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  • Building operative care capacity in a resource limited setting: The Mongolian model of the expansion of sustainable laparoscopic cholecystectomy SURGERY Wells, K. M., Lee, Y., Erdene, S., Erdene, S., Sanchin, U., Sergelen, O., Zhang, C., Rodriguez, B. P., deVries, C. R., Price, R. R. 2016; 160 (2): 509-517

    Abstract

    The benefits of laparoscopic cholecystectomy, including rapid recovery and fewer infections, have been largely unavailable to the majority of people in developing countries. Compared to other countries, Mongolia has an extremely high incidence of gallbladder disease. In 2005, only 2% of cholecystectomies were performed laparoscopically. This is a retrospective review of the transition from open to laparoscopic cholecystectomy throughout Mongolia.A cross-sectional, retrospective review was conducted of demographic patient data, diagnosis type, and operation performed (laparoscopic versus open cholecystectomy) from 2005-2013. Trends were analyzed from 6 of the 21 provinces (aimags) throughout Mongolia, and data were culled from 7 regional diagnostic referral and treatment centers and 2 tertiary academic medical centers. The data were analyzed by individual training center and by year before being compared between rural and urban centers.We analyzed and compared 14,522 cholecystectomies (n=4,086 [28%] men, n=10,436 [72%] women). Men and women were similar in age (men 52.2, standard deviation 14.8; women 49.4, standard deviation 15.7) and in the percentage undergoing laparoscopic cholecystectomy (men 39%, women 42%). By 2013, 58% of gallbladders were removed laparoscopically countrywide compared with only 2% in 2005. In 2011, laparoscopic cholecystectomy surpassed open cholecystectomy as the primary method for gallbladder removal countrywide. More than 315 Mongolian health care practitioners received laparoscopic training in 19 of the country's 21 aimags (states).By 2013, 58% of cholecystectomies countrywide were performed laparoscopically, a dramatic increase over 9years. The expansion of laparoscopic cholecystectomy has transformed the care of biliary tract disease in Mongolia despite the country's limited resources.

    View details for DOI 10.1016/j.surg.2016.04.001

    View details for Web of Science ID 000379888000029

    View details for PubMedID 27238353

  • Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA-the journal of the American Medical Association Osinusi, A., Meissner, E. G., Lee, Y., Bon, D., Heytens, L., Nelson, A., Sneller, M., Kohli, A., Barrett, L., Proschan, M., Herrmann, E., Shivakumar, B., Gu, W., Kwan, R., Teferi, G., Talwani, R., Silk, R., Kotb, C., Wroblewski, S., Fishbein, D., Dewar, R., Highbarger, H., Zhang, X., Kleiner, D., Wood, B. J., Chavez, J., Symonds, W. T., Subramanian, M., McHutchison, J., Polis, M. A., Fauci, A. S., Masur, H., Kottilil, S. 2013; 310 (8): 804-811

    Abstract

    The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations.To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics.Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012).In the study's first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks.The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]).In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P?=?.20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P?=?.009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively.clinicaltrials.gov Identifier: NCT01441180.

    View details for DOI 10.1001/jama.2013.109309

    View details for PubMedID 23982366

  • Expansion of laparoscopic cholecystectomy in a resource limited setting, Mongolia: a 9-year cross-sectional retrospective review. Lancet Wells, K. M., Lee, Y., Erdene, S., Erdene, S., Sanchin, U., Sergelen, O., Presson, A., Zhang, C., Rodriguez, B., Devries, C., Price, R. 2015; 385: S38-?

    Abstract

    The benefits of laparoscopic cholecystectomy have been largely unavailable to most people in developing countries. Mongolia has an extremely high incidence of gallbladder disease. In 2005, only 2% of cholecystectomies were being done laparoscopically. Open cholecystectomies were associated with high rates of wound infections, complications, and increased recovery time. Because of the unacceptable complications associated with open cholecystectomies, and nearly 50% of the nomadic population needing faster post-operative recovery times, a national project for the development of laparoscopic surgery was organised. Multi-institutional collaboration between the Mongolia Health Sciences University, the Dr W C Swanson Family Foundation (SFF), the University of Utah, Intermountain Healthcare, and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) led to the promulgation of a formalised countrywide laparoscopic training programme during the past 9 years. This is a retrospective review of the transition from open to laparoscopic cholecystectomy throughout Mongolia.Demographic patient data, diagnosis, and operation preformed-laparoscopic versus open cholecystectomy, between January, 2005, and September, 2013, were collected and trends were analysed from seven regional diagnostic referral and treatment centres, and two tertiary academic medical centres from six of the 21 provinces (Aimags) throughout Mongolia. Data were analysed by individual training centre, by year, and then compared between rural and urban centres.Nearly 16 000 cholecystectomies were analysed and compared (4417 [282%] men; 11 244 [718%] women). Men and women underwent laparoscopic cholecystectomy with the same frequency (412% men, 432% women) and had similar age (men, mean 522 years [SD 148]; women, mean 494 years [SD 157]). By 2013, 62% of gallbladders were removed laparoscopically countrywide as opposed to only 2% in 2005. More than 315 Mongolian practitioners have received laparoscopic training in 19 of 21 Aimags. On average 60% of cholecystectomies are done laparoscopically in urban surgical centres, up from 2%, versus 55% in rural surgical centres, up from 0%, in 2005. Laparoscopic cholecystectomy surpassed open cholecystectomy as the primary method for gallbladder removal countrywide in 2011.By 2013, 62% of cholecystectomies countrywide were done laparoscopically, a great increase from 9 years ago. Despite being a resource limited country, the expansion of laparoscopic cholecystectomy has transformed the care of biliary tract disease in Mongolia.The University of Utah Center for Global Surgery.

    View details for DOI 10.1016/S0140-6736(15)60833-9

    View details for PubMedID 26313086

  • Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients. Hepatology Meissner, E. G., Lee, Y., Osinusi, A., Sims, Z., Qin, J., Sturdevant, D., McHutchison, J., Subramanian, M., Sampson, M., Naggie, S., Patel, K., Remaley, A. T., Masur, H., Kottilil, S. 2015; 61 (3): 790-801

    Abstract

    Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end-of-treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response [SVR]; n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n=17 SVR; n=8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very-low-density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse.Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis.

    View details for DOI 10.1002/hep.27424

    View details for PubMedID 25203718

  • Comparative Efficacy, Pharmacokinetic, Pharmacodynamic Activity, and Interferon Stimulated Gene Expression of Different Interferon Formulations in HIV/HCV Genotype-1 Infected Patients JOURNAL OF MEDICAL VIROLOGY Osinusi, A., Bon, D., Nelson, A., Lee, Y., Poonia, S., Shivakumar, B., Cai, S. Y., Wood, B., Haagmans, B., Lempicki, R., Herrmann, E., Sneller, M., Polis, M., Masur, H., Kottilil, S. 2014; 86 (2): 177-185

    Abstract

    The effect of different formulations of interferon on therapeutic response in patients coinfected with HIV and HCV is unclear. In this study, the safety, tolerability, viral kinetics (VK) modeling and host responses among HIV/HCV coinfected patients treated with pegylated-IFN or albinterferon alfa-2b (AlbIFN) with weight-based ribavirin were compared. Three trials treated 57 HIV/HCV coinfected genotype-1 patients with PegIFN alfa-2b (1.5?g/kg/week) (n?=?30), PegIFN alfa-2a (180?g/week) (n?=?10), and AlbIFN (900?g/q2week) (n?=?17) in combination with weight-based ribavirin (RBV). HCV RNA, safety labs, and interferon stimulated gene expression (ISG) was evaluated. Adverse events were documented at all study visits. HCV viral kinetics using a full pharmacokinetic/pharmacodynamic model was also evaluated. Baseline patient characteristics were similar across the three studies. All three formulations exhibited comparable safety and tolerability profiles and efficacy. VK/PK/PD parameters for all three studies as measured by mean efficiency and rate of infected cell loss were similar between the three groups. Host responses (ISG expression and immune activation markers) were similar among the three groups. All three regimens induced significant ISG at week 4 (P?

    View details for DOI 10.1002/jmv.23773

    View details for Web of Science ID 000328212900001

    View details for PubMedID 24166150

  • Impaired HCV Clearance in HIV/HCV Coinfected Subjects Treated with PegIFN and RBV Due to Interference of IFN Signaling by IFNaR2a. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research Lee, Y., Zhang, X., Vazquez, E., Shivasabesan, G., Young, H. A., Murphy, A., Wang, H., Suffredini, A. F., Siebenlist, U., Kottilil, S. 2014; 34 (1): 28-34

    Abstract

    Enhanced endogenous interferon (IFN) stimulated gene (ISG) signature has been associated with nonresponsiveness to hepatitis C treatment using pegylated-IFN? (pegIFN?) and ribavirin (RBV) in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected patients. Using a proteomic approach, we identified high levels of IFN? receptor 2a (IFN?R2a) in the serum of null responders to pegIFN?/RBV. IFN?R2a inhibited antiviral activity of all formulations of IFN? in JFH/Huh7.5 cells. Furthermore, serum from null responders, but not from those who achieved sustained virologic response, suppressed IFN-signaling and ISG expression in IFN?-stimulated PBMCs of healthy donors in an IFN?R2a specific fashion. An IFN?R2a transgenic mice model (C57BL/6) was generated that had significantly higher levels of IFN?R2a in the serum than the controls (P=0.001). Total ISG expression in the lymph nodes was significantly higher compared to wild-type mice (P value=0.0016). In addition, IFITM1 and SP110 had significantly increased expression in the liver, IFITM1 and ISG15 in the lymph node, and ISG15 and PLSCR1 in the spleen (P value<0.05). The underlying mechanism of resistance to hepatitis C treatment may involve transsignaling of the JAK/STAT pathway by the sIFN?R2a-IFN?/? complex and result in the enhanced ISG signature observed in null responders. In this regard, the transgenic mice model simulated nonresponders to IFN? therapy and provides valuable insights into the role of sIFN?R2a-IFN? interactions in vivo.

    View details for DOI 10.1089/jir.2013.0032

    View details for PubMedID 24171456

  • A whole recombinant yeast-based therapeutic vaccine elicits HBV x, s and core specific T cells in mice and activates human T cells recognizing epitopes linked to viral clearance. PloS one King, T. H., Kemmler, C. B., Guo, Z., Mann, D., Lu, Y., Coeshott, C., Gehring, A. J., Bertoletti, A., Ho, Z. Z., Delaney, W., Gaggar, A., Subramanian, G. M., McHutchison, J. G., Shrivastava, S., Lee, Y. L., Kottilil, S., Bellgrau, D., Rodell, T., Apelian, D. 2014; 9 (7)

    Abstract

    Chronic hepatitis B infection (CHB) is characterized by sub-optimal T cell responses to viral antigens. A therapeutic vaccine capable of restoring these immune responses could potentially improve HBsAg seroconversion rates in the setting of direct acting antiviral therapies. A yeast-based immunotherapy (Tarmogen) platform was used to make a vaccine candidate expressing hepatitis B virus (HBV) X, surface (S), and Core antigens (X-S-Core). Murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T cell responses elicited by the vaccine. C57BL/6J, BALB/c, and HLA-A*0201 transgenic mice immunized with yeast expressing X-S-Core showed T cell responses to X, S and Core when evaluated by lymphocyte proliferation assay, ELISpot, intracellular cytokine staining (ICS), or tumor challenge assays. Both CD4+ and CD8+ T cell responses were observed. Human T cells transduced with HBc18-27 and HBs183-91 specific T cell receptors (TCRs) produced interferon gamma (IFN? following incubation with X-S-Core-pulsed dendritic cells (DCs). Furthermore, stimulation of peripheral blood mononuclear cells (PBMCs) isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-Core or a related product (S-Core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-Core-expressing yeast elicit functional adaptive immune responses and supports the ongoing evaluation of this therapeutic vaccine in patients with CHB to enhance the induction of HBV-specific T cell responses.

    View details for DOI 10.1371/journal.pone.0101904

    View details for PubMedID 25051027

  • High Efficacy Of GS-7977 In Combination With Low or Full dose Ribavirin for 24 weeks In Difficult To Treat HCV Infected Genotype 1 Patients : Interim Analysis From The SPARE Trial HEPATOLOGY Osinusi, A., Heytens, L., Lee, Y., Bon, D., Shivakumar, B., Nelson, A., Meissner, E. G., Kohli, A., Barrett, L., Proschan, M., Silk, R., Kwan, R., Herrmann, E., Sneller, M., Teferi, G., Talwani, R., Symonds, W. T., Polis, M. A., Masur, H., McHutchison, J. G., Fauci, A. S., Kottilil, S. 2012; 56 (6): 1518-1518
  • Real-time Polymerase Chain Reaction Analysis of Sewage Samples to Determine Oral Polio Vaccine Circulation Duration and Mutation After Mexican National Immunization Weeks. Journal of the Pediatric Infectious Diseases Society Troy, S. B., Ferreyra-Reyes, L., Canizales-Quintero, S., Huang, C., Lee, Y., Bez-Saldaa, R., Ferreira-Guerrero, E., Garca-Garca, L., Maldonado, Y. 2012; 1 (3): 223-229

    Abstract

    Oral polio vaccine (OPV) can mutate and cause outbreaks of paralytic poliomyelitis with prolonged replication. After poliovirus eradication, global use of inactivated polio vaccine (IPV) may be needed until all OPV stops circulating. Mexico, where children receive routine IPV but where OPV is given only during biannual national immunization weeks (NIWs), provides a natural setting to study duration of OPV circulation in a community primarily vaccinated with IPV.One-liter sewage samples from four separate arroyos (creeks) near Orizaba, Mexico, were collected monthly for 12 months. Concentrated sewage underwent RNA extraction, reverse transcription, and real-time polymerase chain reaction (PCR) to detect OPV serotypes 1, 2, and 3 and their variants containing the serotype-specific point mutation in the 5' untranslated region associated with neurovirulence.OPV was detected 3, 4, 5, and 7 months after the May 2010 NIW, but was not detected at 6 or 8 months. A second and third NIW occurred in February 2011 and May 2011, and OPV was detected in the sewage monthly after both of these NIW through July 2011 when collection stopped. The OPV detected was primarily serotype 2 and predominantly contained the point mutations in the 5' untranslated region associated with increased neurovirulence.OPV was detected in sewage as late as 7 months after an NIW in a Mexican community primarily vaccinated with IPV, but was not detected at 8 months, suggesting that OPV circulation may have ceased. These data suggest that in communities with high vaccination rates, 1 or 2 years of IPV administration after OPV cessation could be sufficient to prevent outbreaks of paralytic poliomyelitis from vaccine-derived strains.

    View details for DOI 10.1093/jpids/pis062

    View details for PubMedID 23667738

  • Use of a Novel Real-Time PCR Assay To Detect Oral Polio Vaccine Shedding and Reversion in Stool and Sewage Samples after a Mexican National Immunization Day JOURNAL OF CLINICAL MICROBIOLOGY Troy, S. B., Ferreyra-Reyes, L., Huang, C., Mahmud, N., Lee, Y., Canizales-Quintero, S., Flaster, H., Baez-Saldana, R., Garcia-Garcia, L., Maldonado, Y. 2011; 49 (5): 1777-1783

    Abstract

    During replication, oral polio vaccine (OPV) can revert to neurovirulence and cause paralytic poliomyelitis. In individual vaccinees, it can acquire specific revertant point mutations, leading to vaccine-associated paralytic poliomyelitis (VAPP). With longer replication, OPV can mutate into vaccine-derived poliovirus (VDPV), which causes poliomyelitis outbreaks similar to those caused by wild poliovirus. After wild poliovirus eradication, safely phasing out vaccination will likely require global use of inactivated polio vaccine (IPV) until cessation of OPV circulation. Mexico, where children receive routine IPV but where OPV is given biannually during national immunization days (NIDs), provides a natural setting to study the duration of OPV circulation in a population primarily vaccinated with IPV. We developed a real-time PCR assay to detect and distinguish revertant and nonrevertant OPV serotype 1 (OPV-1), OPV-2, and OPV-3 from RNA extracted directly from stool and sewage. Stool samples from 124 children and 8 1-liter sewage samples from Orizaba, Veracruz, Mexico, collected 6 to 13 weeks after a NID were analyzed. Revertant OPV-1 was found in stool at 7 and 9 weeks, and nonrevertant OPV-2 and OPV-3 were found in stool from two children 10 weeks after the NID. Revertant OPV-1 and nonrevertant OPV-2 and -3 were detected in sewage at 6 and 13 weeks after the NID. Our real-time PCR assay was able to detect small amounts of OPV in both stool and sewage and to distinguish nonrevertant and revertant serotypes and demonstrated that OPV continues to circulate at least 13 weeks after a NID in a Mexican population routinely immunized with IPV.

    View details for DOI 10.1128/JCM.02524-10

    View details for Web of Science ID 000289941000012

    View details for PubMedID 21411577

  • Fatal H1N1-Related Acute Necrotizing Encephalopathy in an Adult. Case reports in critical care Lee, Y., Smith, D. S., Rao, V. A., Siegel, R. D., Kosek, J., Glaser, C. A., Flint, A. C. 2011; 2011: 562516-?

    Abstract

    Acute necrotizing encephalopathy (ANE) is a severe neurological complication of influenza infection, including H1N1 influenza. Many cases of ANE have been reported in the pediatric literature, but very few cases have been described in adults. The cause of ANE remains unknown-the influenza virus is not known to be neurotropic, and evidence of direct viral involvement of the central nervous system (CNS) has not been demonstrated in the limited cases of ANE in which pathological specimens have been obtained. Here we report a fatal case of ANE from H1N1 influenza infection in an adult. Neuroimaging and postmortem analysis both showed widespread brain edema, necrosis, and hemorrhage, but molecular studies and postmortem pathology revealed no evidence of direct viral involvement of the CNS. This case of fatal ANE in an adult is consistent with the hypothesis generated from pediatric cases that the host immune response, and not direct viral invasion of the CNS, is responsible for pathogenesis of ANE.

    View details for DOI 10.1155/2011/562516

    View details for PubMedID 24826323

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