of next day intervention (P < 0.01 each). The average cost of next day operations was higher compared to same day operations ($9890.11 ± 119.64 versus $8744.57 ± 77.67, P < 0.001). CONCLUSIONS: Appendectomies performed 1 d after admission or on the weekend are associated with disadvantageous outcomes. Demographic factors, in addition to hospital attributes, place certain subpopulations at higher risk of next day appendectomies.

Postoperative outcomes in patients with perforated bowel: early versus late intervention.

BACKGROUND: Time to intervention is suggested to be a crucial factor for a number of surgical conditions. In this study, we aim to examine the postoperative outcomes associated with the timing of surgical intervention in patients with perforated bowel. MATERIALS AND METHODS: Cross-sectional study using the Nationwide Inpatient Sample database, 2003-2010. The study population included adult (≥18 y) inpatients who had perforated intestine or colon and underwent bowel surgery. RESULTS: A total of 5412 (64.6%) patients who had an early surgical intervention on same day of admission and 2985 (35.4%) patients who had a delayed surgery were included. Patients with comorbidities or those in hospitals in the Northeast region of the United States were more likely to have a delayed intervention (P < 0.01). In low-risk patients who are aged <65 y old and with no comorbidities, the timing of surgery did not associate with the risk of postoperative complications (P = 0.77) and mortality (P = 0.08), whereas in high-risk patients who are aged ≥65 y old or with comorbidities, an early surgical intervention was associated with a lower risk of complications (odds ratio: 0.77; 95% CI: 0.69-0.87; P < 0.001), and a lower mortality risk (odds ratio: 0.79; 95% CI: 0.68-0.92; P = 0.002). Patients with a delayed intervention were associated with a hospital stay >15 d (P < 0.001) and a higher cost of health services (P < 0.01). CONCLUSIONS: Patients treated in the Northeast of the United States were more likely to experience a delayed surgery. Delay of surgical intervention is associated with unfavorable outcomes only in older patients or those with comorbidities.

Global bidirectional transcription of the Epstein-Barr virus genome during reactivation.

Epstein-Barr virus (EBV) reactivation involves the ordered induction of approximately 90 viral genes that participate in the generation of infectious virions. Using strand-specific RNA-seq to assess the EBV transcriptome during reactivation, we found extensive bidirectional transcription extending across nearly the entire genome. In contrast, only 4% of the EBV genome is currently bidirectionally annotated. Most of the newly identified transcribed regions show little evidence of coding potential, supporting noncoding roles for most of these RNAs. Based on previous cellular long noncoding RNA size calculations, we estimate that there are likely hundreds more EBV genes expressed during reactivation than was previously known. Limited 5' and 3' rapid amplification of cDNA ends (RACE) experiments and findings of novel splicing events by RNA-seq suggest that the complexity of the viral genome during reactivation may be even greater. Further analysis of antisense transcripts at some of the EBV latency gene loci showed that they are "late" genes, they are nuclear, and they tend to localize in areas of the nucleus where others find newly synthesized viral genomes. This raises the possibility that these transcripts perform functions such as new genome processing, stabilization, organization, etc. The finding of a significantly more complex EBV transcriptome during reactivation changes our view of the viral production process from one that is facilitated and regulated almost entirely by previously identified viral proteins to a process that also involves the contribution of a wide array of virus encoded noncoding RNAs. Epstein-Barr virus (EBV) is a herpesvirus that infects the majority of the world's population, in rare cases causing serious disease such as lymphoma and gastric carcinoma. Using strand-specific RNA-seq, we have studied viral gene expression during EBV reactivation and have discovered hundreds more viral transcripts than were previously known. The finding of alternative splicing and the prevalence of overlapping transcripts indicate additional complexity. Most newly identified transcribed regions do not encode proteins but instead likely function as noncoding RNA molecules which could participate in regulating gene expression, gene splicing or even activities such as viral genome processing. These findings broaden the scope of what we need to consider to understand the viral manufacturing process. As more detailed studies are undertaken they will likely change the way we view this process as a whole.

Comparison of Secondary and Primary Thyroid Cancers: Patient Characteristics and Postoperative Outcomes: A Cross-Sectional Analysis of Patients with Primary and Secondary Thyroid Cancers.

BACKGROUND: Secondary thyroid cancer is believed to lead to a more aggressive clinical course than primary thyroid cancer. We aim to examine the difference between primary and secondary thyroid cancer in terms of patient characteristics and perioperative outcomes at the national level. METHODS: A cross-sectional study utilizing the Nationwide Inpatient Sample database for 2003-2010 was merged with County Health Rankings Data. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to identify adult patients with thyroid cancer. RESULTS: A total of 21,581 discharge records were included. Overall, 16,625 (77.0 %) patients had primary cancer, while the rest (23.0 %) had secondary cancer. Younger (<45 years) and older (>65 years) patients, males, and those of White or Hispanic background were more likely to have secondary cancers (p < 0.05 each). The prevalence of secondary cancer was higher in communities of low health risk (24.0 % vs. 21.1 %; p < 0.024). Secondary cancer was more likely to be managed by total thyroidectomy (odds ratio [OR] 2.40, 95 % CI 2.12-2.73) and to require additional radical neck dissection (OR 12.51, 95 % CI 10.98-14.25). Patients with secondary thyroid cancers were at higher risk of postoperative complications (p < 0.01 each). The cost of secondary cancer management was significantly higher than primary cancer (US$12,449.00 ± 302.07 vs. US$7848.12 ± 149.05; p < 0.001). However, compared with intermediate-volume surgeons, the complication risk was lower for high-volume (OR 0.47, 95 % CI 0.24-0.92; p = 0.026). CONCLUSIONS: Secondary thyroid cancer is associated with a higher risk of perioperative complications and higher cost and distinct demographic profile. Patients managed by higher-volume surgeons were less likely to experience disadvantageous outcomes.

The impact of surgical volume on racial disparity in thyroid and parathyroid surgery.

PURPOSE: The aim of this study was to evaluate the association between surgeon volume and patient outcomes among different race ethnicities undergoing thyroid or parathyroid surgery. METHODS: The nationwide inpatient sample was used to identify all thyroidectomy and parathyroidectomy admissions from 2003 to 2009, using International Classification of Diseases, 9th Clinical Modification (ICD-9-CM) procedure codes. Race, demographic, and clinical characteristics of patients were collected, along with surgeon volume, to predict the length of stay (LOS), complication rates, mortality, and total charges by racial group, using univariate and multivariate analyses. RESULTS: A total of 106,314 thyroid and parathyroid surgeries were included in the current analysis. Of these patients, 54 % were Caucasian, 11 % African American, 7 % Hispanic, and 3 % Asian. Mean LOS was longer for African American patients (4 ± 8.7 days) than for Caucasians (2.3 ± 5.5 days) [p < 0.001]. African Americans had higher overall complications (16.8 %) compared with Caucasians (11 %), Hispanics (13.5 %), and Asians (12 %) [p < 0.001]. In-hospital mortality was higher for African Americans (0.8 %) compared with that from other race groups (0.3 %) [p < 0.001]. Mean total charges were significantly higher for African Americans ($33,292 ± $67,387) compared with those for Caucasians ($22,855 ± $40,167) (p < 0.001). African Americans had less access to intermediate- (10-99 cases) and high- (>100 cases) volume surgeons compared with Caucasians-45 versus 49 %, and 16 versus 19 %, respectively (p < 0.001). Higher surgeon volume was associated with improved outcomes (p < 0.001). Racial disparity in all investigated outcomes was still significantly evident even after stratification by surgeon volume. CONCLUSION: Higher surgeon volume is associated with improved patient outcomes. However, our data suggests that the observed racial disparities in thyroid and parathyroid surgery go beyond access to quality healthcare providers.

High circulating estrogens and selective expression of ERß in prostate tumors of Americans: implications for racial disparity of prostate cancer.

Although estrogen receptor beta (ERß) has been implicated in prostate cancer (PCa) progression, its potential role in health disparity of PCa remains elusive. The objective of this study was to examine serum estrogens and prostate tumor ERß expression and examine their correlation with clinical and pathological parameters in African American (AA) versus Caucasian American (CA) men. The circulating 17ß-estradiol (E2) was measured by enzyme immunoassay in blood procured from racially stratified normal subjects and PCa patients. Differential expression profile analysis of ERß was analyzed by quantitative immunohistochemistry using ethnicity-based tissue microarray encompassing 300 PCa tissue cores. In situ ERß expression was validated by quantitative reverse transcription-PCR in matched microdissected normal prostate epithelium and tumor cells and datasets extracted from independent cohorts. In comparison with normal age-matched subjects, circulating E2 levels were significantly elevated in all PCa patients. Further analysis demonstrates an increase in blood E2 levels in AA men in both normal and PCa in comparison with age- and stage-matched counterparts of CA decent. Histochemical score analysis reveals intense nuclear immunoreactivity for ERß in tumor cores of AA men than in CA men. Gene expression analysis in microdissected tumors corroborated the biracial differences in ERß expression. Gene expression analysis from independent cohort datasets revealed correlation between ERß expression and PCa progression. However, unlike in CA men, adjusted multivariate analysis showed that ERß expression correlates with age at diagnosis and low prostate-specific antigen recurrence-free survival in AA men. Taken together, our results suggest that E2-ERß axis may have potential clinical utility in PCa diagnosis and clinical outcome among AA men.

Prospective dual role of mesenchymal stem cells in breast tumor microenvironment.

Breast cancer tissue is a heterogeneous cellular milieu comprising cancer and host cells. The interaction between breast malignant and non-malignant cells takes place in breast tumor microenvironment (TM), and has a crucial role in breast cancer progression. In addition to cellular component of TM, it mainly consists of cytokines released by tumor cells. The tumor-tropic capacity of mesenchymal stem cells (MSCs) and their interaction with breast TM is an active area of investigation. In the present communication, the interplay between the breast resident adipose tissue-derived MSCs (B-ASCs) and breast TM was studied. It was found that a distinct subset of B-ASCs display a strong affinity for conditioned media (CM) from two breast cancer cell lines, MDA-MB 231 (MDA-CM) and MCF-7 (MCF-CM). The expressions of several cytokines including angiogenin, GM-CSF, IL-6, GRO-α and IL-8 in MDA-CM and MCF-CM have been identified. Upon functional analysis a crucial role for GRO-α and IL-8 in B-ASCs migration was detected. The B-ASC migration was found to be via negative regulation of RECK and enhanced expression of MMPs. Furthermore, transcriptome analysis showed that migratory subpopulation express both pro- and anti-tumorigenic genes and microRNAs (miRNA). Importantly, we observed that the migratory cells exhibit similar gene and miRNA attributes as those seen in B-ASCs of breast cancer patients. These findings are novel and suggest that in breast cancer, B-ASCs migrate to the proximity of tumor foci. Characterization of the molecular mechanisms involved in the interplay between B-ASCs and breast TM will help in understanding the probable role of B-ASCs in breast cancer development, and could pave way for anticancer therapies.

Divergent Cytokine and Chemokine Responses at Early Acute Simian Immunodeficiency Virus Infection Correlated with Virus Replication and CD4 T Cell Loss in a Rhesus Macaque Model.

Cytokine and chemokine levels remain one of the significant predictive factors of HIV pathogenesis and disease outcome. Understanding the impact of cytokines and chemokines during early acute infection will help to recognize critical changes during HIV pathogenesis and might assist in establishing improved HIV treatment and prevention methods. Sixty-one cytokines and chemokines were evaluated in the plasma of an SIV-infected rhesus macaque model. A substantial change in 11 cytokines/growth factors and 9 chemokines were observed during acute infection. Almost all the cytokines/chemokines were below the baseline values for an initial couple of days of infection. We detected six important cytokines/chemokines, such as IL-18, IP-10, FLT3L, MCP-1, MCP-2, and MIP-3ß, that can be used as biomarkers to predict the peripheral CD4+ T cell loss and increased viral replication during the acute SIV/HIV infection. Hence, regulating IL-18, IP-10, FLT3L, MCP-1, MCP-2, and MIP-3ß expression might provide an antiviral response to combat acute SIV/HIV infection.

Incidence of acute myocardial infarction and hurricane Katrina: Fourteen years after the storm.

INTRODUCTION: Historically, natural disasters have been known to have an effect on humankind including physical and mental health. Studies dating from the early nineteen hundreds have shown repeated associations between different catastrophic natural disasters and its effects on cardiovascular (CV)health, including increased morbidity and mortality. Knowing that these effects on CV health last sometimes up to a decade, we sought to study the effects of hurricane Katrina on incidence of acute myocardial infarctions (AMI) to see if the effects perpetuated and continued or mitigated after the first decade. METHODS: Ours is a single center, retrospective observational study at TUHSC to compare the incidence of AMI, chronobiology and other demographic characteristics between the 2-year pre-Katrina and 14-year post-Katrina group. After IRB approval, patients were identified using specific ICD 9 and 10 codes. Data was collected by chart review and stored in secure password protected files. Descriptive statistics including mean, standard deviation and percentages were calculated. Statistical analysis comparing mean and standard deviations were performed using Chi-square test and t-test. RESULTS: The pre-Katrina cohort saw a 0.7% incidence of AMI, whereas the post-Katrina cohort saw 3.0% incidence of AMI (p < 0.001). The post- Katrina group was also noted to have significantly higher comorbidities including diabetes, hypertension, polysubstance abuse and coronary artery disease. CONCLUSIONS: Even 14 years after the storm, there was a four-fold increase in the incidence of AMI. Additionally, psychosocial, behavioral and traditional risk factors for CAD were significantly higher more than a decade after the natural disaster as well.

SARS-CoV-2 infection dysregulates NAD metabolism.

Introduction: Severe COVID-19 results initially in pulmonary infection and inflammation. Symptoms can persist beyond the period of acute infection, and patients with Post-Acute Sequelae of COVID (PASC) often exhibit a variety of symptoms weeks or months following acute phase resolution including continued pulmonary dysfunction, fatigue, and neurocognitive abnormalities. We hypothesized that dysregulated NAD metabolism contributes to these abnormalities. Methods: RNAsequencing of lungs from transgenic mice expressing human ACE2 (K18-hACE2) challenged with SARS-CoV-2 revealed upregulation of NAD biosynthetic enzymes, including NAPRT1, NMNAT1, NAMPT, and IDO1 6 days post-infection. Results: Our data also demonstrate increased gene expression of NAD consuming enzymes: PARP 9,10,14 and CD38. At the same time, SIRT1, a protein deacetylase (requiring NAD as a cofactor and involved in control of inflammation) is downregulated. We confirmed our findings by mining sequencing data from lungs of patients that died from SARS-CoV-2 infection. Our validated findings demonstrating increased NAD turnover in SARS-CoV-2 infection suggested that modulating NAD pathways may alter disease progression and may offer therapeutic benefits. Specifically, we hypothesized that treating K18-hACE2 mice with nicotinamide riboside (NR), a potent NAD precursor, may mitigate lethality and improve recovery from SARS-CoV-2 infection. We also tested the therapeutic potential of an anti- monomeric NAMPT antibody using the same infection model. Treatment with high dose anti-NAMPT antibody resulted in significantly decreased body weight compared to control, which was mitigated by combining HD anti-NAMPT antibody with NR. We observed a significant increase in lipid metabolites, including eicosadienoic acid, oleic acid, and palmitoyl carnitine in the low dose antibody + NR group. We also observed significantly increased nicotinamide related metabolites in NR treated animals. Discussion: Our data suggest that infection perturbs NAD pathways, identify novel mechanisms that may explain some pathophysiology of CoVID-19 and suggest novel strategies for both treatment and prevention.

Comparison of Ketamine and Propofol-Based Regimens for Deep Sedation in Children Undergoing Esophagogastroduodenoscopy.

We retrospectively reviewed the charts of 180 children sedated for esophagogastroduodenoscopy (EGD) with ketamine or propofol-based regimens at our institution. Pre-EGD diagnoses and American Society of Anesthesiology physical status were similar in all subjects. Onset of action and recovery time for both regimens were not statistically significant ( p > 0.05). Mean onset of sedation for all patients was 3.85 ± 3.04 minutes, mean Aldrete score was 6.31 ± 0.61, and mean recovery time was 51.85 ± 31.78 minutes ( p > 0.05). Sedation-related adverse events observed include apnea, hypoxemia, bradycardia, hypotension, laryngospasm, skin rash, and wheezing. Deep sedation for pediatric EGD is safe if patients are carefully screened and properly monitored.