bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance of NS3, NS5a AND NS5b Hepatitis C Virus (HCV) Antiviral Resistance Sequencing Assays
Authors: Nutt Jamie , Grantham James , Smith Marilyn , Smith Emily , Wedin Ashley , Tyler Aaron , Miralles Mauricio , Kleiboeker Steve , Wissel Mark 
Published: October 2017

Abstract

Background
HCV genotype 1a (HCV g1a) followed by HCV g1b, –g2, and –g3 are the most common etiologic agents in the ~3 million current HCV-infections in the US. To achieve effective therapy, antiviral drug resistance testing is often essential but not fully available. Knowledge of both the genotype and the presence of HCV mutations in the genes of the major drug targets (NS3, NS5A and NS5B) can assist in optimal treatment selection.

Methods
The HCV genotype of 1000 HCV positive clinical plasmas and sera was determined (HCVg Direct, GenMark). Ten independent Sanger sequencing assays detecting antiviral drug resistance mutations in the genes encoding NS3, NS5a, and NS5b were developed. Six of these assays address mutations in all three genes in the two most common genotypes (HCV g1a and g1b). In addition, four more assays address mutations in NS5a and NS5b of HCV g2 and g3. These mutations are resistance determinants against 11 anti-HCV drugs as shown in Figure 1. A streamlined workflow employs conventional reverse transcriptase PCR, gel electrophoresis, spectrophotometry, bi-directional Sanger sequencing and reporting. The assays were designed to cover hot spot regions and capturing all known resistance mutations in NS3, NS5a and NS5b.

Results
Consistent with previous US HCV incidence reports, g1a, g1b, g2, and g3 comprised 99% of 1000 sequentially tested HCV patient specimens (62%, 12%, 11%, and 14%, respectively). Testing of more than 20 clinical samples each for g1a, g1b, g2, and g3 resulted in successful detection of NS3, NS5a, and NS5b mutations that confer drug resistance. The design successfully permitted detection of relevant mutations known to date for all 11 drugs. The number of reportable mutations range from 20 ‒ 36, 9 ‒ 49, and 10 ‒ 29 for the NS3, NS5a, and NS5b inhibitors, respectively (Figure 1).

Conclusion
These assays provide the most comprehensive commercially available antiviral drug resistance information to date for mutations in HCV NS3, NS5A, and NS5B. This testing will assist physicians in deciding on the most appropriate treatment options for their patients.

Disclosures
J. Nutt, Viracor Eurofins Laboratories: Employee, Salary; &#x2028;J. Grantham, Viracor Eurofins Laboratories: Employee, Salary; M. Smith, Viracor Eurofins Laboratories: Employee, Salary; E. Smith, Viracor Eurofins Laboratories: Employee, Salary; A. Wedin, Viracor Eurofins Laboratories: Employee, Salary; &#x2028;A. Tyler, Viracor Eurofins Laboratories: Employee, Salary; M. Miralles, Viracor Eurofins Laboratories: Employee, Salary; S. Kleiboeker, Viracor Eurofins Laboratories: Employee, Salary; M. Wissel, Viracor Eurofins Laboratories: Employee, Salary
Comparison of 30- and 90-Day Mortality Rates in Patients with Cultures Positive for Carbapenem-resistant Enterobacteriaceae and Acinetobacter in Atlanta, 2011–2015
Authors: Sexton Mary Elizabeth , Bower Chris , Sukumaran Stephen , Jacob Jesse T 
Published: October 2017

Abstract

Background
Carbapenem-resistant Enterobacteriaceae (CRE) and Acinetobacter baumannii (CRAB) pose a threat to public health, but comparisons of disease burden are limited. We compared survival in patients following cultures positive for CRE or CRAB.

Methods
The Georgia Emerging Infections Program performs active population-based and laboratory-based surveillance for CRE and CRAB in metropolitan Atlanta, GA. Using standard CDC definitions, we included patients who had incident carbapenem-nonsusceptible E. coli, Klebsiella spp., Enterobacter spp., or Acinetobacter baumannii isolated from urine only (noninvasive infection) or a sterile site (invasive infection) between 8/2011 and 12/2015. Death dates, verified by Georgia Vital Statistics records, were used to calculate 30- and 90-day mortality rates. We used the chi-square test for mortality rates and the log-rank test for survival analysis to 90 days to compare patients with invasive CRAB, noninvasive CRAB, invasive CRE, and noninvasive CRE.

Results
There were 535 patients with CRE (87 invasive, 448 noninvasive) and 279 (78 invasive, 201 noninvasive) with CRAB. Nearly all patients with CRE and CRAB had healthcare exposures (97.2% vs. 100%) and most were immunosuppressed (62.6% vs. 56.3%). Both 30-day (24.4% vs. 18.3%, p = 0.04) and 90-day (37.6% vs. 30.5%, p = 0.04) mortality were higher in patients with CRAB than CRE. Patients with invasive infections were more likely to die at 90 days than those with noninvasive infections (53.3% vs. 38.4%, p &lt; 0.0001). Overall mortality rates for invasive infection were similar between CRAB and CRE at 30 (44.9% vs. 34.5% p = 0.2) and 90 days (59.0% vs. 48.3%, p = 0.2). Using survival analysis at 90 days, invasive CRAB had the worst outcomes, followed by invasive CRE, noninvasive CRAB and noninvasive CRE &#x2028;(p &lt; 0.0001, see Figure).

Conclusion
Ninety -day mortality for invasive infections with CRE and CRAB was ~50%, and patients with CRAB had lower survival than those with CRE, suggesting that prevention efforts may need to prioritize CRAB as highly as CRE in facilities with endemic CRAB. With the high proportion of healthcare exposures and immunosuppression, these infections may signify poor prognosis or directly contribute to mortality.

Disclosures
All authors: No reported disclosures.
Differences in Pre- and Post-dischcarge Methicillin-resistant Staphylococcus aureus (MRSA) infection rates by colonization status in US Department of Veterans Affairs (VA) hospitals
Authors: Nelson Richard E , Evans Martin , Jones Makoto , Samore Matthew , Kralovic Stephen , Roselle Gary , Rubin Michael 
Published: October 2017

Abstract

Background
Little is known about how MRSA infection rates differ between patients who are colonized on admission compared with those who acquire colonization during an inpatient stay. In addition, most studies focus on MRSA infections that are diagnosed prior to discharge while ignoring those that are identified post-discharge. The VA implemented an active surveillance program for MRSA in 2007 in which all inpatients are tested for MRSA on admission. This surveillance data along with the ability to follow patients longitudinally allowed us to estimate the difference in infection rates for those who import vs. those who acquire &#x2028;MRSA colonization during their stay and to characterize post-discharge MRSA infections.

Methods
We constructed a dataset of 3,659,911 acute care inpatient admissions to 125 VA hospitals nationwide between January 1, 2008 and December 31/2015 who had surveillance tests performed for MRSA carriage. Admissions were restricted to individuals with at least 365 days of VA activity prior to admission. We categorized these admissions into 3 groups: no colonization, importation, and acquisition based on MRSA test results throughout the admission. We then captured MRSA infections in these individuals prior to discharge and at 30 and 90 days post-discharge. Infections were defined as positive MRSA cultures taken from sterile sites (including blood, catheter site, or bone).

Results
During the 8-year period, we identified 4,037 total pre-discharge MRSA infections, 2,793 MRSA infections at 30 days post-discharge, and 7,018 infections at 90 days post-discharge. During the pre-discharge time period, patients who acquired MRSA carriage were more likely to progress to an infection prior to discharge than those who imported the pathogen (RR = 2.6, P &lt; 0.001). For patients who acquired MRSA carriage, the percentage who progressed to infection prior to discharge decreased from 2.0% in 2010 to 1.4% in 2015. The results from our analyses can be found in Figures 1–3.

Conclusion
We found that roughly half of post-discharge infections were in patients who acquired the organism pre-discharge. These may be preventable with optimal infection control. In addition, there were nearly twice as many post-discharge MRSA infections at 90 days than during the pre-discharge period.

Disclosures
All authors: No reported disclosures.
Investigating Immune Correlates of Protection to Tuberculosis Using an Ultra-Low Dose Infection in a Mouse Model
Authors: Gern Benjamin , Plumlee Courtney , Gerner Michael , Urdahl Kevin 
Published: October 2017

Abstract

Background
Mycobacterium tuberculosis (M.tb) is the leading infectious cause of mortality; however, there is no vaccine that confers lasting protection. To investigate the immune response to M.tb, we have developed an ultra-low dose (ULD) infection model in mice that better reflects the heterogeneous outcomes of human infection. Additionally, we have identified a blood transcriptional signature, taken at day 24, that predicts future bacterial burden after day 70.

Methods
Mice were infected with an ULD (1–3 CFU) of H37Rv M.tb. Control mice were infected with 50–100 CFU. Blood was drawn at day 24 for RNA signature. At early (day 34–35), and late (day 82–83) time points, mice were injected with an intravascular label. Individual lungs were then assessed for bacterial burden, phenotypic and spatial analysis of immune cells by flow cytometry, and histocytometry, a type of immunohistochemistry that allows for imaging of &gt;12 colors

Results
At day 35, the following cell populations were correlated with an RNA signature score predicting disease progression: ESAT-6 tetramer+ CD4+ T cells (R2 = 0.35, P &lt; 0.01), TB10.4 tetramer+ CD8+ T cells (R2 = 0.34, P &lt; 0.01), and B cells (R2 = 0.28, p = 0.01) within the lung parenchyma, as well as CD11b+ cells, negative for CD64, Ly6c, Ly6g and MHCII (R2 = 0.38, p &lt; 0.01) within the lung vasculature. These same populations were correlated with elevated CFU at day 83, as well as dendritic cells (R2 = 0.53, p &lt; 0.01). No populations were correlated with a protective RNA score. We have observed the complex spatial organization of granulomas while optimizing our histocytometry panel. This includes infected macrophages (Fig 1) interdigitated with B cell aggregates, associated with naïve T cells, interspersed with CD44+ T cells, with diffuse staining for Ki67, suggestive of tertiary lymphoid structures (Figure 2).

Conclusion
This model replicates heterogeneity of TB seen in humans, while also providing a way to correlate differences in the immune response to future outcome. We have associated distinct immune cell subsets with the failure to control TB. With a larger sample size and data from histocytometry, we will have improved resolution to discern protective elements of the immune response to TB, which we can then test mechanistically in our model.

Disclosures
All authors: No reported disclosures.
Interferon gene expression as marker of immune maturation and response to vaccination
Authors: Cao Raquel Giacomelli , Smith Bennett , Bunsow Eleonora , Heinonen Santtu , Mertz Sara , Ye Fang , Best Victoria , Klis Fiona Van Der , Smits Gaby , Mejias Asuncion , Ramilo Octavio 
Published: October 2017

Abstract

Background
Interferons (IFN) play a major role in regulating innate and adaptive immune responses. Studies in adults and older children demonstrated significant correlations between IFN gene expression and antibody responses to influenza vaccines. However, there is still an incomplete understanding of the role of IFN in the ontogeny of the infant immune system and how they affect the immune response to vaccines in this population. Our objective with this study is to define longitudinal age-related changes in interferon gene expression and the changes induced by routine vaccinations.

Methods
We enrolled 2 cohorts of healthy children: 81 children aged &lt; 2 years evaluated at one-time point to assess age-dependent changes in IFN gene expression; and 47 &lt; 1 year olds evaluated at three times, before vaccination (day (d) 0) and d7 and d30 post-vaccination. Peripheral blood samples were collected to measure: (a) immune transcriptional profiles by microarrays; (b) immune cell populations by flow cytometry, and (c) antibody titers to PCV13, Hib and DTaP in the vaccination cohort.

Results
Analysis of first cohort demonstrated significant underexpression of IFN genes (n = 120) in infants aged &lt;6 months compared with those 12–24 months. By 9 months IFN expression was similar to the older children. IFN gene expression correlated with the numbers of neutrophils and monocytes across all age groups. The second cohort was evaluated at three time points (d0, d7, and d30) during routine vaccinations at 2, 6, and 12 months. We compared transcriptional profiles post-vaccination with d0 for each group and observed consistent overexpression of IFN-related genes at d7 in the three age groups. In 2-month-old infants, we observed significant correlations between IFN genes (TAP1, IFIT1/2/3, OASL and GBP1) at d0 (before vaccination) and increase in antibody titers of the three vaccines analyzed (r = 0.5–0.7; P &lt; 0.05). Among the top 15 genes who have the most significant correlations, eight are exclusively induced by type I IFN, six by type II IFN, and one is shared between the two types.

Conclusion
IFN gene expression at baseline is markedly reduced in infants &lt;6 months. Routine vaccines were associated with marked increased in IFN gene expression at 2, 6, and 12 months. Baseline IFN expression at 2 months correlated with antibody responses to vaccines.

Disclosures
O. Ramilo, Abbvie: Board Member, Consulting fee; Regeneron: Board Member, Consulting fee; Janssen: Board Member and Investigator, Consulting fee and Research grant; NIH: Grant Investigator, Research grant
Colorado’s Statewide Antimicrobial Stewardship (AMS) Collaborative Final Results. Facilitating Syndrome-Specific Interventions for Skin and Soft-tissue Infection (SSTI) and Urinary Tract Infection (UTI)
Authors: Wald Heidi , Hulett Teri , Knepper Bryan , Barber Gerard , Shihadeh Kati , Meyer Marc , Hammer John 
Published: October 2017

Abstract

Background
Colorado Hospital Association (CHA) led a statewide collaborative to engage hospitals in AMS, focused on interventions for UTI and SSTI. The collaborative goals were to reduce the use of fluoroquinolones (FQs) for UTIs, increase the proportion of diagnosed UTIs meeting objective criteria, reduce exposure to antibiotics with broad Gram-negative activity for SSTI, and shorten treatment durations for UTI and SSTI. We evaluated the effect of the collaborative on these measures.

Methods
Diagnostic (UTI) and treatment guidance (UTI and SSTI) were developed by a local expert panel. Collaborative methodology was used to engage local hospital AMS teams in guideline implementation. Teams submitted data for 80 cases during the baseline period (2014) and 20 cases per quarter during the intervention period (October 2015–December 2016) for each condition. Primary analyses were changes in trends of the main outcomes by interrupted time series analysis. Secondary analyses were the aggregate changes in the main outcomes between the baseline and intervention periods.

Results
Twenty-seven acute care hospitals (bed range 15–567) participated in the collaborative. Data were reported for 1,530 UTI and 722 SSTI cases from the baseline period and for 2,514 UTI and 1,030 SSTI cases from the intervention. Interrupted time series analyses of the main outcomes are shown in Figure. The trend in exposure to FQs for UTIs decreased significantly from baseline to the intervention (P = 0.03). Changes in the trends for the other outcomes did not reach statistical significance. In the secondary analyses, exposure to FQs declined from 49% at baseline to 40% during the intervention (UTI), and the proportion of diagnosed UTIs meeting objective criteria increased from 51% to 54% (P = 0.10). Among SSTI cases, exposure to antibiotics with broad Gram-negative activity declined from 61% to 53% (P = 0.001), and the median duration of therapy declined from 13 to 11 days (P &lt; 0.0001).

Conclusion
A statewide collaborative successfully engaged hospitals to participate in AMS. Intended changes in prescribing practices for the collaborative were observed; however, the degree of success varied by outcome. Additional work is needed to explore factors associated with success or lack thereof among the individual hospitals.

Disclosures
H. Wald, Colorado Hospital Association: Consultant, Consulting fee; T. Hulett, Colorado Hospital Association: Consultant and Employee, Salary; G. Barber, Merck: Speaker’s Bureau, Speaker honorarium
Measles CEA
Authors: Hyle Emily 
Published: October 2017

Abstract

Background
Most measles importations are due to returning US travelers infected during international travel. We projected clinical outcomes and assessed cost-effectiveness of pretravel evaluation for measles immunity and MMR vaccination among eligible adult US international travelers.

Methods
We designed a decision tree to investigate pretravel evaluation compared with no evaluation from the societal perspective. Data from the Global TravEpiNet Consortium and published literature informed input parameters (Figure 1). Outcomes included measles cases averted per 10 million travelers, costs, and the incremental cost-effectiveness ratio (ICER, Δcosts/Δmeasles cases averted); we considered ICERs &lt; $100,000/measles case averted to be cost-effective. We performed sensitivity analyses to assess the impact of varying the probability of exposure based on travel destination, and the percentage of travelers with pre-existing measles immunity.

Results
In the base case, departure after pretravel evaluation resulted in 16 measles importations and 46 transmissions per 10 million travelers and cost $132 million, vs without pretravel evaluation (26 importations and 87 transmissions per 10 million travelers, costing $22 million). Pretravel evaluation averted 51 measles cases per 10 million travelers with an ICER of $2.2 million per case averted. Results were most sensitive to the probability of measles exposure and the traveler’s pre-existing immunity (Figure 2). Pretravel evaluation was cost-effective for travelers to Asia if pre-existing measles immunity was &lt;80%. Evaluation was always cost-effective for travelers to Africa when pre-existing immunity was less than 100% and became cost saving when the percentage of immune travelers was lower (&lt;70%). Travelers who were more likely to be non-immune and were visiting destinations with higher probabilities of exposure were most likely to benefit from pretravel evaluation for measles immunity at excellent economic value.

Conclusion
As risk of measles exposure increases and likelihood of travelers’ pre-existing immunity decreases, it can be cost-effective or cost saving to assess US international travelers’ measles immunity status and vaccinate with MMR prior to departure.

Disclosures
All authors: No reported disclosures.
Analysis of Invasive Pneumococcal Infections Due to 13-Pneumococcal Conjugate Vaccine Serotypes at 8 US Children’s Hospitals During 2014 to 2016
Authors: Kaplan Sheldon L , Barson William J , Lin Philana Ling , Romero Jose R , Bradley John S , Tan Tina , Givner Laurence B , Hoffman Jill , Hulten Kristina , Mason Edward O 
Published: October 2017

Abstract

Background
The 13-Valent Pneumococcal Conjugate Vaccine (PCV13) was licensed in 2010 and is directed against serotypes (ST) 1,3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Details of cases of invasive pneumococcal disease (IPD) due to PCV13 ST since 2010 in the US are sparse. We describe IPD cases due to PCV13 ST seen at 8 US children’s hospitals over years 2014 to 2016 which may aid in understanding why some IPD cases due to these ST have persisted.

Methods
Children with IPD have been prospectively identified at 8 children’s hospitals in the US since 1993. Data from 2014 through 2016 were analyzed. Demographic, clinical data and number and dates of PCV doses were collected on case report forms and isolates were sent to a central laboratory for serotyping. PCV doses are counted if IPD occurred &gt; 2 weeks after a dose.

Results
PCV13 ST accounted for 19.7% (27/137), 26.8% (30/112) and 26% (33/127) of IPD cases in 2014, 2015 and 2016, respectively. ST 3, 19A and 19F accounted for 90% of the PCV13 ST IPD cases. &gt;50% of the children had received ≤2 doses of PCV13 prior to IPD. (Table) Of the 30 children with 0 doses of PCV, 15 were of an age at diagnosis for which ≥ 2 doses of PCV was recommended. An underlying condition was noted in 18. For PCV13 ST, the types of IPD were pneumonia (n = 39), mastoiditis (n = 15), bacteremia (n = 15), meningitis (n = 12) and other sites of infection (n = 9). Whereas the numbers of yearly cases were similar for ST3 (12, 10, 13) and ST19A (8, 10, 6), the numbers for 19F increased slightly (3, 8, 10).

Conclusion
Four to 6 years after PCV13 was introduced, PCV13 ST (especially ST 3, 19A and 19F) accounted for about 25% of IPD in children. For all of the PCV13 ST, over half of these IPD cases occurred in children who had received ≤ 2 doses of the recommended PCV schedule; 25% of cases occurred in children who had not received any doses but were of the age at diagnosis that at least 2 PCV doses should have been received. Additional PCV13 ST IPD cases may be preventable if the PCV13 schedule is followed as recommended.

Disclosures
S. L. Kaplan, Pfizer: Grant Investigator and Speaker at PCV13 Launch Meeting in China, Research grant and Speaker honorarium; J. S. Bradley, Merck & Co., Inc.: Investigator, Research support
Changes in Pneumonia Incidence and Infant Mortality 5 Years Following Introduction of the 13-valent Pneumococcal Conjugate Vaccine in a “3+0” Schedule in Nicaragua
Authors: Becker-Dreps Sylvia , Blette Bryan , Briceno Rafaela , Aleman Jorge , Hudgens Michael G , Moreno Gilberto , Ordonez Ana , Rocha Julio , Weber David J , Amaya Erick 
Published: October 2017

Abstract

Background
Streptococcus pneumoniae causes an estimated 826,000 deaths of children in the world each year and many health facility visits. To reduce the burden of pneumococcal disease, many nations have added pneumococcal conjugate vaccines to their national immunization schedules. Nicaragua was the first country eligible for funding from the GAVI Alliance to introduce the 13-valent pneumococcal conjugate vaccine (PCV13), provided to infants at 2, 4, and 6 months of age. The goal of this study was to evaluate the population impact of the first five years of the program.

Methods
Numbers of visits for pneumonia, pneumonia-related deaths, bacterial meningitis, and infant deaths between 2008 and 2015 were collected from all 107 public health facilities in León Department. Vital statistics data provided additional counts of pneumonia-related deaths that occurred outside health facilities. Adjusted incidence rates and incidence rate ratios (IRRa) in the vaccine (2011–2015) and pre-vaccine periods (2008–2010) were estimated using official population estimates as exposure time.

Results
The IRRa for pneumonia hospitalizations was 0.70 (95% confidence interval [CI]: 0.66, 0.75) for infants, and 0.92 (95% CI: 0.85, 0.99) for one year olds. The IRRa for post-neonatal infant mortality was 0.56 (95% CI: 0.41, 0.77). In the population as a whole, ambulatory visits and hospitalizations for pneumonia, as well as pneumonia-related mortality and rates of bacterial meningitis were lower in the vaccine period.

Conclusion
Five years following program introduction, reductions were observed in health facility visits for pneumonia in immunized age groups and infant mortality, which would be hard to achieve with any other single public health intervention. Future study is warranted to understand whether the lack of a booster dose (e.g.,, at 12 months) may be responsible for the small reductions in pneumonia hospitalizations observed in one year-olds as compared with infants.

Disclosures
S. Becker-Dreps, Pfizer: Consultant and Grant Investigator, Consulting fee and Research grant; D. J. Weber, Pfizer: Consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium