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.

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.

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.

Riluzole regulates pancreatic cancer cell metabolism by suppressing the Wnt-ß-catenin pathway.

Most cancer cells rely on aerobic glycolysis to support uncontrolled proliferation and evade apoptosis. However, pancreatic cancer cells switch to glutamine metabolism to survive under hypoxic conditions. Activation of the Wnt/ß-catenin pathway induces aerobic glycolysis by activating enzymes required for glucose metabolism and regulating the expression of glutamate transporter and glutamine synthetase. The results demonstrate that riluzole inhibits pancreatic cancer cell growth and has no effect on human pancreatic normal ductal epithelial cells. RNA-seq experiments identified the involvement of Wnt and metabolic pathways by riluzole. Inhibition of Wnt-ß-catenin/TCF-LEF pathway by riluzole suppresses the expression of PDK, MCT1, cMyc, AXIN, and CyclinD1. Riluzole inhibits glucose transporter 2 expression, glucose uptake, lactate dehydrogenase A expression, and NAD + level. Furthermore, riluzole inhibits glutamate release and glutathione levels, and elevates reactive oxygen species. Riluzole disrupts mitochondrial homeostasis by inhibiting Bcl-2 and upregulating Bax expression, resulting in a drop of mitochondrial membrane potential. Finally, riluzole inhibits pancreatic cancer growth in KPC (Pdx1-Cre, LSL-Trp53R172H, and LSL-KrasG12D) mice. In conclusion, riluzole can inhibit pancreatic cancer growth by regulating glucose and glutamine metabolisms and can be used to treat pancreatic cancer.

Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques.

Angiotensin converting enzyme-2 (ACE2) and associated proteins play a pivotal role in various physiological and pathological events, such as immune activation, inflammation, gut barrier maintenance, intestinal stem cell proliferation, and apoptosis. Although many of these clinical events are quite significant in SIV/HIV infection, expression profiling of these proteins has not been well reported. Considering the different pathological consequences in the gut after HIV infection, we hypothesized that the expression of ACE2 and associated proteins of the Renin-angiotensin system (RAS) could be compromised after SIV/HIV infection. We quantified the gene expression of ACE2 as well as AGTR1/2, ADAM17, and TMPRSS2, and compared between SIV infected and uninfected rhesus macaques (Macaca mulatta; hereafter abbreviated RMs). The gene expression analysis revealed significant downregulation of ACE2 and upregulation of AGTR2 and inflammatory cytokine IL-6 in the gut of infected RMs. Protein expression profiling also revealed significant upregulation of AGTR2 after infection. The expression of ACE2 in protein level was also decreased, but not significantly, after infection. To understand the entirety of the process in newly regenerated epithelial cells, a global transcriptomic study of enteroids raised from intestinal stem cells was performed. Interestingly, most of the genes associated with the RAS, such as DPP4, MME, ANPEP, ACE2, ENPEP, were found to be downregulated in SIV infection. HNFA1 was found to be a key regulator of ACE2 and related protein expression. Jejunum CD4+ T cell depletion and increased IL-6 mRNA, MCP-1 and AGTR2 expression may signal inflammation, monocyte/macrophage accumulation and epithelial apoptosis in accelerating SIV pathogenesis. Overall, the findings in the study suggested a possible impact of SIV/HIV infection on expression of ACE2 and RAS-associated proteins resulting in the loss of gut homeostasis. In the context of the current COVID-19 pandemic, the outcome of SARS-CoV-2 and HIV co-infection remains uncertain and needs further investigation as the significance profile of ACE2, a viral entry receptor for SARS-CoV-2, and its expression in mRNA and protein varied in the current study. There is a concern of aggravated SARS-CoV-2 outcomes due to possible serious pathological events in the gut resulting from compromised expression of RAS- associated proteins in SIV/HIV infection.

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.

Identification, Characterization, and Transcriptional Reprogramming of Epithelial Stem Cells and Intestinal Enteroids in Simian Immunodeficiency Virus Infected Rhesus Macaques.

Epithelial cell injury and impaired epithelial regeneration are considered key features in HIV pathogenesis and contribute to HIV-induced generalized immune activation. Understanding the molecular mechanisms underlying the disrupted epithelial regeneration might provide an alternative approach for the treatment of HIV-mediated enteropathy and immune activation. We have observed a significant increased presence of α defensin5+ (HD5) Paneth cells and proliferating Ki67+ epithelial cells as well as decreased expression of E-cadherin expression in epithelial cells during SIV infection. SIV infection did not significantly influence the frequency of LGR5+ stem cells, but the frequency of HD5+ cells was significantly higher compared to uninfected controls in jejunum. Our global transcriptomics analysis of enteroids provided novel information about highly significant changes in several important pathways like metabolic, TCA cycle, and oxidative phosphorylation, where the majority of the differentially expressed genes were downregulated in enteroids grown from chronically SIV-infected macaques compared to the SIV-uninfected controls. Despite the lack of significant reduction in LGR5+ stem cell population, the dysregulation of several intestinal stem cell niche factors including Notch, mTOR, AMPK and Wnt pathways as well as persistence of inflammatory cytokines and chemokines and loss of epithelial barrier function in enteroids further supports that SIV infection impacts on epithelial cell proliferation and intestinal homeostasis.

COVID 19 in-hospital mortality, body mass index and obesity related conditions.

OBJECTIVE: Obese patients with respiratory failure need more intensive care and invasive mechanical ventilation than their non-obese counterparts. We aimed to evaluate the impact of body mass index and obesity related conditions on fatal outcome during a hospitalization for COVID-19. METHODS: From March 1 to April 30, 2020, 425 consecutive patients with severe acute respiratory syndrome coronavirus 2 were hospitalized at University Medical Center, in New Orleans. Clinical variables, comorbidities, and hospital course were extracted from electronic medical records. Special attention was given to obesity related conditions like hypertension, type 2 diabetes, and dyslipidemia. Severe obesity was defined as a body mass index ≥35-<40 kg/m2 and morbid obesity as body mass index ≥40 kg/m2. Risk of mortality was determined by applying multivariate binary logistic regression modeling to risk factor variables (age, sex, race, and Charlson comorbid score). RESULTS: Patients were mostly African American (77.9%) and 51.0% were women. Age and Charlson comorbidity index scores averaged 60 (50-71 years) and 3.0 (1.25-5), respectively. In-hospital mortality was greater in morbidly obese than non-morbidly obese patients. Of the 64 severely obese patients, 16 had no obesity related conditions, and 48 had at least one obesity related condition: hypertension (60%), type 2 diabetes mellitus (28%), and dyslipidemia (20%). In-hospital mortality was greater in severely obese patients with than without at least one obesity related condition. CONCLUSION: During a hospitalization for COVID-19, severely obese patients with at least one obesity related condition and morbidly obese patients have a high mortality.

Enhanced Intestinal TGF-ß/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques.

Transforming growth factor-ß signaling (TGF-ß) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-ß promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-ß production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-ß in a majority of intestinal CD3-CD20-CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-ß receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-ß production by intestinal CD3-CD20-CD68+ cells and increased TGF-ß/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-ß and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-ß production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-ß expression by therapeutic TGF-ß blockers may help to create effective antiviral mucosal immune responses.

Effects of Social Housing Changes on Immunity and Vaccine-Specific Immune Responses in Adolescent Male Rhesus Macaques.

Nonhuman primates (NHPs) in research institutions may be housed in a variety of social settings, such as group housing, pair housing or single housing based on the needs of studies. Furthermore, housing may change over the course of studies. The effects of housing and changes in housing on cell activation and vaccine mediated immune responses are not well documented. We hypothesized that animals moved indoors from group to single housing (GH-SH) would experience more stress than those separated from groups into pair housing (GH-PH), or those placed briefly into pair housing and separated 5 weeks later into single housing (GH-PH-SH). We also compared the effects of separation from group to pair housing with the separation from pair to single housing. Eighteen male rhesus macaques were followed over the course of changes in housing condition over 10-14 weeks, as well as prior to and after primary vaccination with a commercially available measles vaccine. We identified two phenotypic biomarkers, namely total CD8 population and proliferating B cells, that differed significantly across treatment groups over time. At 10 weeks post-separation, levels of proliferating B cells were higher in GH-SH subjects compared to GH-PH subjects, and in the latter, levels were lower at 10 weeks than prior to removal from group housing. At 2 weeks post-separation from group to single housing, the frequency of CD8+ T cells was higher in GH-SH subjects compared to one week post separation from pair into single housing in the GH-PH-SH subjects. Comparing the same elapsed time since the most recent separation activated CD20 populations were persistently higher in the GH-SH animals than the GH-PH-SH animals. Housing configuration did not influence vaccine-mediated responses. Overall, our study found benefits of pair housing over single housing, suggesting that perturbations in immune function will be more severe following separation from group to single housing than from pair to single housing, and supporting the use of short-duration pair housing even when animals must subsequently be separated. These findings are useful for planning the housing configurations of research NHPs used for vaccine studies and other studies where immune response is being assessed.

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.

Targeting TRAF3IP2, Compared to Rab27, is More Effective in Suppressing the Development and Metastasis of Breast Cancer.

Here we investigated the roles of Rab27a, a player in exosome release, and TRAF3IP2, an inflammatory mediator, in development and metastasis of breast cancer (BC) in vivo. Knockdown (KD) of Rab27a (MDAKDRab27a) or TRAF3IP2 (MDAKDTRAF3IP2) in triple negative MDA-MB231 cells reduced tumor growth by 70-97% compared to wild-type tumors (MDAw). While metastasis was detected in MDAw-injected animals, none was detected in MDAKDRab27a- or MDAKDTRAF3IP2-injected animals. Interestingly, micrometastasis was detected only in the MDAKDRab27a-injected group. In addition to inhibiting tumor growth and metastasis, silencing TRAF3IP2 disrupted inter-cellular inflammatory mediator-mediated communication with mesenchymal stem cells (MSCs) injected into contralateral mammary gland, evidenced by the lack of tumor growth at MSC-injected site. Of translational significance, treatment of pre-formed MDAw-tumors with a lentiviral-TRAF3IP2-shRNA not only regressed their size, but also prevented metastasis. These results demonstrate that while silencing Rab27a and TRAF3IP2 each inhibited tumor growth and metastasis, silencing TRAF3IP2 is more effective; targeting TRAF3IP2 inhibited tumor formation, regressed preformed tumors, and prevented both macro- and micrometastasis. Silencing TRAF3IP2 also blocked interaction between tumor cells and MSCs injected into the contralateral gland, as evidenced by the lack of tumor formation on MSCs injected site. These results identify TRAF3IP2 as a novel therapeutic target in BC.

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.

Investigation of Radiation Oncologists' Awareness of Online Reputation Management.

BACKGROUND: Online reputation management (ORM) is an emerging practice strategy that emphasizes the systematic and proactive monitoring of online reviews relating to one's professional reputation. OBJECTIVE: We developed this survey project to assess whether radiation oncologists are aware of ORM and how it is utilized in their practices. We hypothesized that ORM is largely unknown by most practicing radiation oncologists and that little time is spent actively managing their reputations. METHODS: An online survey was submitted to 1222 radiation oncologists using the Qualtrics research platform. Physician emails were gathered from the American Society for Radiation Oncology member directory. A total of 85 physicians initiated the survey, whereas 76 physicians completed more than or equal to 94% (15/16) of the survey questions and were subsequently used in our analyses. The survey consisted of 15 questions querying practice demographics, patient satisfaction determination, ORM understanding, and activities to address ORM and 1 question for physicians to opt-in to a US $50 Amazon gift card raffle. The survey data were summarized using a frequency table, and data were analyzed using the Chi-square test, Fisher exact test, and Spearman correlation coefficients. RESULTS: We calculated a 7% (85/1222) response rate for our survey, with a completion rate of 89% (76/85). A majority of respondents (97%, 74/76) endorsed being somewhat or strongly concerned about patient satisfaction (P<.001). However, 58% (44/76) of respondents reported spending 0 hours per week reviewing or managing their online reputation and 39% (30/76) reported spending less than 1 hour per week (P<.001). A majority of physicians (58%, 44/76) endorsed no familiarity with ORM (P<.001) and 70% (53/76) did not actively manage their online reputation (P<.001). Although 83% (63/76) of respondents strongly or somewhat believed that patients read online reviews (P<.001), 57% (43/76) of respondents did not check their online reviews (P=.25) and 80% (61/76) endorsed never responding to online reviews (P<.001). Moreover, 58% (44/76) of the respondents strongly or somewhat supported the idea of managing their online reputation going forward (P=.001). In addition, 11 out of the 28 pairs of questions asked in our correlation studies reached statistical significance. Degree of concern for patient satisfaction and the notion of managing one's ORM going forward were the 2 most frequently correlated topics of statistical significance in our analyses. CONCLUSIONS: ORM is presently under-recognized in radiation oncology. Although most practitioners are concerned about patient satisfaction, little effort is directed toward the internet on this matter. ORM offers an area of practice improvement for many practicing radiation oncologists.

Regional Differences in the Treatment of Localized Prostate Cancer: An Analysis of Surgery and Radiation Utilization in the United States.

PURPOSE: Men with localized prostate cancer have various treatment options available in their management. The optimal approach is controversial and can be influenced by multiple factors. This study aimed to investigate the influence of geographic region on the selection of treatment for prostate cancer. METHODS AND MATERIALS: Using the National Cancer Database, we identified men diagnosed with localized prostate cancer between 2010 and 2014. The United States was divided into 11 regions per the American Cancer Society Divisions. The first course of treatment was recorded as radiation therapy (RT), radical prostatectomy (RP), or active surveillance (AS). The RT subgroup consisted of patients receiving all forms of RT, including external beam and brachytherapy, or RT plus androgen deprivation therapy. The RP subgroup consisted of patients receiving RP alone or combined with RT or androgen deprivation therapy. A χ2 test was performed to assess the association between region and frequency of RT and RP. RESULTS: This study included 462,811 men with localized prostate cancer who were treated in the United States, of whom 63.46% underwent RP, 31.54% underwent RT, and 5.00% underwent AS. Significant regional differences in RP and RT were observed (P ≤ .0001). RP was used most commonly in the Midwest (75.07%) and High Plains (73.37%) regions, whereas RP was least used in the South Atlantic (59.04%) region. Similarly, RT was used most commonly in South Atlantic (40.96%) and New England (38.98%) regions and least commonly in the Midwest (24.93%) region. AS was used most in the New England (7.27%) and Midwest (6.8%) regions and least used in the High Plains (2.57%) and Mid-South (2.84%) regions. CONCLUSIONS: Regional differences exist in the United States with regard to the definitive treatment of localized prostate cancer. The etiology for these regional differences is likely multifactorial.

Expanding Research Capacity in Sub-Saharan Africa Through Informatics, Bioinformatics, and Data Science Training Programs in Mali.

Bioinformatics and data science research have boundless potential across Africa due to its high levels of genetic diversity and disproportionate burden of infectious diseases, including malaria, tuberculosis, HIV and AIDS, Ebola virus disease, and Lassa fever. This work lays out an incremental approach for reaching underserved countries in bioinformatics and data science research through a progression of capacity building, training, and research efforts. Two global health informatics training programs sponsored by the Fogarty International Center (FIC) were carried out at the University of Sciences, Techniques and Technologies of Bamako, Mali (USTTB) between 1999 and 2011. Together with capacity building efforts through the West Africa International Centers of Excellence in Malaria Research (ICEMR), this progress laid the groundwork for a bioinformatics and data science training program launched at USTTB as part of the Human Heredity and Health in Africa (H3Africa) initiative. Prior to the global health informatics training, its trainees published first or second authorship and third or higher authorship manuscripts at rates of 0.40 and 0.10 per year, respectively. Following the training, these rates increased to 0.70 and 1.23 per year, respectively, which was a statistically significant increase (p < 0.001). The bioinformatics and data science training program at USTTB commenced in 2017 focusing on student, faculty, and curriculum tiers of enhancement. The program's sustainable measures included institutional support for core elements, university tuition and fees, resource sharing and coordination with local research projects and companion training programs, increased student and faculty publication rates, and increased research proposal submissions. Challenges reliance of high-speed bandwidth availability on short-term funding, lack of a discounted software portal for basic software applications, protracted application processes for United States visas, lack of industry job positions, and low publication rates in the areas of bioinformatics and data science. Long-term, incremental processes are necessary for engaging historically underserved countries in bioinformatics and data science research. The multi-tiered enhancement approach laid out here provides a platform for generating bioinformatics and data science technicians, teachers, researchers, and program managers. Increased literature on bioinformatics and data science training approaches and progress is needed to provide a framework for establishing benchmarks on the topics.

The Incidence, Risk Factors, and Chronobiology of Acute Myocardial Infarction Ten Years After Hurricane Katrina.

OBJECTIVE: The purpose of this study was to investigate the 10-year impact of Hurricane Katrina on the incidence of acute myocardial infarction (AMI) along with contributing risk factors and any alteration in chronobiology of AMI. METHODS: A single-center, retrospective, comparison study of AMI incidence was performed at Tulane University Health Sciences Center from 2 years before Hurricane Katrina to 10 years after Hurricane Katrina. A 6-year, pre-Katrina and 10-year, post-Katrina cohort were also compared according to pre-specified demographic, clinical, and chronobiological data. RESULTS: AMI incidence increased from 0.7% (150/21,079) to 2.8% (2,341/84,751) post-Katrina (P<0.001). The post-Katrina cohort had higher rates of coronary artery disease (36.4% vs. 47.9%, P=0.01), diabetes mellitus (31.3% vs. 39.9%, P=0.04), hyperlipidemia (45.4% vs. 59.3%, P=0.005), smoking (34.4% vs. 53.8%, P<0.001), drug abuse (10.2% vs. 15.4%, P=0.02), psychiatric illness (6.7% vs. 14.9%, P<0.001), medication non-adherence (7.3% vs. 15.3%, P<0.001), and lack of employment (7.2% vs. 16.4%, P<0.001). The post-Katrina group had increased rates of AMI during nights (29.8% vs. 47.8%, P<0.001) and weekends (16.1% vs. 29.1%, P<0.001). CONCLUSIONS: Even 10 years after the storm, Hurricane Katrina continues to be associated with increased incidence of AMI, higher prevalence of traditional cardiovascular and psychosocial risk factors, and an altered chronobiology of AMI toward nights and weekends. (Disaster Med Public Health Preparedness. 2019;13:217-222).

Quantification of Viral RNA and DNA Positive Cells in Tissues From Simian Immunodeficiency Virus/Simian Human Immunodeficiency Virus Infected Controller and Progressor Rhesus Macaques.

Eradication of human immunodeficiency virus 1 (HIV-1) from an infected individual cannot be achieved using current antiretroviral therapy (ART) regimens. Viral reservoirs established in early infection remain unaffected by ART and are able to replenish systemic infection upon treatment interruption. Simian immunodeficiency virus (SIV) infected macaque models are useful for studying HIV pathogenesis, treatments, and persistent viral reservoirs. Here, we used the SIV macaque model to examine and quantify RNA and DNA positive cells in tissues from macaques that control viral replication (controllers) and those that have persistently high plasma viremia (progressors). A positive correlation was detected between tissue RNA+ cells and plasma viral load in both mesenteric lymph node (LN) and spleen. Similarly, a positive correlation also observed between DNA+ cells and plasma viral load in ileum and jejunum. Controllers had a lower frequency of both RNA and DNA+ cells in several tissues compared to progressors. However, DNA+ cells were prevalent in mesenteric LN, inguinal LN, colon, midbrain, and bone marrow tissues in both controller and progressors. Organized lymphoid tissues of LNs, spleen, and intestine were found as the major tissues positive for virus. Viral RNA and DNA positive cells were detected in brain and thymus in macaques with high plasma viremia and SIV-encephalitis. Both T cells and macrophages were shown to be infected in several tissues, indicating vaccines and ART should be specifically designed to protect these cells in organized lymphoid tissues. These results indicate ART should target infected cells in secondary lymphoid organs to reduce both productively and latently infected cells.

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.