ABSTRACT
Natural infection with simian retrovirus (SRV) has long been recognized in rhesus macaques (RMs) and may result in an AIDS-like disease. Importantly, SRV infections persist as a problem in recently imported macaques. Therefore, there is a clear need to control SRV spread in macaque colonies. We developed a recombinant vesicular stomatitis virus (VSV)-SRV vaccine consisting of replication-competent hybrid VSVs that express SRV gag and env in separate vectors. The goal of this study was to assess the immunogenicity and protective efficacy of the VSV-SRV serotype 2 vaccine prime-boost approach in RMs. The VSV-SRV vector (expressing either SRV gag or env) vaccines were intranasally administered in 4 RMs, followed by a boost 1 month after the first vaccination. Four RMs served as controls and received the VSV vector alone. Two months after the boost, all animals were intravenously challenged with SRV-2 and monitored for 90 days. After the SRV-2 challenge, all four controls became infected, and viral loads (VLs) ranged from 10(6) to 10(8) SRV RNA copies/ml of plasma. Two animals in the control group developed simian AIDS within 7 to 8 weeks postinfection and were euthanized. Anemia and weight loss were observed in the remaining controls. During acute infection, severe B-cell depletion and no significant changes in T-cell population were observed in the control group. Control RMs with greater preservation of B cells and lower VLs survived longer. SRV-2 was undetectable in vaccinated animals, which remained healthy, with no clinical or biological signs of infection and preservation of B cells. Our study showed that the VSV-SRV vaccine is a strong approach for preventing clinically relevant type D retrovirus infection and disease in RMs, with protection of 4/4 RMs from SRV infection and prevention of B-cell destruction. B-cell protection was the strongest correlate of the long-term survival of all vaccinated and control RMs.
Subject(s)
B-Lymphocytes/immunology , Genetic Vectors/administration & dosage , Macaca mulatta , Mason-Pfizer monkey virus/immunology , SAIDS Vaccines/administration & dosage , Simian Acquired Immunodeficiency Syndrome/prevention & control , Vesiculovirus/genetics , Animals , Gene Products, env/genetics , Gene Products, env/immunology , Gene Products, env/metabolism , Gene Products, gag/genetics , Gene Products, gag/immunology , Gene Products, gag/metabolism , Immunization , Immunization, Secondary , Mason-Pfizer monkey virus/genetics , Mason-Pfizer monkey virus/pathogenicity , SAIDS Vaccines/genetics , SAIDS Vaccines/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/mortality , Simian Acquired Immunodeficiency Syndrome/virology , VaccinationABSTRACT
BACKGROUND: Living donor liver transplantation offers an attractive option to reduce the waitlist mortality. However, in recent years, the rising prevalence of obesity and nonalcoholic fatty liver disease has posed a serious threat to the donor pool while simultaneously increasing demand for liver transplant. To our knowledge, there have been no major published studies in the United States documenting a diet and exercise intervention to expand the living donor pool. Hereby, we established a pilot program called "Lose Weight to Donate" and present our initial experience. METHODS: Our center instituted a remotely monitored diet and exercise pilot program to increase eligibility for living liver donation. Potential donors with any of the following were included: body mass index >30 kg/m2, hepatic steatosis >5% on screening MRI, or isolated hypertension. RESULTS: Over 19 mo, 7 individuals enrolled in the program of remote monitoring for at least 6-8 wk. Initial and follow-up abdominal MRI was performed in 5 of these individuals to assess steatosis, anatomy, and volume. Initial steatosis was highly variable (fat signal fraction range, 8%-26%). Follow-up MRI fat signal fraction values and hepatic volume all decreased to varying degrees. Ultimately, 2 of 7 individuals donated, whereas a third was approved, but the intended recipient was transplanted in the interim. CONCLUSIONS: These results indicate the feasibility of a remotely monitored program to expand donation in light of the rising incidence of hepatic steatosis and obesity.
ABSTRACT
BACKGROUND: Anonymous living liver donations (ALLDs) raise ethical concerns regarding the donors' motivations. Thus, ALLDs are not as widely accepted as directed donations from friends and family. Literature on ALLDs is limited. Understanding this particular group of individuals is crucial, as they could further help mitigate the shortage of liver grafts worldwide. METHODS: A literature review was performed to identify current definitions, ethical considerations, different approaches, and barriers to ALLD worldwide. Furthermore, we present our current experience after the establishment of a protocol to enable an ALLD program in our center and surveyed potential donors to better understand their motives throughout the process. RESULTS: Literature regarding ALLD is scarce. Canada leads the experience with the majority of case reports published to date. Survey-based evaluation of this unique group of individuals reflects the selflessness nature of anonymous living donors and shows that most of them experience the donation as a positive and life-changing event. In our experience, 41 individuals initiated the process of ALLD during the study period. Most were lost to follow-up or deemed ineligible. Five candidates fully completed the donation process and successfully underwent living liver donation. Given that 2 candidates have a follow-up period <3 mo from donation, we have only included data on the first 3 donors in this analysis. Eight individuals (19.5%) responded to the survey with respondents sharing similar reasons for initiating ALLD but varied and multifactorial reasons for terminating. CONCLUSIONS: Different institutional protocols can be used to accomplish ALLD, including the one utilized by our institution. Adopting policies to allow for ALLDs and reducing modifiable factors that contribute to ending donation has the potential to increase grafts and decrease wait times.Supplemental Visual Abstract: http://links.lww.com/TP/C251.
ABSTRACT
Effective genetic diagnosis requires the correlation of genetic variant data with detailed phenotypic information. However, manual encoding of clinical data into machine-readable forms is laborious and subject to observer bias. Natural language processing (NLP) of electronic health records has great potential to enhance reproducibility at scale but suffers from idiosyncrasies in physician notes and other medical records. We developed methods to optimize NLP outputs for automated diagnosis. We filtered NLP-extracted Human Phenotype Ontology (HPO) terms to more closely resemble manually extracted terms and identified filter parameters across a three-dimensional space for optimal gene prioritization. We then developed a tiered pipeline that reduces manual effort by prioritizing smaller subsets of genes to consider for genetic diagnosis. Our filtering pipeline enabled NLP-based extraction of HPO terms to serve as a sufficient replacement for manual extraction in 92% of prospectively evaluated cases. In 75% of cases, the correct causal gene was ranked higher with our applied filters than without any filters. We describe a framework that can maximize the utility of NLP-based phenotype extraction for gene prioritization and diagnosis. The framework is implemented within a cloud-based modular architecture that can be deployed across health and research institutions.
ABSTRACT
Retrospective molecular epidemiology was performed on samples from four sooty mangabey (SM) colonies in the United States to characterize simian immunodeficiency virus SIVsm diversity in SMs and to trace virus circulation among different primate centers (PCs) over the past 30 years. The following SIVsm sequences were collected from different monkeys: 55 SIVsm isolates from the Tulane PC sampled between 1984 and 2004, 10 SIVsm isolates from the Yerkes PC sampled in 2002, 7 SIVsm isolates from the New Iberia PC sampled between 1979 and 1986, and 8 SIVsm isolates from the California PC sampled between 1975 and 1977. PCR and sequencing were done to characterize the gag, pol, and env gp36 genes. Phylogenetic analyses were correlated with the epidemiological data. Our analysis identified nine different divergent phylogenetic lineages that cocirculated in these four SM colonies in the Unites States in the past 30 years. Lineages 1 to 5 have been identified previously. Two of the newly identified SIVsm lineages found in SMs are ancestral to SIVmac251/SIVmac239/SIVmne and SIVstm. We further identified the origin of these two macaque viruses in SMs from the California National Primate Research Center. The diversity of SIVsm isolates in PCs in the United States mirrors that of human immunodeficiency virus type 1 (HIV-1) group M subtypes and offers a model for the molecular epidemiology of HIV and a new approach to vaccine testing. The cocirculation of divergent SIVsm strains in PCs resulted in founder effects, superinfections, and recombinations. This large array of SIVsm strains showing the same magnitude of diversity as HIV-1 group M subtypes should be extremely useful for modeling the efficacy of vaccination strategies under the real-world conditions of HIV-1 diversity. The genetic variability of SIVsm strains among PCs may influence the diagnosis and monitoring of SIVsm infection and, consequently, may bias the results of pathogenesis studies.