Background: Globally 1% of individuals are infected with hepatitis C virus (HCV). In South Africa (SA), the prevalence ranges between 0.3% - 1% with few prospective screening data available. Similarly, local data on transmission modes of HCV are limited but probably include parenteral routes and pre-1992 blood or blood product products. The risk of heterosexually transmission is low but is increased in men who have sex with men (MSM) with co- transmission risk of both HIV and HCV. Objectives: Given a limited local understanding, we sought to better understand HCV characteristics and prevalence in 2 groups of HIV-infected men. Methods: HIV positive men in the greater Cape Town metropolitan area were recruited. Sexual orientation was self-identified and demographic and other personal data obtained via a confidentially administered questionnaire. Participants were screened for HCV after a blood draw and positive HCV Ab tests were tested for HCV RNA. Risk factors associated with HCV seropositivity were determined. Results: Five hundred HIV positive men were recruited; 215 (43%) non-MSM and 285 (57%) MSM, with median age 36 years (IQR 20 – 64) and 37 years (IQR 21 – 56), in the MSM and non-MSM group, respectively, p = NS. Overall, 3.4% (n=17) screened HCV positive, 5.6% (n=16) MSM and 0.5% (n=1) non-MSM, with 82.4% viremic for HCV RNA. In respect to genotype (GT) distribution, 50% were infected with GT1, 14.3% GT4 and 35.7% were GT2. In terms of risk, MSM were more likely to have used drugs (54.4% vs. 30.2%, p<0.001) and to have used all five modes of drugs administration (13% of MSM vs. 0.5% of non- MSM for injected drugs, 36.1% vs. 2.3% inhaled, 10% vs. 0% for the rectal route, 48.1% vs. 28.8% for smoked and 27.4% vs. 2.3% for oral drugs). More MSM than non-MSM (46.3% vs. 16.7%) reported sex whilst using recreational drugs and similarly more MSM (21.4% vs. 14%) reported having sex with a sex worker (SW).Risk factors for HCV seropositivity included drug use history (odds ratio (OR) 6.28, 98% confidence interval (CI). 1.78 – 22.12: p=0.004) and in MSM, sex with SW (OR 5.5, 95% 2.06 – 14.68; p=0.001) or use of recreational drugs with sex (OR 6.88, 95% CI 2.21 -21.44; p=0.001). Conclusion: HCV prevalence in HIV positive MSM is higher than previously appreciated or documented in South Africa. Risk factors include injecting drug use, use of recreational drugs with sex and sex with SWs. Targeted interventions are required to address this emerging challenge to achieve the viral hepatitis elimination ideal by 2030.

Background Hepatitis C (HCV) in South Africa is incompletely characterised and understood. Epidemiological and clinical data will better inform our understanding and assist national policy decision making. On the background of more than two decades of clinical challenges in HCV management, the advent of direct acting antivirals (DAA) now makes HCV elimination plausible. To better understand the base from which we come, we elected to review and characterise our HCV experience at Groote Schuur Hospital (GSH) in the Pegylated interferon (Peg-IFN) and Ribavirin (RBV) management era. Methods Patients with chronic HCV attending GSH Liver Clinic from 2002 to 2014, were included, in the analysis. Relevant data were extracted from a registry and existing clinical records accessed. Two brands of Peg-IFN were available and those treated with the first generation add-on protease inhibitor, telaprevir, were included. Results 238 patients were included in the analysis, median age of 47 (IQR 37-58) years, men 60.5%. Men were significantly younger than women, 43.5 (35-52) vs 55 (42-64) years, respectively, p< 0.0001. Ethnically, the majority were white (55.9%) or mixed-ancestry (21.8%), 16.4% were HIV co-infected, 3.7% hepatitis B (HBV) co-infected and 0.4% triple infected with HCV, HBV and HIV. The most likely mode of HCV acquisition was blood/blood product exposure prior to 1992 (32.8%) and injecting drug use (IDU) 17.6%, while 30.3%, had no clear risk factor identifiable. Genotypes (GT) 1 to 5 were observed with GT-1 (34.9%) predominating. In those biopsied, (n=90), 30% ≥F3 fibrosis, with 15.6% cirrhotic. With IL28B polymorphisms, heterozygous CT (23.9%) and CC genotype (15.5%), were most frequent. 32.6% accessed Peg-IFN/Ribavirin-based therapy, 6.5% (n=5) with add-on telaprevir. GT-1 (35.1%) was most prevalent in the treatment group, followed by GT-3 (26%) and GT-5 (18.2%); 10% were HIV co-infected. Overall SVR rate was 75.3% with 37% of GT-1 not achieving SVR; 49.4% experienced adverse events including cytopaenias (32.5%) and depression (15.6%) with 15.6% requiring erythropoietin for anaemia and 15.6% GM-CSF for neutropaenia. Conclusion HCV patients in the Peg-IFN/Ribavirin management era typified the epidemiology of HCV. GT distribution was pangenotypic and treatment outcomes were encouraging despite treatment challenges. Patient selection, IL28B and sensible cytopaenia support, likely accounted for this. However numbers treated were limited and the DAA era of therapy allows for a rapid expansion of therapy with now growing numbers of patients and a changing local epidemiology.

Endoskopiska undersökningar har blivit vanligare och ökat i antal. Detta på grund av den  ökade livslängden. Möjligheten att behandla och att bota sjukdomar har också blivit bättre.  Screening av kolorektalcancer leder också till ett ökat antal patienter. De endoskopiska  undersökningarna har tidigare endast utförts av läkare. För att patienterna inte skall behöva  vänta för länge på undersökning har det införts endoskoperande sjuksköterskor runt om i  världen. Omvårdnaden runt de patienter som behöver genomgå endoskopiska undersökningar  är mycket viktig då undersökningarna kan upplevas som obehagliga och smärtsamma.    Syftet är att belysa vad som finns beskrivet angående patienttillfredsställelse och kvalité vid  endoskopiska undersökningar genomförda av sjuksköterskor.      Metod som valts till detta arbete är forskningsöversikt. Sammanlagt ingår 19 artiklar från  olika delar av världen.    Resultatet visar att patienttillfredsställelsen är god och att många patienter föredrar  endoskoperande sjuksköterskor. Kvalitén på undersökningarna var god och i jämförelse med  läkare är sjuksköterskor mer noggranna och finner flera avvikande fynd. Dock tar de  sjuksköterskeutförda undersökningarna längre tid i jämförelse med undersökningar utförda av  läkare.     Enligt denna forskningsöversikt har artiklarna i detta arbete visat att patienttillfredsställelsen  är god vid endoskopiska undersökningar genomförda av sjuksköterskor. Resultatet av denna  studie visar att sjuksköterskor genomför endoskopiska undersökningar med god kvalité och  med hög säkerhet för patienterna. Detta sammantaget med att väntetiderna för  undersökningarna kan kortas med hjälp av sjuksköterskor kan här ses en vinst för patienterna.

With the start of NASA’s Artemis program, astronauts will soon leave the protection of Earth’s magnetosphere. Previous studies have established a theme of liver dysregulation associated with the harmful radiation and microgravity experienced in deep space. MicroRNAs (miRNAs) are key regulators of many of the pathologies observed during and after spaceflight, including hepatic fibrosis, making them strong potential biomarkers and therapeutic targets. Therefore, in the present study we investigated the effects of simulated microgravity, galactic cosmic radiation (GCR), and solar particle events (SPE) on miRNAs and mRNAs involved in the TGF-β signaling pathway, a key regulator of fibrosis, senescence, and inflammation in the liver. We also analyzed the ability of an antagomir treatment which targets miR-16-5p, miR-125b-5p, and let-7a-5p to modulate these spaceflight-associated changes in liver health. Our results indicate that the observed miRNA profile widely varied depending on whether GCR or SPE irradiation were administered. Likewise, while the antagomir treatment was successful at downregulating expression of its target mRNAs, the type of radiation received greatly influenced whether the miRNA shifts observed correlated with changes in downstream gene expression; the GCR group was the most effected and the SPE the least in terms of both miRNA and mRNA expression. Overall, the current study highlights the profound effects of cosmic radiation on the hepatic miRNA profile and confirms the potential of antagomir treatment as a therapeutic for spaceflight induced changes in expression.

Background: Stroke is the fifth leading cause of death in Tennessee. The Tennessee Stroke Registry (TSR) Act requires East Tennessee State University’s College of Public Health to maintain a stroke database of participating hospitals and produce an annual report. Currently, twelve hospitals submit data to the TSR. Objectives: The TSR seeks to provide stroke information to Tennessee residents, policy makers, and health-care professionals. This presentation will highlight the key findings of the 2015 TSR report and will serve as an update to the 2014 report presented at the 2015 Tennessee Public Health Association conference. Methods: Data for the TSR was collected via Quintiles, American Heart Association’s online database. Microsoft Excel and ArcMap 10.3.x were used to conduct a descriptive analysis of stroke across Tennessee, observing characteristics of both stroke overall and of individual subtypes. Results: Seventy-nine percent of strokes in Tennessee in 2015 were ischemic. Some subtypes showed significantly different proportions of males versus females. For instance, females made up 63% of subarachnoid hemorrhage patients. The average age of stroke patients in Tennessee was 67.1 years, but varied for subtypes, ranging from 58.2 to 69 years. The majority of stroke patients (75.1%) had a recorded history of hypertension. Counties with high stroke mortality rates tended to cluster in areas of few certified stroke centers. Conclusion: Stroke subtypes exhibited different characteristics than stroke overall and geographic disparities were highlighted through the descriptive mapping. Identifying and understanding these differences and disparities can help in addressing ways to improve stroke care in Tennessee.

Colorectal cancer (CRC) is defined as a cancer appearing in the colon or in the rectum. In Sweden, ~ 6300 individuals were diagnosed with the disease in 2014 and ~ 2550 individuals diagnosed with CRC die each year due to their cancer. Surgery is the main treatment option of CRC and a survival rate of ~ 10 % is estimated if distant metastases have developed. It is therefore of importance to find factors that may be useful together with tumour, node, metastasis (TNM) stage to establish early CRC diagnosis, prognosis and follow-up of CRC patients. The aim of this thesis was to study the possible association of CD93, PLA2G4C, PDGF-D and inflammatory cytokines with CRC disease progression. In a prospective study approach CD93 and PLA2G4C single nucleotide polymorphisms (SNPs) were of potential importance in CRC prognosis. The T/T genotype of CD93 was associated with an increased CD93 expression in CRC tissue. Further, CRC patients carrying this genotype were associated with disseminated CRC at diagnosis and a lower recurrence-free survival after surgery. The A allele of a SNP of PLA2G4C was a stronger predictor for CRC-specific mortality than the conventional risk factors used in the clinic for selection of TNM stage II patients for adjuvant treatment. This indicates that the T/T genotype of CD93 and the A allele of PLA2G4C may be potential genetic factors related to disease severity and spread. Furthermore, they distinguish CRC patients that may benefit from a more comprehensive follow-up and adjuvant treatment. To study the putative involvement of PDGF-D in CRC the effects of PDGF-D signalling was studied in vitro. PDGF-D signalling altered the expression of genes of importance in CRC carcinogenesis and proliferation which was blocked by imatinib, a tyrosine kinase inhibitor. This indicates that PDGF-D signalling may be an important pathway in CRC progression and a potential target in CRC treatment. The analysis of various inflammatory cytokines in plasma at diagnosis showed an association between high levels and increased total- or CRC-specific mortality two years after surgery. High levels of CCL1 and CCL24 was the only cytokines strongly correlated with a worse CRC prognosis after statistical adjustments and may be of interest for further evaluation. In conclusion, this thesis presents circulating and genetic factors such as CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 that may be of importance in CRC progression and may be of clinical value together with TNM stage in establishing prognosis. / Kolorektal cancer är en tumör i kolon eller rektum. I Sverige diagnosticerades år 2014 ca6300 individer med denna cancertyp och ca 2550 personer dör årligen till följd av kolorektalcancer. Operation är det huvudsakliga behandlingsalternativet för kolorektal cancer och vidfjärrmetastaser är överlevnaden &lt; 10 %. Det är därför viktigt att hitta markörer somtillsammans med TNM-stadium kan ge tidig information om sjukdomens prognos och lämpliguppföljning av patienter. Utveckling av kolorektal cancer sker genom ackumulering av genetiska mutationer ochepigenetisk nedreglering av tumörsuppressorgener. Därutöver spelar interaktionen mellantumören och dess närmaste omgivning, innehållande tillväxt- och inflammatoriska faktorer,en viktig roll i tumörens utveckling och metastasering. Syftet med avhandlingen var att studera associationen mellan CD93, PLA2G4C, PDGF-D samtinflammatoriska cytokiner och kolorektal cancer progression. En prospektiv studie visade att CD93 och PLA2G4C SNP var potentiellt viktiga förbedömningav kolorektal cancer prognos. T/T genotypen av SNP rs2749817 i CD93 var associerad medhögre uttryck av CD93 i kolorektal cancer vävnad, främst bland patienter i stadium IV.Därutöver observerades fler återfall efter operation hos patienter med T/T genotypen. Aallelen hos PLA2G4C SNP rs1549637 är en möjligtvis bättre markör för cancerspecifiköverlevnad vid stadium II än faktorer som idag används för att selektera patienter tilladjuvant behandling. Sammantaget antyder detta att T/T genotypen av CD93 och A allelenav PLA2G4C kan vara genetiska markörer relaterade till allvarlig tumörsjukdom ochspridning. Därutöver kan de eventuellt selektera patienter som kräver tätare uppföljning ochadjuvant behandling. För att studera den förmodade inblandningen av PDGF-D i kolorektal cancer undersöktesdess effekt på PDGF-D signalering in vitro. PDGF-D signaleringen förändradegenexpressionen av gener involverade i tumörutveckling och spridning, vilken kundeblockeras av tyrosinkinashämmaren imatinib. Det antyder att PDGF-D signalering kan vara enviktig faktor vid kolorektal cancer progression och ett potentiellt mål för behandling. Analysen av ett flertal inflammatoriska cytokiner visade en korrelation mellan högacytokinnivåer och ökad cancerspecifik och total dödlighet två år efter operation. Höga CCL1och CCL24 nivåer var de enda faktorerna som förblev signifikant associerade medcancerspecifik mortalitet vid fördjupad statistisk analys och bör studeras vidare. Sammanfattningsvis presenterar denna avhandling cirkulerande och genetiska faktorersåsom CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 som eventuellt är viktiga vid bedömning avkolorektal cancer progression tillsammans med TNM stadium.

Alcoholic fatty liver disease (AFLD) is a significant public health concern. Excessive alcohol (ethanol) consumption causes liver cell damage and death, which results in eventual failure of the liver and death. AFLD is the number one cause of liver-related mortality in the United States. Our lab works with the novel protein C1q TNF Related Protein 3 (CTRP3), which inhibits non-alcoholic fatty liver disease, however the effects on AFLD are unknown. Therefore, the purpose of this experiment is to determine if CTRP3 prevents ethanol-induced liver cell death. The H4IIE rat hepatoma cell line was chosen for experimentation as a cell culture model of liver tissue. To determine a suitable alcohol level H4IIE cells were treated with 50, 100, and 200 mmol of ethanol for 18-24 hours. Trypan Blue was used to identify the dead/damaged cells, as only dead/damaged cells will be stained blue with this protocol. We observed that 100 mmol of ethanol consistently induced ~10% mortality rate in these cells. Next, we tested the ability of CTRP3 to reduce ethanol-induced mortality. We added purified CTRP3 protein to the cell media along with the 100 mmol ethanol treatment. The addition of CTRP3 reduced the amount of alcohol-induced cell death/damage in the H4IIE cell line by approximately 60%. Our next goal was to determine how CTRP3 reduces ethanol-induced death. The Akt signaling pathway is a well-known inhibitor of cell death. Therefore, to determine if CTRP3 attenuated ethanol-induced cell damage/death through activation of the Akt signaling pathway, another set of cells was treated with 100 mmol of ethanol and CTRP3 (with or without insulin). Western blots were used to compare the amount of active Akt (phosphorylated) in the CTRP3-treated and non-treated cells. A Western blot utilizes an electric current to separate denatured protein samples on a SDS-page gel, separating the proteins based on size. The smaller the protein the faster it migrates across the gel. The proteins are then transferred to a membrane for analysis, through exposure to commercial antigens and chemiluminescence imaging. There was no change in the amount of total or active Akt between the samples treated with or without CTRP3. We conclude that CTRP3 protects liver cells from ethanol-induced damage/death, but not through activation of the Akt pathway.

Alcohol abuse is the third leading cause of preventable death in the United States. Excessive intake of alcohol can result to alcoholic fatty liver disease, the number one cause of live related mortalities in the US. The outlining purpose for this project is to determine the alcohol-induced changes in the liver cell protein signaling. For this project, we treated H4IIE rat hepatoma cells (with 100 and 200 mM ethanol overnight). H4IIE cells were chosen because they are a commonly used liver cell culture line that maintains characteristics of intact liver cells. After treatment we collected and prepared the cells for protein signaling analysis, using standard western blotting procedure. A western blot detects relative quantity of proteins in a sample. Briefly, protein samples are separated by size through electrophoresis, smaller proteins move faster through the gel so that the larger proteins are toward the top and smaller towards the bottom. The proteins are then transferred to a nitrocellulose membrane and protein concentration is detected by chemiluminescence. We chose to examine the effects of ethanol on the activation of the key regulator of metabolic signaling, Protein Kinase B/Akt (Akt). Based on our results, ethanol has no effect on the total amount of Akt in the H4IIE liver cells. However, ethanol significantly attenuates insulin-induced activation of Akt in a dose-dependent manner, as seen by a reduction in the amount of phosphorylated Akt. Therefore, we conclude that treatments that increase Akt activation may be a viable option for the treatment of alcoholic fatty liver disease.

The Relationship Between Central Venous Catheter and Post-operative Complications in Patients Undergoing Hepatic Resection David C. O’Connor, Ph.D., DNAP, CRNA A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University Virginia Commonwealth University, 2018 Dissertation Chair: Clarence J. Biddle, Ph.D., CRNA Hepatic resection is indicated for primary and secondary malignancies. Use of a low central venous pressure technique is associated with decreased blood loss in these cases. This technique has evolved; central venous catheters and high dose morphine are no longer used, and patients are extubated earlier. The purpose of this study is to assess a relationship between these changes and outcomes. Central venous pressure has fallen out of favor as an accurate fluid measurement. Central venous catheters are associated with many complications. Outcomes in patients undergoing hepatic resection have improved over 20 years at one high volume institution. Guided by Donabedian’s theory of measuring outcomes, a non-randomized, non-experimental, retrospective, cohort design was conducted. The independent variables were intraoperative insertion of a central venous catheter, use of morphine, and time of extubation. The dependent variables were superficial and deep wound infections, number and severity of complications. The population sample is patients who submitted to partial hepatectomy at Memorial Sloan Kettering Cancer Center from 2007-2016. Data was obtained from hepatobiliary and anesthesia databases at Memorial Sloan Kettering Cancer Center. Data of 2518 from a possible 3903 patients were analyzed with chi square, univariate, Poisson and multivariate regressions. Univariate analysis for presence of CVC was significant for 90-day mortality (p 0.013). Use of morphine was significant for superficial wound infection (p 0.035), and a decrease in complications (p <.001). Amount of morphine was associated with fewer severe complications (p <.001). Incidental findings included a relationship between gender, total amount of fluids and number of segments resected. The significance of CVC with 90-day mortality was eliminated with stepwise multivariate regression. The findings support the change in anesthetic practice with clinical significance. Incidental findings regarding fluids and segments are supported in the literature. Future research should include goal directed fluid therapy and investigation of the relationship between gender and outcomes.

En la presente tesis se ha analizado la actividad hepática de una enzima (prolilhidroxilasa) que interviene en la síntesis del colágeno y la concentración sérica de un péptido (péptido aminoterminal del procolágeno tipo III) que se origina durante el proceso de síntesis del mismo en un grupo de pacientes con una hepatopatía alcohólica de diversa severidad diagnosticados por biopsia hepática y se ha observado una relación entre los niveles de actividad hepática de la prolil-hidroxilasa y la concentración sérica del péptido aminoterminal del procolágeno tipo III con la intensidad de la fibrosis hepática. También se ha hallado una relación lineal directa entre ambos parámetros lo que sugiere que ambos marcadores son índices de fibrosis y fibrogénesis hepatica en la hepatopatía alcohólica y podrían ser de utilidad en el control evolutivo de estos pacientes.