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1.  A nairovirus isolated from African bats causes haemorrhagic gastroenteritis and severe hepatic disease in mice 
Nature Communications  2014;5:5651.
Bats can carry important zoonotic pathogens. Here we use a combination of next-generation sequencing and classical virus isolation methods to identify novel nairoviruses from bats captured from a cave in Zambia. This nairovirus infection is highly prevalent among giant leaf-nosed bats, Hipposideros gigas (detected in samples from 16 individuals out of 38). Whole-genome analysis of three viral isolates (11SB17, 11SB19 and 11SB23) reveals a typical bunyavirus tri-segmented genome. The strains form a single phylogenetic clade that is divergent from other known nairoviruses, and are hereafter designated as Leopards Hill virus (LPHV). When i.p. injected into mice, the 11SB17 strain causes only slight body weight loss, whereas 11SB23 produces acute and lethal disease closely resembling that observed with Crimean–Congo Haemorrhagic Fever virus in humans. We believe that our LPHV mouse model will be useful for research on the pathogenesis of nairoviral haemorrhagic disease.
Bats carry viruses that can cause disease in other animals and in humans. Here, Ishii et al. identify new nairoviruses from African bats and show that some of them can produce a severe haemorrhagic disease in laboratory mice that is similar to Crimean–Congo haemorrhagic fever in humans.
PMCID: PMC4268697  PMID: 25451856
2.  The Influence of Adjuvant Radiation Therapy Dose on Overall Survival for Resected Pancreatic Adenocarcinoma 
Cancer  2013;119(12):2350-2357.
Adjuvant radiation therapy (A-RT) for resected pancreatic adenocarcinoma (PAC) is controversial. We aim to determine if there is an association between overall survival (OS) and A-RT dose.
National Cancer Data Base (NCDB) data were obtained for all patients who underwent A-RT for resected PAC from 1998-2002. Univariate (UV) and multivariable (MV) survival analysis were performed along with Kaplan-Meier (KM) estimates for A-RT levels < 40 Gy, 40 to < 50 Gy, 50 to < 55 Gy, and ≥ 55 Gy.
1,385 patients met inclusion criteria. Median age was 64 (29-87); all patients underwent surgical resection and A-RT +/- chemotherapy. 231 patients were AJCC 5th edition stage I, 273 stage II, 734 stage III, and 126 stage IVA; 21 were unknown. Median A-RT dose was 45 Gy (1.63 Gy-69 Gy). Median OS was 21 months (95% CI 19 - 23). On MV analysis A-RT dose < 40 Gy (HR, 1.30 [95% CI 1.03-1.66]; p = 0.031), A-RT dose 40 to < 50 Gy (HR, 1.17 [95% CI 1.00-1.37]; p = 0.05), and A-RT dose ≥ 55 Gy (HR, 1.44 [95% CI 1.08-1.93]; p = 0.013) predicted worse OS when compared with the reference category of 50 to < 55 Gy.
A-RT doses of less than 40 Gy, 40 to < 50 Gy, and ≥ 55 Gy were associated with inferior OS. The dose of A-RT delivered appears to influence OS and a prospective study evaluating the addition of optimally delivered A-RT for resected PAC is needed.
PMCID: PMC3904231  PMID: 23625519
Pancreatic Adenocarcinoma adjuvant Radiation Therapy; Resected Pancreatic Adenocarcinoma; Post-operative management in resected pancreatic adenocarcinoma; Adjuvant radiation dose in resected pancreatic adenocarcinoma
3.  School factors as barriers to and facilitators of a preventive intervention for pediatric type 2 diabetes 
School-based interventions are essential to prevent pediatric obesity and type 2 diabetes. School environmental factors influence implementation of these interventions. This article examines how school factors acted as barriers to and facilitators of the HEALTHY intervention. The HEALTHY study was a cluster-randomized trial of a multicomponent intervention implemented in 21 schools. Interview data were analyzed to identify barriers and facilitators. Barriers included teacher frustration that intervention activities detracted from tested subjects, student resistance and misbehavior, classroom management problems, communication equipment problems, lack of teacher/staff engagement, high cost and limited availability of nutritious products, inadequate facility space, and large class sizes. Facilitators included teacher/staff engagement, effective classroom management, student engagement, schools with direct control over food service, support from school leaders, and adequate facilities and equipment. Contextual barriers and facilitators must be taken into account in the design and implementation of school-based health interventions.
PMCID: PMC4041924  PMID: 24904696
School; Intervention; Prevention; Health behavior; Diabetes; Obesity
4.  The influence of radiation therapy dose escalation on overall survival in unresectable pancreatic adenocarcinoma 
Radiation therapy (RT) dose escalation in unresectable pancreatic adenocarcinoma (PAC) remains investigational. We examined the association between total RT dose and overall survival (OS) in patients with unresectable PAC.
Methods and materials
National cancer data base (NCDB) data were obtained for patients who underwent definitive chemotherapy and RT (chemo-RT) for unresectable PAC. Univariate (UV) and multivariate (MV) survival analysis were performed along with Kaplan-Meier (KM) estimates for incremental RT dose levels.
A total of 977 analyzable patients met inclusion criteria. Median tumor size was 4.0 cm (0.3-40 cm) and median RT dose was 45 Gy. Median OS was 10 months (95% CI, 9-10 months). On MV analysis RT dose <30 Gy [HR, 2.38 (95% CI, 1.85-3.07); P<0.001] and RT dose ≥30 to <40 Gy [HR, 1.41 (95% CI, 1.04-1.91); P=0.026] were associated with lower OS when compared with dose ≥55 Gy. Patients receiving RT doses from 40 to <45, 45 to <50, 50 to <55, and ≥55 Gy did not differ in OS.
Lack of benefit to OS with conventionally delivered RT above 40 Gy is shown. Optimal RT dose escalation methods in unresectable PAC remain an important subject for investigation in prospective clinical trials.
PMCID: PMC3999628  PMID: 24772334
Radiation dose escalation pancreatic cancer; radiation dose escalation in pancreatic adenocarcinoma (PAC); unresectable pancreatic cancer; PAC and radiation therapy (RT); RT dose in unresectable pancreatic cancer; PAC and intensity modulated radiation therapy (IMRT); dose response pancreatic cancer
7.  Endoscopic vein harvest of the lesser saphenous vein in the supine position: a unique approach to an old problem† 
To obtain a suitable conduit from the lesser (short) saphenous system for use in coronary artery bypass surgery. We wanted to perform this while the patient was in the supine position as to not disrupt the standard operation, and at the same time, utilizing the endoscopic vein harvest technique with its obvious abilities to decrease vein harvest morbidity. We also theorized that through endoscopic techniques instead of the open technique we could harvest greater lengths of conduit, thus providing quality vein segments for additional grafts if needed.
We were able to perform endoscopic vein harvest while in the supine position with one unique centrally located incision that has not been previously described.
The lesser saphenous vein harvested in the described technique provided excellent conduit for our patients that were conduit poor. The endoscopic technique allowed increased length of harvested segments, by giving us the ability to travel under the gastrocnemius muscle with minimal morbidity as opposed to the open technique, where the traditional endpoint is the aforementioned muscle. Conduits were harvested successfully from 14 of 16 candidates. No wound infections or healing problems were experienced. Neurovascular integrity was maintained in all patients.
Endoscopic vein harvest of the lesser saphenous vein with the patient in the supine position is safe, effective and affords conduits for a unique subset of patients undergoing coronary artery bypass grafting.
PMCID: PMC3523626  PMID: 23049078
Coronary artery bypass grafting; Greater saphenous vein; Lesser saphenous vein; Endoscopic vein harvest; Repeat CABG; Society of Thoracic Surgeons
8.  The Four and a Half LIM Family Members Are Novel Interactants of the Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein 
Journal of Virology  2013;87(13):7435-7444.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL). The viral regulatory protein Tax1 plays a pivotal role in T-cell transformation and ATL development. Previous studies in our laboratory, using the yeast 2-hybrid approach to screen a T-cell library for Tax1-interacting partners, identified the cellular Four and a Half Lim domain protein 3 (FHL3) as a possible Tax1-interacting candidate. FHL3 is a member of the FHL family of proteins, which function as transcriptional coactivators and cytoskeleton regulators and have a role in cancer progression and development. The aim of this study was to investigate the physical and functional interaction between Tax1 and members of the FHL family of proteins. We show that Tax1 and FHL3 interact both in vitro and in vivo. Furthermore, both FHL1 and -2 also interact with Tax1. We have demonstrated that FHL3 enhances Tax1-mediated activation of the viral long terminal repeat (LTR) without affecting basal activity and that FHL1 to -3 regulate NF-κB activation by Tax1 in a cell-specific manner. In addition, we have found that the interaction between Tax1 and FHL1 to -3 affects the localization of these proteins, leading to their redistribution in cells. Tax1 also affected FHL3 cytoskeleton function by increasing FHL3-mediated cell spreading. Overall, our results suggest that the interaction between Tax1 and the FHL family alters both the transactivating activity and the subcellular localization of Tax1 and provide new insights into molecular mechanisms that underlie the oncogenic nature of this HTLV-1 protein.
PMCID: PMC3700305  PMID: 23616667
9.  L’eggo My Ego: Reducing the Gender Gap in Math by Unlinking the Self from Performance 
Stereotype threat can vary in source, with targets being threatened at the individual and/or group level. This study examines specifically the role of self-reputational threat in women’s underperformance in mathematics. A pilot study shows that women report concerns about experiencing self-reputational threat that are distinct from group threat in the domain of mathematics. In the main study, we manipulated whether performance was linked to the self by asking both men and women to complete a math test using either their real name or a fictitious name. Women who used a fictitious name, and thus had their self unlinked from the math test, showed significantly higher math performance and reported less self-threat and distraction, relative to those who used their real names. Men were unaffected by the manipulation. These findings suggest that women’s impaired math performance is often due to the threat of confirming a negative stereotype as being true of the self. The implications for understanding the different types of threats faced by stereotyped groups, particularly among women in math settings, are discussed.
PMCID: PMC3821772  PMID: 24223027
Stereotype Threat; Self; Self Threat; Gender; Math Performance
10.  Poor Aerobic Fitness May Contribute to Cognitive Decline in HIV-infected Older Adults 
Aging and Disease  2013;4(6):311-319.
The HIV-infected older adult (HOA) community is particularly vulnerable to cognitive impairment. Previous studies in the general older adult population have reported that lower scores on tests of cognitive function often correlate negatively with aerobic fitness [5–7]. HIV-infected individuals have significantly reduced aerobic fitness and physical function compared to HIV-uninfected individuals. Determining important correlates of cognitive ability may be beneficial in not only detecting precursors to future cognitive impairments, but also target areas for interventions. The purpose of this study was to investigate the relationship between cognitive ability and aerobic fitness in HIV-infected older adults. We conducted a cross-sectional study of HOA on antiretroviral therapy (ART) >50 years of age. Domain specific cognitive function was assessed by means of a neuropsychological battery. Aerobic fitness (VO2peak) was assessed using a graded, progressive treadmill test. Thirty-seven HOA on ART (mean±SD: age 59±6 years, BMI 28±5, CD4 663±337 cells/ml, duration since HIV diagnosis 17±7 years; 81% males) completed the cognitive tests. Several domains of cognition were significantly associated with VO2peak by Spearman correlation analysis (p<0.05). By step-wise adjusted regression VO2peak was most frequently and significantly related to many cognitive domains such as verbal and visual memory, visual perception, and language (p<0.05). We found that participants with higher Vo2peak were less likely to have more severe forms of HIV-associated neurocognitive disorders (HAND) such as mild neurocognitive disorder (OR=0.65; p=0.01) and HIV-associated dementia (OR=0.64; p=0.0006). In HOA and in conclusion, aerobic fitness is related to cognitive performance on various tasks. The likelihood of cognitive impairment increased with lower fitness levels. Therefore, increased fitness may serve an important factor in maintenance of cognition and neural integrity for aging HIV-infected individuals. Future prospective and large scale studies are needed to evaluate the effect of fitness and vascular stiffness and function on cognition and brain structure among HOA.
PMCID: PMC3843648  PMID: 24307964
HIV; older adults; aerobic fitness; cognition
13.  Process evaluation results from the HEALTHY physical education intervention 
Health Education Research  2011;27(2):307-318.
Process evaluation is an assessment of the implementation of an intervention. A process evaluation component was embedded in the HEALTHY study, a primary prevention trial for Type 2 diabetes implemented over 3 years in 21 middle schools across the United States. The HEALTHY physical education (PE) intervention aimed at maximizing student engagement in moderate-to-vigorous physical activity through delivery of structured lesson plans by PE teachers. Process evaluation data collected via class observations and interventionist interviews assessed fidelity, dose delivered, implementor participation, dose received and barriers. Process evaluation results indicate a high level of fidelity in implementing HEALTHY PE activities and offering 225 min of PE every 10 school days. Concerning dose delivered, students were active for approximately 33 min of class, representing an average of 61% of the class time. Results also indicate that PE teachers were generally engaged in implementing the HEALTHY PE curriculum. Data on dose received showed that students were highly engaged with the PE intervention; however, student misbehavior was the most common barrier observed during classes. Other barriers included teacher disengagement, large classes, limited gym space and poor classroom management. Findings suggest that the PE intervention was generally implemented and received as intended despite several barriers.
PMCID: PMC3303206  PMID: 22156231
14.  A New Frailty Syndrome: Central Obesity and Frailty in Human immunodeficiency virus (HIV)-Infected Older Adults 
To evaluate the relationships between body composition and physical frailty in community-dwelling HIV-infected older adults (HOA).
Academic hospital-based infectious disease clinic in Rochester NY
Community-dwelling HIV-infected adults >50 years of age.
Subjective and objective measures of functional status were evaluated by using the Physical Performance Test (PPT), graded treadmill test, knee strength, gait speed, balance and Functional Status Questionnaires (FSQ). Body composition was evaluated by using Dual Energy X-ray Absorptiometry (DXA) and Magnetic Resonance Imaging (MRI).
We studied 40 HOA on antiretroviral therapy (with mean: age 58 years, BMI 29, CD4 569 cells/ml, duration since HIV diagnosis 17 years; 28% female and 57% Caucasian) who were able to ambulate without assistive devices. Sixty percent (25/40) of the subjects met our standard criteria for physical frailty. Both frail (FR) and non-frail (NF) subjects were comparable in age, gender, CD4 count and viral load. Compared to NF HOA, FR HOA showed impairments in PPT, peak aerobic power (VO2peak), FSQ, walking speed, balance and muscle quality. Importantly, FR HOA had greater body mass index (BMI), fat mass and truncal fat with lipodystrophy. Moreover, PPT score was inversely related to both trunk fat (r=−0.34; p=0.045) and intermuscular fat (IMF) to total fat ratio (r=−60; p=0.02) after adjusting for covariates.
HOA represent an emerging cohort of older adults who frequently experience frailty at a much younger age compared to the general older population. Central obesity and fat redistribution are important predictors of frailty among community-dwelling HOA. These findings suggest that physical frailty in HOA may be amenable to lifestyle interventions, especially exercise and diet therapy.
PMCID: PMC3302930  PMID: 22315957
HIV; older adults; frailty; function; obesity; lipodystrophy
16.  The Implications of Long-Term Acute Care Hospital Transfer Practices for Measures of In-Hospital Mortality and Length of Stay 
Rationale: The National Quality Forum recently endorsed in-hospital mortality and intensive care unit length of stay (LOS) as quality indicators for patients in the intensive care unit. These measures may be affected by transferring patients to long-term acute care hospitals (LTACs).
Objectives: To quantify the implications of LTAC transfer practices on variation in mortality index and LOS index for patients in academic medical centers.
Methods: We used a cross-sectional study design using data reported to the University HealthSystem Consortium from 2008–2009. Data were from patients who were mechanically ventilated for more than 96 hours.
Measurements and Main Results: Using linear regression, we measured the association between mortality index and LTAC transfer rate, with the hospital as the unit of analysis. Similar analyses were conducted for LOS index and cost index. A total of 137 hospitals were analyzed, averaging 534 transfers to LTAC per hospital during the study period. Mean ± SD in-hospital mortality was 24 ± 6.4%, and observed LOS was 30.4 ± 8.2 days. The mean LTAC transfer rate was 15.7 ± 13.7%. Linear regression demonstrated a significant correlation between transfer rate and mortality index (R2 = 0.14; P < 0.0001) and LOS index (R2 = 0.43; P < 0.0001).
Conclusions: LTAC hospital transfer rate has a significant impact on reported mortality and LOS indices for patients requiring prolonged acute mechanical ventilation. This is an example of factors unrelated to quality of medical care or illness severity that must be considered when interpreting mortality and LOS as quality indicators.
PMCID: PMC3361349  PMID: 21940788
National Quality Forum; American Thoracic Society; quality improvement
17.  Interplay between the HTLV-2 Tax and APH-2 proteins in the regulation of the AP-1 pathway 
Retrovirology  2012;9:98.
In contrast with human T-cell leukemia virus type 1 (HTLV-1) that causes ATL (adult T-cell leukemia), HTLV-2 has not been causally linked to malignant disease. The minus strand of the HTLV genomes encode the regulatory proteins HTLV-1 bZIP factor (HBZ) for HTLV-1 and antisense protein of HTLV-2 (APH-2) for HTLV-2. Unlike the viral proteins Tax1 and Tax2, both HBZ and APH-2 are constitutively expressed in infected cells suggesting that they may play important roles in the pathogenesis of these viruses. To date, very little is known about the function of APH-2 except that it inhibits Tax2-mediated transcription of HTLV-2 genes. In the present study, we investigated the role of APH-2 in basal and Tax2B-mediated activation of the AP-1 pathway.
We demonstrate that, unlike HBZ, APH-2 stimulates basal AP-1 transcription by interacting with c-Jun and JunB through its non-conventional bZIP domain. In addition, when Tax2 and APH-2 are co-expressed, they physically interact in vivo and in vitro and APH-2 acts as an inhibitor of Tax2-mediated activation of AP-1 transcription.
This report is the first to document that HTLV-2 can modulate the AP-1 pathway. Altogether our results reveal that, in contrast with HBZ, APH-2 regulates AP-1 activity in a Tax2-dependant manner. As the AP-1 pathway is involved in numerous cellular functions susceptible to affect the life cycle of the virus, these distinct biological properties between HBZ and APH-2 may contribute to the differential pathogenic potential of HTLV-1 and HTLV-2.
PMCID: PMC3531308  PMID: 23206352
HTLV-2; APH-2; Tax2; AP-1; Jun
18.  Is There Diagnostic Value in Detection of Immunoglobulin G Antibodies to the Epstein–Barr Virus Early Antigen? 
BioResearch Open Access  2012;1(6):291-296.
The Epstein–Barr virus early antigen (EBV EA) complex consists of multiple proteins with potential significance for diagnosis of EBV-related diseases. In many individuals, detection of antibody to the early antigen (EA) is a sign of active infection, but 20% of healthy people may have this antibody for years. We studied the role of EA immunoglobulin G (IgG) in individuals with atypical antibody responses in the diagnosis of infectious mononucleosis (IM) and in EBV-infected transplant patients. EA IgG was present in 72% of confirmed IM patients. A trend was observed between high viral loads and the presence of EA IgG and between low viral loads and the absence of EA IgG in EBV-associated disease negative liver transplant recipients. Three assays that measure serum EA IgG were compared; enzyme-linked immunosorbent assay (ELISA), chemiluminescent immunoassay (CLIA), and immunoblot assay. The automated CLIA was found to be more accurate than the ELISA when using the immunoblot assay as a “gold standard” assay in the detection of EA IgG. There may be a potential role for EA IgG testing, together with EBV viral load, in the prediction of transplant recipients at risk of EBV-associated disease; however, EA IgG does not play a significant role in the differential diagnosis of EBV infection in immunocompetent individuals.
PMCID: PMC3559238  PMID: 23514966
early antigen; Epstein–Barr virus; infectious mononucleosis; liver transplant
19.  Nucleolar Protein Trafficking in Response to HIV-1 Tat: Rewiring the Nucleolus 
PLoS ONE  2012;7(11):e48702.
The trans-activator Tat protein is a viral regulatory protein essential for HIV-1 replication. Tat trafficks to the nucleoplasm and the nucleolus. The nucleolus, a highly dynamic and structured membrane-less sub-nuclear compartment, is the site of rRNA and ribosome biogenesis and is involved in numerous cellular functions including transcriptional regulation, cell cycle control and viral infection. Importantly, transient nucleolar trafficking of both Tat and HIV-1 viral transcripts are critical in HIV-1 replication, however, the role(s) of the nucleolus in HIV-1 replication remains unclear. To better understand how the interaction of Tat with the nucleolar machinery contributes to HIV-1 pathogenesis, we investigated the quantitative changes in the composition of the nucleolar proteome of Jurkat T-cells stably expressing HIV-1 Tat fused to a TAP tag. Using an organellar proteomic approach based on mass spectrometry, coupled with Stable Isotope Labelling in Cell culture (SILAC), we quantified 520 proteins, including 49 proteins showing significant changes in abundance in Jurkat T-cell nucleolus upon Tat expression. Numerous proteins exhibiting a fold change were well characterised Tat interactors and/or known to be critical for HIV-1 replication. This suggests that the spatial control and subcellular compartimentaliation of these cellular cofactors by Tat provide an additional layer of control for regulating cellular machinery involved in HIV-1 pathogenesis. Pathway analysis and network reconstruction revealed that Tat expression specifically resulted in the nucleolar enrichment of proteins collectively participating in ribosomal biogenesis, protein homeostasis, metabolic pathways including glycolytic, pentose phosphate, nucleotides and amino acids biosynthetic pathways, stress response, T-cell signaling pathways and genome integrity. We present here the first differential profiling of the nucleolar proteome of T-cells expressing HIV-1 Tat. We discuss how these proteins collectively participate in interconnected networks converging to adapt the nucleolus dynamic activities, which favor host biosynthetic activities and may contribute to create a cellular environment supporting robust HIV-1 production.
PMCID: PMC3499507  PMID: 23166591
20.  Hepatitis C Virus in Vietnam: High Prevalence of Infection in Dialysis and Multi-Transfused Patients Involving Diverse and Novel Virus Variants 
PLoS ONE  2012;7(8):e41266.
Hepatitis C virus (HCV) is a genetically diverse pathogen infecting approximately 2–3% of the world's population. Herein, we describe results of a large, multicentre serological and molecular epidemiological study cataloguing the prevalence and genetic diversity of HCV in five regions of Vietnam; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. Individuals (n = 8654) with varying risk factors for infection were analysed for the presence of HCV Ab/Ag and, in a subset of positive specimens, for HCV RNA levels (n = 475) and genotype (n = 282). In lower risk individuals, including voluntary blood donors, military recruits and pregnant women, the prevalence of infection was 0.5% (n = 26/5250). Prevalence rates were significantly higher (p<0.001) in intravenous drug users (IDUs; 55.6%, n = 556/1000), dialysis patients (26.6%, n = 153/575) commercial sex workers (CSWs; 8.7%, n = 87/1000), and recipients of multiple blood transfusions (6.0%, n = 32/529). The prevalence of HCV in dialysis patients varied but remained high in all regions (11–43%) and was associated with the receipt of blood transfusions [OR: 2.08 (1.85–2.34), p = 0.001], time from first transfusion [OR: 1.07 (1.01–1.13), p = 0.023], duration of dialysis [OR: 1.31 (1.19–1.43), p<0.001] and male gender [OR: 1.60 (1.06–2.41), p = 0.026]. Phylogenetic analysis revealed high genetic diversity, particularly amongst dialysis and multi-transfused patients, identifying subtypes 1a (33%), 1b (27%), 2a (0.4%), 3a (0.7%), 3b (1.1%), 6a (18.8%), 6e (6.0%), 6h (4.6%), 6l (6.4%) and 2 clusters of novel genotype 6 variants (2.1%). HCV genotype 1 predominated in Vietnam (60%, n = 169/282) but the proportion of infections attributable to genotype 1 varied between regions and risk groups and, in the Southern part of Vietnam, genotype 6 viruses dominated in dialysis and multi-transfused patients (73.9%). This study confirms a high prevalence of HCV infection in Vietnamese IDUs and, notably, reveals high levels of HCV infection associated with dialysis and blood transfusion.
PMCID: PMC3419252  PMID: 22916104
21.  Recombination in Hepatitis C Virus: Identification of Four Novel Naturally Occurring Inter-Subtype Recombinants 
PLoS ONE  2012;7(7):e41997.
Recombination in Hepatitis C virus (HCV) is considered to be rare. In this study, we performed a phylogenetic analysis of 1278 full-length HCV genome sequences to identify potential recombination events. Nine inter-genotype recombinants were identified, all of which have been previously reported. This confirms the rarity of inter-genotype HCV recombinants. The analysis also identified five inter-subtype recombinants, four of which are documented for the first time (EU246930, EU246931, EU246932, and EU246937). Specifically, the latter represent four different novel recombination types (6a/6o, 6e/6o, 6e/6h, and 6n/6o), and this was well supported by seven independent methods embedded in RDP. The breakpoints of the four novel HCV recombinants are located within the NS5B coding region and were different from all previously reported breakpoints. While the locations of the breakpoints identified by RDP were not identical, they are very close. Our study suggests that while recombination in HCV is rare, this warrants further investigation.
PMCID: PMC3404033  PMID: 22911872
22.  Screening and Preventive Services for Older Adults 
Federal, professional and academic efforts are converging to address the preventive care needs of older Americans. Medicare is placing an increased emphasis on preventive care services for older adults. With the passage of the Affordable Care Act, access to preventive services has been enhanced by reducing out of pocket costs for older adults, and increasing reimbursement to health care providers. In 2010-2011 newly revised guidelines for Screening and Preventive Services have been issued by the United States Preventive Services Task Force (USPSTF) and the Centers for Disease Control and Prevention (CDC). In addition to these guidelines and the landmark changes in Medicare coverage, there are significant new attempts to modify national screening recommendations based on age and expected risk/benefit for older adults. These population-specific guidelines with new emphasis on functional status and multiple risk factor reduction are of increasing importance to an aging population where more conventional disease-focused guidelines are less suitable for maintaining physical function and quality of life. Evidence-based measures of physical performance appropriate for primary care office use are being developed and piloted. As a result of these policies, guidelines and tools, we have the ability to offer older adults more comprehensive, cost-effective screening and preventive measures than in any other previous time.
PMCID: PMC3142556  PMID: 21748739
Screening; preventive services; older adults; Affordable Care Act; Medicare; USPSTF; ACOVE; gait speed
23.  Clinical outcomes of radiotherapy as initial local therapy for Graves’ ophthalmopathy and predictors of the need for post-radiotherapy decompressive surgery 
The optimal initial local treatment for patients with Graves’ ophthalmopathy (GO) is not fully characterized. The purpose of this retrospective study is to describe the clinical outcomes of RT as initial local therapy for GO and define predictors of the need for post-RT salvage bony decompressive surgery.
91 patients with active GO and without prior surgery were treated with RT as initial local therapy between 01/1999 and 12/2010, with a median follow-up period of 18.3 months (range 3.7 - 142 months). RT dose was 24 Gy in 12 fractions. 44 patients (48.4%) had prior use of steroids, with 31 (34.1%) being on steroids at the initiation of RT. The most common presenting symptoms were diplopia (79%), proptosis (71%) and soft tissue signs (62%).
84 patients (92.3%) experienced stabilization or improvement of GO symptoms. 58 patients (64%) experienced improvement in their symptoms. 19 patients (20.9%) underwent salvage post-RT bony decompressive surgery. Smoking status and total symptom score at 4 months were independent predictors of post-RT bony decompression with odds ratios of 3.23 (95% CI 1.03 – 10.2) and 1.59 (95% CI 1.06 – 2.4), respectively. Persistent objective vision loss at 4 months post-RT was the most important symptom type in predicting salvage decompression. Chronic dry eye occurred in 9 patients (9.9%) and cataracts developed in 4 patients (4.4%).
RT is effective and well tolerated as initial local therapy for active GO, with only 21% of patients requiring decompressive surgery post RT. Most patients experience stabilization or improvement of GO symptoms, but moderate to significant response occurs in the minority of patients. Smoking status and total symptom severity at 4 months, primarily persistent objective vision loss, are the primary determinants of the need for post-RT salvage bony decompression. Patients who smoke or present with predominantly vision loss symptoms should be advised as to their lower likelihood of symptomatic response to RT and their increased likelihood of requiring post-RT decompressive surgery.
PMCID: PMC3485155  PMID: 22713684
Radiation therapy; Graves’ disease; Orbital radiation; Graves’ ophthalmopathy; Graves’ orbitopathy
24.  A Multicentre Molecular Analysis of Hepatitis B and Blood-Borne Virus Coinfections in Viet Nam 
PLoS ONE  2012;7(6):e39027.
Hepatitis B (HBV) infection is endemic in Viet Nam, with up to 8.4 million individuals estimated to be chronically infected. We describe results of a large, multicentre seroepidemiological and molecular study of the prevalence of HBV infection and blood-borne viral coinfections in Viet Nam. Individuals with varying risk factors for infection (n = 8654) were recruited from five centres; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. A mean prevalence rate of 10.7% was observed and levels of HBsAg were significantly higher in injecting drug users (IDUs) (17.4%, n = 174/1000) and dialysis patients (14.3%, n = 82/575) than in lower-risk groups (9.4%; p<0.001). Coinfection with HIV was seen in 28% of HBV-infected IDUs (n = 49/174) and 15.2% of commercial sex workers (CSWs; n = 15/99). HCV infection was present in 89.8% of the HBV-HIV coinfected IDUs (n = 44/49) and 40% of HBV-HIV coinfected CSWs (n = 16/40). Anti-HDV was detected in 10.7% (n = 34/318) of HBsAg positive individuals. Phylogenetic analysis of HBV S gene (n = 187) showed a predominance of genotype B4 (82.6%); genotypes C1 (14.6%), B2 (2.7%) and C5 (0.5%) were also identified. The precore mutation G1896A was identified in 35% of all specimens, and was more frequently observed in genotype B (41%) than genotype C (3%; p<0.0001). In the immunodominant ‘a’ region of the surface gene, point mutations were identified in 31% (n = 58/187) of sequences, and 2.2% (n = 4/187) and 5.3% (n = 10/187) specimens contained the major vaccine escape mutations G145A/R and P120L/Q/S/T, respectively. 368 HBsAg positive individuals were genotyped for the IL28B SNP rs12979860 and no significant association between the IL28B SNP and clearance of HBsAg, HBV viral load or HBeAg was observed. This study confirms the high prevalence of HBV infection in Viet Nam and also highlights the significant levels of blood-borne virus coinfections, which have important implications for hepatitis-related morbidity and development of effective management strategies.
PMCID: PMC3374772  PMID: 22720022
25.  Association of Cancer With Geriatric Syndromes in Older Medicare Beneficiaries 
Journal of Clinical Oncology  2011;29(11):1458-1464.
To identify whether a history of cancer is associated with specific geriatric syndromes in older patients.
Patients and Methods
Using the 2003 Medicare Current Beneficiary Survey, we analyzed a national sample of 12,480 community-based elders. Differences in prevalence of geriatric syndromes between those with and without cancer were estimated. Multivariable logistic regressions were used to evaluate whether cancer was independently associated with geriatric syndromes.
Two thousand three hundred forty-nine (18%) reported a history of cancer. Among those with cancer, 60.3% reported one or more geriatric syndromes as compared with 53.2% of those without cancer (P < .001). Those with cancer overall had a statistically significantly higher prevalence of hearing trouble, urinary incontinence, falls, depression, and osteoporosis than those without cancer. Adjusting for possible confounders, those with a history of cancer were more likely to experience depression (adjusted odds ratio [OR], 1.15; 95% CI, 1.02 to 1.30; P = .023), falls (adjusted OR, 1.17; 95% CI, 1.04 to 1.32; P = .010), osteoporosis (adjusted OR, 1.21; 95% CI, 1.06 to 1.38; P = .004), hearing trouble (adjusted OR, 1.28; 95% CI, 1.08 to 1.52; P = .005), and urinary incontinence (adjusted OR, 1.42; 95% CI, 1.20 to 1.69; P < .001). Analysis of specific cancer subtypes showed that lung cancer was associated with vision, hearing, and eating trouble; prostate cancer was associated with incontinence and falls; cervical/uterine cancer was associated with falls and osteoporosis; and colon cancer was associated with depression and osteoporosis.
Elderly patients with cancer experience a higher prevalence of geriatric syndromes than those without cancer. Prospective studies that establish the causal relationships between cancer and geriatric syndromes are necessary.
PMCID: PMC3082984  PMID: 21402608

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