Gentle Guardian of the Mentally Ill: The Story of One Missourian

In July of this year Dr. Emmett F. Hoctor, superintendent of Farmington State Hospital in Missouri, retired from this post after 38 years of dedicated tabors. Mr. Jack Stapleton, Jr., reporting for The Farmington Press, contributed the following interesting tribute to this devoted Catholic physician whose years of zealous care of the mentally ill at the Farmington institution are a source of edification to all who know him. The article is reprinted with the kind permission of the editor of The Farmington Press

A sequential classification rule based on multiple quantitative tests in the absence of a gold standard

In many medical applications, combining information from multiple biomarkers could yield a better diagnosis than any single one on its own. When there is a lack of a gold standard, an algorithm of classifying subjects into the case and non-case status is necessary for combining multiple markers. The aim of this paper is to develop a method to construct a composite test from multiple applicable tests and derive an optimal classification rule under the absence of a gold standard. Rather than combining the tests, we treat the tests as a sequence. This sequential composite test is based on a mixture of two multivariate normal latent models for the distribution of the test results in case and non-case groups, and the optimal classification rule is derived returning the greatest sensitivity at a given specificity. This method is applied to a real-data example and simulation studies have been carried out to assess the statistical properties and predictive accuracy of the proposed composite test. This method is also attainable to implement nonparametrically

Ethnicity and smoking-associated DNA methylation changes at HIV co-receptor GPR15

Smoking is associated with poorer health outcomes for both African and European Americans. In order to better understand whether ethnic-specific genetic variation may underlie some of these differences, we compared the smoking-associated genome-wide methylation signatures of African Americans with those of European Americans, and followed up this analysis with a focused examination of the most ethnically divergent locus, cg19859270, at the GPR15 gene. We examined the association of methylation at this locus to the rs2230344 SNP and GPR15 gene and protein expression. Consistent with prior analyses, AHRR residue cg05575921 was the most differentially methylated residue in both African Americans and European Americans. However, the second most differentially methylated locus in African Americans, cg19859270, was only modestly differentially methylated in European Americans. Interrogation of the methylation status of this CpG residue found in GPR15, a chemokine receptor involved in HIV pathogenesis, showed a significant interaction of ethnicity with smoking as well as a marginal effect of genotype at rs2230344, a neighboring non-synonymous SNP, but only among African Americans. Gene and protein expression analyses showed that demethylation at cg19859270 was associated with an increase in both mRNA and protein levels. Since GPR15 is involved in the early stages of viral replication for some HIV-1 and HIV-2 isolates, and the prevalence of HIV is increased in African Americans and smokers, these data support a possible role for GPR15 in the ethnically dependent differential prevalence of HIV

Evidence against GB virus C infection in dromedary camels

A recent publication described finding GB virus C (GBV-C) RNA in four of twenty two dromedary camel sera, and sequence analysis found that these viruses were phylogenetically clustered within human GBV-C isolates. Since all other GB viruses to date form monophyletic groups according to their host species, the close relationship between the sequences generated from camel sera and human GBV-C isolates seemed implausible, leading us to conduct an independent analysis of the sequences. Our investigation found three lines of evidence arguing against GBV-C infection in dromedary camels. First, strong evidence of artifactual sequence generation was identified for some of the sequences. Secondly, the sequence diversity within individual camel sera was ten- to one-hundred fifty two-fold greater than that described for GBV-C within a human host. Finally, GBV-C sequences generated from each camel shared near complete identity with human isolates previously described by the same laboratory. Taken together, these data strongly suggest laboratory contamination. We suggest that additional validation experiments are needed before it is possible to conclude that camels are permissive for GBV-C infection

Proposed Revision to the Taxonomy of the Genus Pestivirus; Family Flaviviridae

We propose the creation of seven new species in the genus Pestivirus (family Flaviviridae) in addition to the four existing species, and naming species in a host-independent manner using the format Pestivirus X. Only the virus species names would change; virus isolates would still be referred to by their original names. The original species would be re-designated as Pestivirus A (original designation Bovine viral diarrhea virus 1), Pestivirus B (Bovine viral diarrhea virus 2), Pestivirus C (Classical swine fever virus) and Pestivirus D (Border disease virus). The seven new species (and example isolates) would be Pestivirus E (pronghorn pestivirus), Pestivirus F (Bungowannah virus), Pestivirus G (giraffe pestivirus), Pestivirus H (Hobi-like pestivirus), Pestivirus I (Aydin-like pestivirus), Pestivirus J (rat pestivirus) and Pestivirus K (atypical porcine pestivirus). A bat-derived virus and pestiviruses identified from sheep and goat (Tunisian sheep pestiviruses), which lack complete coding region sequences, may represent two additional species

Expanded classification of hepatitis C Virus into 7 genotypes and 67 Subtypes:updated criteria and assignment web resource

The 2005 consensus proposal for the classification of hepatitis C virus (HCV) presented an agreed and uniform nomenclature for HCV variants and the criteria for their assignment into genotypes and subtypes. Since its publication, the available dataset of HCV sequences has vastly expanded through advancement in nucleotide sequencing technologies and an increasing focus on the role of HCV genetic variation in disease and treatment outcomes. The current study represents a major update to the previous consensus HCV classification, incorporating additional sequence information derived from over 1,300 (near-)complete genome sequences of HCV available on public databases in May 2013. Analysis resolved several nomenclature conflicts between genotype designations and using consensus criteria created a classification of HCV into seven confirmed genotypes and 67 subtypes. There are 21 additional complete coding region sequences of unassigned subtype. The study additionally describes the development of a Web resource hosted by the International Committee for Taxonomy of Viruses (ICTV) that maintains and regularly updates tables of reference isolates, accession numbers, and annotated alignments (http://talk.ictvonline.org/links/hcv/hcv-classification.htm). The Flaviviridae Study Group urges those who need to check or propose new genotypes or subtypes of HCV to contact the Study Group in advance of publication to avoid nomenclature conflicts appearing in the literature. While the criteria for assigning genotypes and subtypes remain unchanged from previous consensus proposals, changes are proposed in the assignment of provisional subtypes, subtype numbering beyond “w,” and the nomenclature of intergenotypic recombinant. Conclusion: This study represents an important reference point for the consensus classification of HCV variants that will be of value to researchers working in clinical and basic science fields. (Hepatology 2014;59:318-327

A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN\u3csup\u3e®\u3c/sup\u3e) in 56-80-Year-Old Subjects

Background Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA) was assessed in a 56–80 years old population. Methods MVA with a virus titer of 1 x 108 TCID50/dose was administered via subcutaneous injection to 56–80 year old vaccinia-experienced subjects (N = 120). Subjects received either two injections of MVA (MM group) or one injection of Placebo and one injection of MVA (PM group) four weeks apart. Safety was evaluated by assessment of adverse events (AE), focused physical exams, electrocardiogram recordings and safety laboratories. Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration) and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue) and were recorded on a memory aid for an 8-day period following each injection. The immunogenicity of the vaccine was evaluated in terms of humoral immune responses measured with a vaccinia-specific enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT) before and at different time points after vaccination. Results Vaccinations were well tolerated by all subjects. No serious adverse event related to MVA and no case of myopericarditis was reported. The overall incidence of unsolicited AEs was similar in both groups. For both groups immunogenicity responses two weeks after the final vaccination (i.e. Visit 4) were as follows: Seroconversion (SC) rates (doubling of titers from baseline) in vaccine specific antibody titers measured by ELISA were 83.3% in Group MM and 82.8% in Group PM (difference 0.6% with 95% exact CI [-13.8%, 15.0%]), and 90.0% for Group MM and 77.6% for Group PM measured by PRNT (difference 12.4% with 95% CI of [-1.1%, 27.0%]). Geometric mean titers (GMT) measured by ELISA two weeks after the final vaccination for Group MM were 804.1 and 605.8 for Group PM (with ratio of GMTs of 1.33 with 95% CI of [0.96, 1.84]). Similarly, GMTs measured by PRNT were 210.3 for Group MM and 126.7 for Group PM (with ratio 1.66 and 95% CI [0.95, 2.90]). Conclusions One or two doses of MVA were safe and immunogenic in a 56–80 years old vaccinia-experienced population. No cases of myopericarditis were observed following vaccinations with MVA. The safety, reactogenicity and immunogenicity were similar to that seen in younger (18–55 year old) healthy populations as investigated in other MVA trials. The results suggest that a single dose of MVA in a 56–80 years old population was well tolerated and sufficient to rapidly boost the long-term B cell memory response induced by a prior vaccination with a traditional smallpox vaccine. Trial Registration ClinicalTrials.gov NCT00857493

Characterization of a Peptide Domain within the GB Virus C NS5A Phosphoprotein that Inhibits HIV Replication

BACKGROUND:GBV-C infection is associated with prolonged survival in HIV-infected people and GBV-C inhibits HIV replication in co-infection models. Expression of the GBV-C nonstructural phosphoprotein 5A (NS5A) decreases surface levels of the HIV co-receptor CXCR4, induces the release of SDF-1 and inhibits HIV replication in Jurkat CD4+ T cell lines. METHODOLOGY/PRINCIPAL FINDINGS:Jurkat cell lines stably expressing NS5A protein and peptides were generated and HIV replication in these cell lines assessed. HIV replication was significantly inhibited in all cell lines expressing NS5A amino acids 152-165. Substitution of an either alanine or glycine for the serine at position 158 (S158A or S158G) resulted in a significant decrease in the HIV inhibitory effect. In contrast, substituting a phosphomimetic amino acid (glutamic acid; S158E) inhibited HIV as well as the parent peptide. HIV inhibition was associated with lower levels of surface expression of the HIV co-receptor CXCR4 and increased release of the CXCR4 ligand, SDF-1 compared to control cells. Incubation of CD4+ T cell lines with synthetic peptides containing amino acids 152-167 or the S158E mutant peptide prior to HIV infection resulted in HIV replication inhibition compared to control peptides. CONCLUSIONS/SIGNIFICANCE:Expression of GBV-C NS5A amino acids 152-165 are sufficient to inhibit HIV replication in vitro, and the serine at position 158 appears important for this effect through either phosphorylation or structural changes in this peptide. The addition of synthetic peptides containing 152-167 or the S158E substitution to Jurkat cells resulted in HIV replication inhibition in vitro. These data suggest that GBV-C peptides or a peptide mimetic may offer a novel, cellular-based approach to antiretroviral therapy

Proposed update to the taxonomy of the genera Hepacivirus and Pegivirus within the Flaviviridae family

Proposals are described for the assignment of recently reported viruses, infecting rodents, bats and other mammalian species, to new species within the Hepacivirus and Pegivirus genera (Family Flaviviridae). Assignments into 14 Hepacivirus species (Hepacivirus A to N) and 11 Pegivirus species (Pegivirus A to K) are based on phylogenetic relationships and sequence distances between conserved regions extracted from complete coding sequences of each proposed taxon. We propose that the species hepatitis C virus is renamed Hepacivirus C in order to acknowledge its unique historical position and so as to minimise confusion. Despite the newly documented genetic diversity of hepaciviruses and pegiviruses, members of these genera remain phylogenetically distinct, and differ in hepatotropism and the possession of a basic core protein; pegiviruses in general lack these features. However, other characteristics that were originally used to support their division into separate genera are no longer definitive; there is overlap between the two genera in the type of internal ribosomal entry site (IRES) and the presence of miR-122 sites in the 5'untranslated region (UTR), the predicted number of N-linked glycosylation sites in the envelope E1 and E2 proteins, the presence of poly U tracts in the 3' UTR and the propensity of viruses to establish a persistent infection. While all classified hepaciviruses and pegiviruses have mammalian hosts, the recent description of a hepaci-/pegi-like virus from a shark and the likely existence of further homologues in other non-mammalian species indicates that further species or genera remain to be defined in the future