Low Risk of Death, but Substantial Program Attrition, in Pediatric HIV Treatment Cohorts in Sub-Saharan Africa

BACKGROUND: To date, an estimated 10% of children eligible for antiretroviral treatment (ART) receive it, and the frequency of retention in programs is unknown. We evaluated the 2-year risks of death and loss to follow-up (LTFU) of children after ART initiation in a multicenter study in sub-Saharan Africa. METHODS: Pooled analysis of routine individual data from 16 participating clinics produced overall Kaplan-Meier estimates of the probabilities of death or LTFU after ART initiation. Risk factors analysis used Weibull regression, accounting for between-cohort heterogeneity. RESULTS: The median age of 2405 children at ART initiation was 4.9 years (12%, younger than 12 months), 52% were male, 70% had severe immunodeficiency, and 59% started ART with a nonnucleoside reverse transcriptase inhibitor. The 2-year risk of death after ART initiation was 6.9% (95% confidence interval [CI]: 5.9 to 8.1), independently associated with baseline severe anemia (adjusted hazard ratio [aHR]: 4.10 [CI: 2.36 to 7.13]), immunodeficiency (adjusted aHR: 2.95 [CI: 1.49 to 5.82]), and severe clinical status (adjusted aHR: 3.64 [CI: 1.95 to 6.81]); the 2-year risk of LTFU was 10.3% (CI: 8.9 to 11.9), higher in children with severe clinical status. CONCLUSIONS: Once on treatment, the 2-year risk of death is low but the LTFU risk is substantial. ART is still mainly initiated at advanced disease stage in African children, reinforcing the need for early HIV diagnosis, early initiation of ART, and procedures to increase program retention.

Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Divalent metal transporter-1 (SLC11A2/DMT1) uses the H+ electrochemical gradient as the driving force to transport divalent metal ions such as Fe2+, Mn2+ and others metals into mammalian cells. DMT1 is ubiquitously expressed, most notably in proximal duodenum, immature erythroid cells, brain and kidney. This transporter mediates H+-coupled transport of ferrous iron across the apical membrane of enterocytes. In addition, in cells such as to erythroid precursors, following transferrin receptor (TfR) mediated endocytosis; it mediates H+-coupled exit of ferrous iron from endocytic vesicles into the cytosol. Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery. In the present study, we performed a ligand-based virtual screening of the Princeton database (700,000 commercially available compounds) to search for pharmacophore shape analogs of recently reported DMT1 inhibitors. We discovered a new compound, named pyrimidinone 8, which mediates a reversible linear non-competitive inhibition of human DMT1 (hDMT1) transport activity with a Ki of ∼20 μM. This compound does not affect hDMT1 cell surface expression and shows no dependence on extracellular pH. To our knowledge, this is the first experimental evidence that hDMT1 can be allosterically modulated by pharmacological agents. Pyrimidinone 8 represents a novel versatile tool compound and it may serve as a lead structure for the development of therapeutic compounds for pre-clinical assessment.

T-cell reprogramming through targeted CD4-coreceptor and T-cell receptor expression on maturing thymocytes by latent Circoviridae family member porcine circovirus type 2 cell infections in the thymus

Although porcine circovirus type 2 (PCV2)-associated diseases have been evaluated for known immune evasion strategies, the pathogenicity of these viruses remained concealed for decades. Surprisingly, the same viruses that cause panzootics in livestock are widespread in young, unaffected animals. Recently, evidence has emerged that circovirus-like viruses are also linked to complex diseases in humans, including children. We detected PCV2 genome-carrying cells in fetal pig thymi. To elucidate virus pathogenicity, we developed a new pig infection model by in vivo transfection of recombinant PCV2 and the immunosuppressant cofactor cyclosporine A. Using flow cytometry, immunofluorescence and fluorescence in situ hybridization, we found evidence that PCV2 dictates positive and negative selection of maturing T cells in the thymus. We show for the first time that PCV2-infected cells reside at the corticomedullary junction of the thymus. In diseased animals, we found polyclonal deletion of single positive cells (SPs) that may result from a loss of major histocompatibility complex class-II expression at the corticomedullary junction. The percentage of PCV2 antigen-presenting cells correlated with the degree of viremia and, in turn, the severity of the defect in thymocyte maturation. Moreover, the reversed T-cell receptor/CD4-coreceptor expression dichotomy on thymocytes at the CD4(+)CD8(interm) and CD4SP cell stage is viremia-dependent, resulting in a specific hypo-responsiveness of T-helper cells. We compare our results with the only other better-studied member of Circoviridae, chicken anemia virus. Our data show that PCV2 infection leads to thymocyte selection dysregulation, adding a valuable dimension to our understanding of virus pathogenicity.

Outcomes of Infants Starting Antiretroviral Therapy in Southern Africa, 2004-2012.

BACKGROUND There are limited published data on the outcomes of infants starting antiretroviral therapy (ART) in routine care in Southern Africa. This study aimed to examine the baseline characteristics and outcomes of infants initiating ART. METHODS We analyzed prospectively collected cohort data from routine ART initiation in infants from 11 cohorts contributing to the International Epidemiologic Database to Evaluate AIDS in Southern Africa. We included ART-naive HIV-infected infants aged <12 months initiating ≥3 antiretroviral drugs between 2004 and 2012. Kaplan-Meier estimates were calculated for mortality, loss to follow-up (LTFU), transfer out, and virological suppression. We used Cox proportional hazard models stratified by cohort to determine baseline characteristics associated with outcomes mortality and virological suppression. RESULTS The median (interquartile range) age at ART initiation of 4945 infants was 5.9 months (3.7-8.7) with follow-up of 11.2 months (2.8-20.0). At ART initiation, 77% had WHO clinical stage 3 or 4 disease and 87% were severely immunosuppressed. Three-year mortality probability was 16% and LTFU 29%. Severe immunosuppression, WHO stage 3 or 4, anemia, being severely underweight, and initiation of treatment before 2010 were associated with higher mortality. At 12 months after ART initiation, 17% of infants were severely immunosuppressed and the probability of attaining virological suppression was 56%. CONCLUSIONS Most infants initiating ART in Southern Africa had severe disease with high probability of LTFU and mortality on ART. Although the majority of infants remaining in care showed immune recovery and virological suppression, these responses were suboptimal.

Alcoholic Cirrhosis Increases Risk for Autoimmune Diseases: A Nationwide Registry-Based Cohort Study

BACKGROUND & AIMS Alcoholic cirrhosis is associated with hyperactivation and dysregulation of the immune system. In addition to its ability to increase risk for infections, it also may increase the risk for autoimmune diseases. We studied the incidence of autoimmune diseases among patients with alcoholic cirrhosis vs controls in Denmark. METHODS We collected data from nationwide health care registries to identify and follow up all citizens of Denmark diagnosed with alcoholic cirrhosis from 1977 through 2010. Each patient was matched with 5 random individuals from the population (controls) of the same sex and age. The incidence rates of various autoimmune diseases were compared between patients with cirrhosis and controls and adjusted for the number of hospitalizations in the previous year (a marker for the frequency of clinical examination). RESULTS Of the 24,679 patients diagnosed with alcoholic cirrhosis, 532 developed an autoimmune disease, yielding an overall increased adjusted incidence rate ratio (aIRR) of 1.36 (95% confidence interval [CI], 1.24-1.50). The strongest associations were with Addison's disease (aIRR, 2.47; 95% CI, 1.04-5.85), inflammatory bowel disease (aIRR, 1.56; 95% CI, 1.26-1.92), celiac disease (aIRR, 5.12; 95% CI, 2.58-10.16), pernicious anemia (aIRR, 2.35; 95% CI, 1.50-3.68), and psoriasis (aIRR, 4.06; 95% CI, 3.32-4.97). There was no increase in the incidence rate for rheumatoid arthritis (aIRR, 0.89; 95% CI, 0.69-1.15); the incidence rate for polymyalgia rheumatica decreased in patients with alcoholic cirrhosis compared with controls (aIRR, 0.47; 95% CI, 0.33-0.67). CONCLUSIONS Based on a nationwide cohort study of patients in Denmark, alcoholic cirrhosis is a risk factor for several autoimmune diseases.

Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia.

BACKGROUND Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies. METHODS A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response. RESULTS Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity. CONCLUSIONS Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).

Evaluation of epidemiological and clinical factors in survival of patients with de novo myelodysplastic syndrome at the University of Texas MD Anderson cancer center

Little is known about epidemiological markers that are associated with survival of patients with myelodysplastic syndromes (MDS). We conducted a secondary case-based analysis of 465 de novo MDS patients from the University of Texas MD Anderson Cancer Center (UTMDACC). We investigated the association between demographic as well as occupational exposure markers and survival while incorporating known clinical markers of prognosis. In our patient population, 60.6% were men and the majority were white (93.1%). The distribution of MDS subtypes by the French–American–British (FAB) classification was 81 (19%) refractory anemia (RA), 46 (9.9%) refractory anemia with ringed sideroblasts (RARS), 57 (12.3%) chronic myelomonocytic leukemia (CMML), 173 (37.2%) RA with excess blasts (RAEB), and 86 (18.5%) RAEB in transformation (RAEBT). We found that those older at diagnosis (> 60 years of age) (HR = 1.68, CI = 1.26-2.25) were at a higher risk of dying compared to younger patients. Similarly, high pack years of smoking (>= 30 pack years of smoking) (HR = 1.34, CI = 1.02-1.74), and agricultural chemical exposure (HR = 1.61, CI = 1.05-2.46) were significantly associated with overall lower survival when compared to patients with none or medium exposures. Among clinical markers, greater than 5% bone marrow blasts (HR = 1.81 CI = 1.27-2.56), poor cytogenetics (HR = 3.20, CI = 2.37-4.33)), and platelet cytopenias (<100000/ul) (HR = 1.46, CI = 1.11-1.92) were also significantly associated with overall MDS survival.^ The identification of epidemiological markers could help physicians stratify patients and customize treatment strategies to improve the outcome of MDS based on patient lifestyle information such as smoking exposure and agrochemical exposure. We hope that this study highlights the impact of these exposures in MDS prognosis.^

A movement from traditional malarial chemoprophylaxis to the use of intermittent preventive treatment as a method of protection for children diagnosed with sickle-cell disease: A proposal for consideration based on a systematic review of the literature

Approximately 200,000 African children are born with sickle-cell anemia each year. Research has shown that individuals with hemoglobin disorders, particularly sickle-cell anemia, have increased susceptibility to contracting malaria. Currently it is recommended that patients diagnosed with sickle-cell anemia undergo malaria chemoprophylaxis in order to decrease their chances of malarial infection. However, studies have shown that routine administration of these drugs increases the risk of drug resistance and could possibly impair the development of naturally acquired immunity. Clinical trials have shown intermittent preventive treatment (IPT) to be an effective method of protection against malaria. The objective of this report was to review previously conducted clinical trials that study the effects of intermittent preventive treatment on malaria and anemia in infants and children. Based on the review, implications for its appropriateness as a protective measure against malaria for infants and children diagnosed with sickle-cell disease were provided.^ The 18 studies reviewed were randomized controlled trials that focused on IPT’s effect on malaria (7 studies), anemia (1 study), or both (8 studies). In addition to these 16, one study looks at IPT’s effect on molecular resistance to malaria, and another study is a follow-up to a study in order to review IPT’s potential to cause a rebound effect. The 18 th study in this review specifically looks at IPT’s protective efficacy in children with SCA. The studies in this report were restricted to randomized controlled trials that have been performed from 2000 to 2010. Reports on anemia were included to illustrate possible added benefits of the use of IPT specific to burdens associated with SCA other than malaria susceptibility. The outcomes of these studies address several issues of concern involving the administration of IPT: protective efficacy (in reference to age, seasonal versus perennial malaria regions, and overall effectiveness against malaria and anemia), drug resistance, drug rebound effect, drug side-effects, and long-term effects. Overall, these showed that IPT has a significant level of protective efficacy against malaria and/or anemia in children. More specifically, the IPT study evaluating children diagnosed with sickle-cell anemia proved IPT to be a more effective method of protection than traditional chemoprophylaxis. ^

Secondary analysis of effectivness of tinidazole-containing-quadruple eradication therapy in asymptomatic H. pylori infected children in El Paso

Helicobacter pylori infection is frequently acquired during childhood. This microorganism is known to cause gastritis, and duodenal ulcer in pediatric patients, however most children remain completely asymptomatic to the infection. Currently there is no consensus in favor of treatment of H. pylori infection in asymptomatic children. The firstline of treatment for this population is triple medication therapy including two antibacterial agents and one proton pump inhibitor for a 2 week duration course. Decreased eradication rate of less than 75% has been documented with the use of this first-line therapy but novel tinidazole-containing quadruple sequential therapies seem worth investigating. None of the previous studies on such therapy has been done in the United States of America. As part of an iron deficiency anemia study in asymptomatic H. pylori infected children of El Paso, Texas, we conducted a secondary data analysis of study data collected in this trial to assess the effectiveness of this tinidazole-containing sequential quadruple therapy compared to placebo on clearing the infection. Subjects were selected from a group of asymptomatic children identified through household visits to 11,365 randomly selected dwelling units. After obtaining parental consent and child assent a total of 1,821 children 3-10 years of age were screened and 235 were positive to a novel urine immunoglobulin class G antibodies test for H. pylori infection and confirmed as infected using a 13C urea breath test, using a hydrolysis urea rate >10 μg/min as cut-off value. Out of those, 119 study subjects had a complete physical exam and baseline blood work and were randomly allocated to four groups, two of which received active H. pylori eradication medication alone or in combination with iron, while the other two received iron only or placebo only. Follow up visits to their houses were done to assess compliance and occurrence of adverse events and at 45+ days post-treatment, a second urea breath test was performed to assess their infection status. The effectiveness was primarily assessed on intent to treat basis (i.e., according to their treatment allocation), and the proportion of those who cleared their infection using a cut-off value >10 μg/min of for urea hydrolysis rate, was the primary outcome. Also we conducted analysis on a per-protocol basis and according to the cytotoxin associated gene A product of the H. pylori infection status. Also we compared the rate of adverse events across the two arms. On intent-to-treat and per-protocol analyses, 44.3% and 52.9%, respectively, of the children receiving the novel quadruple sequential eradication cleared their infection compared to 12.2% and 15.4% in the arms receiving iron or placebo only, respectively. Such differences were statistically significant (p<0.001). The study medications were well accepted and safe. In conclusion, we found in this study population, of mostly asymptomatically H. pylori infected children, living in the US along the border with Mexico, that the quadruple sequential eradication therapy cleared the infection in only half of the children receiving this treatment. Research is needed to assess the antimicrobial susceptibility of the strains of H. pylori infecting this population to formulate more effective therapies. ^

Racial differences in heart failure with preserved ejection fraction in the ambulatory heart failure population

Racial differences in heart failure with preserved ejection fraction (HFpEF) have rarely been studied in an ambulatory, financially "equal access" cohort, although the majority of such patients are treated as outpatients. ^ Retrospective data was collected from 2,526 patients (2,240 Whites, 286 African American) with HFpEF treated at 153 VA clinics, as part of the VA External Peer Review Program (EPRP) between October 2000 and September 2002. Kaplan Meier curves (stratified by race) were created for time to first heart failure (HF) hospitalization, all cause hospitalization and death and Cox proportional multivariate regression models were constructed to evaluate the effect of race on these outcomes. ^ African American patients were younger (67.7 ± 11.3 vs. 71.2 ± 9.8 years; p < 0.001), had lower prevalence of atrial fibrillation (24.5 % vs. 37%; p <0.001), chronic obstructive pulmonary disease (23.4 % vs. 36.9%, p <0.001), but had higher blood pressure (systolic blood pressure > 120 mm Hg 77.6% vs. 67.8%; p < 0.01), glomerular filtration rate (67.9 ± 31.0 vs. 61.6 ± 22.6 mL/min/1.73 m2; p < 0.001), anemia (56.6% vs. 41.7%; p <0.001) as compared to whites. African Americans were found to have higher risk adjusted rate of HF hospitalization (HR 1.52, 95% CI 1.1 - 2.11; p = 0.01), with no difference in risk-adjusted all cause hospitalization (p = 0.80) and death (p= 0.21). ^ In a financially "equal access" setting of the VA, among ambulatory patients with HFpEF, African Americans have similar rates of mortality and all cause hospitalization but have an increased risk of HF hospitalizations compared to whites.^

Health status of Saudi women, the case of Yanbu al-Sinaiya

Detailed data on the health status of Saudi women are lacking. This cross sectional study attempts to provide a comprehensive description of the health status of Saudi females between the ages of 15-45 residing in Yanbu Al-Siniyah. The purpose is to assess women's needs for health services. The health status indicators are chronic tracer conditions, reported symptoms and multidimensional functioning levels. The generic functioning instrument of the Medical Outcome Study was used to estimate physical, social, and role functioning; degree of pain and health perceptions. The information was obtained by interviewing subjects and abstracting facts from their medical records. The results show functioning scores are in the "well health" range for physical, social, role and pain. Crowding and education have an equal or stronger effect of reducing functioning levels than the diagnosed tracer conditions. The highest prevalence conditions having a definite functional impact and diagnosed adequately in primary care are anemia, urinary tract infection, hemorrhoids, rheumatoid arthritis, caries and gingivitis. Reported symptoms strongly reducing function levels in this study are dyspnea, heart pain, incontinence, eye and skin problems, and joint ache. The impact of the reliability and validity of the measures used and other limitations of the results are discussed. Finally, some policy implications and suggestions for future study are presented. ^

BENZENE TOXICITY AND THE OCCURRENCE OF BENZENE IN THE AMBIENT AIR OF THE HOUSTON AREA

This study was conducted by either literature review or actual field survey. Results are summarized as follows: (1) Long-term occupational exposure of workers to benzene vapor at levels of 3-7 ppm, 2-3 ppm and 1.6 ppm may result in a decreased level of leucocyte alkaline phosphates, an increased incidence of chromosome aberrations and an increased level of ALA in erythrocytes, respectively; (2) Benzene is capable of causing fetotoxic effects in animals at levels as low as 10 ppm by volume; (3) Exposure of animals to or less than 1 ppm benzene vapor may result in leucopenia, an inverse ratio of muscle antagonist chronaxy and a decreased level of ascorbic acid in fetus's and mother's liver as well as whole embryo; (4) Benzene is causally associated with the increased incidence of pancytopenia, including unicytopenia, bicytopenia and aplastic anemia, and chromosome aberrations in occupational exposure population, and at best benzene must also be considered as a leukemogen; (5) Since it can be emitted into the atmosphere from both man-made and natural sources, benzene in some concentrations is present everywhere in the various compartments of the environment; (6) The findings of the emission of benzene from certain natural sources indicate that reducing benzene to a zero-level of exposure is theoretically impossible; (7) The annual average of benzene concentration detected in the Houston ambient air is 2.50 ppb, which is about 2.4 times higher than the nation-wide annual average exposure level and may have been some health implications to the general public; (8) In the Houston area, stationary sources are more important than mobile sources in contributing to benzene in the ambient air. ^

Policy analysis of iron micronutrient programs at USAID: The FANTA program in East Africa and the micronutrient initiative in Bihar region of India, using comparative cost effective and cost benefit analysis

It is the aim of this paper to examine iron supplementation programs which receive funding from United States Agency for International Development (USAID) but approach combating iron deficiency anemia in two vastly different ways. A brief literature review and background information on iron deficiencies and the differences between supplementation programs and micronutrient fortification were reviewed. Two non-governmental organizations (NGO's) were examined for this paper: the Food and Nutrition Technical Assistance II (FANTA) and the MicroNutrient Initiative. The FANTA program included an educational component to their supplementation program while the MicroNutrient Initiative solely used supplementation of micronutrients to their population. Methods used were cost-benefit analysis and cost-effectiveness analysis to determine the overall effectiveness of each program in reducing iron deficiency anemia in each population, if the added costs of the incentives in the FANTA program changed the cost-effectiveness of the program compared to the MicroNutrient Initiative program and to determine which program imparted the greatest benefit to each population by reducing the disease burden in Disability Adjusted Life Years (DALY). Results showed that the unit cost of the FANTA program per person was higher than the MicroNutrient Initiative program due to the educational component. The FANTA program reduced iron deficiency anemia less overall but cost less for each percentage point of anemia decreased in their respective populations. The MicroNutrient Initiative program had a better benefit cost ratio for the populations it served. The MicroNutrient Initiative's large scale program imparted many advantages by reducing unit cost per person and decreasing iron deficiency anemia. The FANTA program was more effective at decreasing iron deficiency anemia with less money: $5,660 per 1% decrease in iron deficiency anemia versus $18,450 per 1% decrease in iron deficiency anemia for the MicroNutrient Initiative program. ^ In conclusion, economic analysis cannot measure all of the benefits associated with programs that contain an educational component or large scale supplementation. More information needs to be gathered by NGOs and reported to USAID, such as detailed prevalence rates of iron deficiency anemia among the populations served. Further research is needed to determine the effects an educational supplementation program has on compliance rates of participants and motivation to participate in supplementation programs whose aim is to decrease iron deficiency anemia in a targeted population.^

Prevalence and determinants of hepatitis B co-infection among a United States Veterans Administration cohort with hepatitis C

Background and aim. Hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection is associated with increased risk of cirrhosis, decompensation, hepatocellular carcinoma, and death. Yet, there is sparse epidemiologic data on co-infection in the United States. Therefore, the aim of this study was to determine the prevalence and determinants of HBV co-infection in a large United States population of HCV patients. ^ Methods. The National Veterans Affairs HCV Clinical Case Registry was used to identify patients tested for HCV during 1997–2005. HCV exposure was defined as two positive HCV tests (antibody, RNA or genotype) or one positive test combined with an ICD-9 code for HCV. HCV infection was defined as only a positive HCV RNA or genotype. HBV exposure was defined as a positive test for hepatitis B core antibodies, hepatitis B surface antigen, HBV DNA, hepatitis Be antigen, or hepatitis Be antibody. HBV infection was defined as only a positive test for hepatitis B surface antigen, HBV DNA, or hepatitis Be antigen within one year before or after the HCV index date. The prevalence of exposure to HBV in patients with HCV exposure and the prevalence of HBV infection in patients with HCV infection were determined. Multivariable logistic regression was used to identify demographic and clinical determinants of co-infection. ^ Results. Among 168,239 patients with HCV exposure, 58,415 patients had HBV exposure for a prevalence of 34.7% (95% CI 34.5–35.0). Among 102,971 patients with HCV infection, 1,431 patients had HBV co-infection for a prevalence of 1.4% (95% CI 1.3–1.5). The independent determinants for an increased risk of HBV co-infection were male sex, positive HIV status, a history of hemophilia, sickle cell anemia or thalassemia, history of blood transfusion, cocaine and other drug use. Age >50 years and Hispanic ethnicity were associated with a decreased risk of HBV co-infection. ^ Conclusions. This is the largest cohort study in the United States on the prevalence of HBV co-infection. Among veterans with HCV, exposure to HBV is common (∼35%), but HBV co-infection is relatively low (1.4%). There is an increased risk of co-infection with younger age, male sex, HIV, and drug use, with decreased risk in Hispanics.^

FANCM AND FAAP24 MAINTAIN GENOMIC STABILITY THROUGH COOPERATIVE AND UNIQUE FUNCTIONS

Fanconi anemia (FA) is a rare recessive genetic disease with an array of clinical manifestations including multiple congenital abnormalities, progressive bone marrow failure and profound cancer susceptibility. A hallmark of cells derived from FA patients is hypersensitivity to DNA interstrand crosslinking agents such as mitomycin C (MMC) and cisplatin, suggesting that FA- and FA-associated proteins play important roles in protecting cells from DNA interstrand crosslink (ICL) damage. Two genes involved in the FA pathway, FANCM and FAAP24, are of particular interest because they contain DNA interacting domains. However, there are no definitive patient mutations for these two genes, and the resulting lack of human genetic model system renders their functional studies difficult. In this study, I established isogenic human FANCM- and FAAP24-null mutants through homologous replacement-mediated gene targeting in HCT-116 cells, and systematically investigated the functions of FANCM and FAAP24 inchromosome stability, FA pathway activation, DNA damage checkpoint signaling, and ICL repair. I found that the FANCM-/-/FAAP24-/- double mutant was much more sensitive to DNA crosslinking agents than FANCM-/- and FAAP24-/- single mutants, suggesting that FANCM and FAAP24 possess epistatic as well as unique functions in response to ICL damage. I demonstrated that FANCM and FAAP24 coordinately support the activation of FA pathway by promoting chromatin localization of FA core complex and FANCD2 monoubiqutination. They also cooperatively function to suppress sister chromatid exchange and radial chromosome formation, likely by limiting crossovers in recombination repair. In addition, I defined novel non-overlapping functions of FANCM and FAAP24 in response to ICL damage. FAAP24 plays a major role in activating ICL-induced ATR-dependent checkpoint, which is independent of its interaction with FANCM. On the other hand, FANCM promotes recombination-independent ICL repair independently of FAAP24. Mechanistically, FANCM facilitates recruitment of nucleotide excision repair machinery and lesion bypass factors to ICL damage sites through its translocase activity. Collectively, my studies provide mechanistic insights into how genome integrity is both coordinately and independently protected by FANCM and FAAP24.