bluuebunny/crossref_metadata_2025 huggingface dataset:
Stain-Free Resolution of Unmyelinated Axons in Transgenic Mice Using Fluorescence Microscopy
Authors: Mohan Suresh , Coto Hernández Iván , Selig Martin K , Shibata Shinsuke , Jowett Nate
Published: October 2019

Though unmyelinated fibers predominate axon counts within peripheral nerves, they are frequently excluded in histomorphometric assessment as they cannot be readily resolved by light microscopy. Herein, we demonstrate stain-free resolution of unmyelinated axons in Sox10-Venus mice by widefield fluorescence imaging of sciatic nerve cryosections. Optional staining of cryosections using a rapid and nontoxic myelin-specific dye (FluoroMyelin Red) enables robust synchronous resolution of myelinated and unmyelinated fibers, comprising a high-throughput platform for neural histomorphometry.
Linear polarization in gamma-ray burst prompt emission
Authors: Gill Ramandeep , Granot Jonathan , Kumar Pawan
Published: October 2019

Despite being hard to measure, GRB prompt γ-ray emission polarization is a valuable probe of the dominant emission mechanism and the GRB outflow’s composition and angular structure. During the prompt emission the GRB outflow is ultra-relativistic with Lorentz factors Γ ≫ 1. We describe in detail the linear polarization properties of various emission mechanisms: synchrotron radiation from different magnetic field structures (ordered: toroidal Btor or radial B∥, and random: normal to the radial direction B⊥), Compton drag, and photospheric emission. We calculate the polarization for different GRB jet angular structures (e.g. top-hat, Gaussian, power-law) and viewing angles θobs. Synchrotron with B⊥ can produce large polarizations, up to $25\%\lesssim \Pi \lesssim 45\%$, for a top-hat jet but only for lines of sight just outside (θobs − θj ∼ 1/Γ) the jet’s sharp edge at θ = θj. The same also holds for Compton drag, albeit with a slightly higher overall Π. Moreover, we demonstrate how Γ-variations during the GRB or smoother jet edges (on angular scales ≳ 0.5/Γ) would significantly reduce Π. We construct a semi-analytic model for non-dissipative photospheric emission from structured jets. Such emission can produce up to $\Pi \lesssim 15\%$ with reasonably high fluences, but this requires steep gradients in Γ(θ). A polarization of $50\%\lesssim \Pi \lesssim 65\%$ can robustly be produced only by synchrotron emission from a transverse magnetic field ordered on angles ≳ 1/Γ around our line of sight (like a global toroidal field, Btor, for 1/Γ < θobs < θj). Therefore, such a model would be strongly favored even by a single secure measurement within this range. We find that such a model would also be favored if $\Pi \gtrsim 20\%$ is measured in most GRBs within a large enough sample, by deriving the polarization distribution for our different emission and jet models.
Convergent Evolution of Hydrogenosomes from Mitochondria by Gene Transfer and Loss
Authors: Lewis William H , Lind Anders E , Sendra Kacper M , Onsbring Henning , Williams Tom A , Esteban Genoveva F , Hirt Robert P , Ettema Thijs J G , Embley T Martin
Published: October 2019

Hydrogenosomes are H2-producing mitochondrial homologs found in some anaerobic microbial eukaryotes that provide a rare intracellular niche for H2-utilizing endosymbiotic archaea. Among ciliates, anaerobic and aerobic lineages are interspersed, demonstrating that the switch to an anaerobic lifestyle with hydrogenosomes has occurred repeatedly and independently. To investigate the molecular details of this transition, we generated genomic and transcriptomic data sets from anaerobic ciliates representing three distinct lineages. Our data demonstrate that hydrogenosomes have evolved from ancestral mitochondria in each case and reveal different degrees of independent mitochondrial genome and proteome reductive evolution, including the first example of complete mitochondrial genome loss in ciliates. Intriguingly, the FeFe-hydrogenase used for generating H2 has a unique domain structure among eukaryotes and appears to have been present, potentially through a single lateral gene transfer from an unknown donor, in the common aerobic ancestor of all three lineages. The early acquisition and retention of FeFe-hydrogenase helps to explain the facility whereby mitochondrial function can be so radically modified within this diverse and ecologically important group of microbial eukaryotes.
DSS1 interacts with and stimulates RAD52 to promote the repair of DSBs
Authors: Stefanovie Barbora , Hengel Sarah R , Mlcouskova Jarmila , Prochazkova Jana , Spirek Mario , Nikulenkov Fedor , Nemecek Daniel , Koch Brandon G , Bain Fletcher E , Yu Liping , Spies Maria , Krejci Lumir
Published: October 2019

The proper repair of deleterious DNA lesions such as double strand breaks prevents genomic instability and carcinogenesis. In yeast, the Rad52 protein mediates DSB repair via homologous recombination. In mammalian cells, despite the presence of the RAD52 protein, the tumour suppressor protein BRCA2 acts as the predominant mediator during homologous recombination. For decades, it has been believed that the RAD52 protein played only a back-up role in the repair of DSBs performing an error-prone single strand annealing (SSA). Recent studies have identified several new functions of the RAD52 protein and have drawn attention to its important role in genome maintenance. Here, we show that RAD52 activities are enhanced by interacting with a small and highly acidic protein called DSS1. Binding of DSS1 to RAD52 changes the RAD52 oligomeric conformation, modulates its DNA binding properties, stimulates SSA activity and promotes strand invasion. Our work introduces for the first time RAD52 as another interacting partner of DSS1 and shows that both proteins are important players in the SSA and BIR pathways of DSB repair.
A retrospective, quantitative assessment of disease burden in patients with leptomeningeal metastases from non-small-cell lung cancer
Authors: Nevel Kathryn S , DiStefano Natalie , Lin Xuling , Skakodub Anna , Ogilvie Shahiba Q , Reiner Anne S , Pentsova Elena , Boire Adrienne
Published: October 2019

Background

Improvements in detection and molecular characterization of leptomeningeal metastasis from lung cancer (LC-LM) coupled with cerebrospinal fluid (CSF)-penetrating targeted therapies have altered disease management. A barrier to formal study of these therapies in LM is quantification of disease burden. Also, outcomes of patients with targetable mutations in LC-LM are not well defined. This study employs molecular and radiographic measures of LM disease burden and correlates these with outcome.

Methods

We reviewed charts of 171 patients with LC-LM treated at Memorial Sloan Kettering. A subset had MRI and CSF studies available. Radiographic involvement (n = 76) was scored by number of gadolinium-enhancing sites in 8 locations. CSF studies included cytopathology, circulating tumor cell (CTC) quantification (n = 16), and cell-free DNA (cfDNA) analysis (n = 21). Clinical outcomes were compared with Kaplan–Meier log-rank test and Cox proportional hazards methodologies.

Results

Median overall survival was 4.2 months (95% CI: 3.6–4.9); 84 patients (49%) harbored targetable mutations. Among bevacizumab-naïve patients with MRI and CSF cytology at time of LC-LM diagnosis, extent of radiographic involvement correlated with risk of death (hazard ratio [HR]: 1.16; 95% CI: 1.02–1.33; P = 0.03), as did CSF CTC (HR: 3.39, 95% CI: 1.01–11.37; P = 0.048) and CSF cfDNA concentration (HR: 2.58; 95% CI: 0.94–7.05; P = 0.06). Those without a targetable mutation were almost 50% more likely to die (HR: 1.49; 95% CI: 1.06–2.11; P = 0.02).

Conclusions

Extent of radiographic involvement and quantification of CSF CTC and cfDNA show promise as prognostic indicators. These findings support molecular characterization and staging for clinical management, prognostication, and clinical trial stratification of LC-LM.
82. First 5 Years of Experience with the Illinois Extensively Drug-Resistant Organism (XDRO) Registry and Implementation of Automated Alerting
Authors: Lin Michael Y , Tang Angela , Fealy Amy E , Gao Wei , Markovski George , Xiang Yingxu , Trick William
Published: October 2019

Background

The Illinois XDRO Registry was created in November 2013 as an information system for XDROs; currently, the registry includes carbapenem-resistant Enterobacteriaceae (CRE), carbapenemase-producing Pseudomonas aeruginosa, and Candida auris. All Illinois healthcare facilities can manually query the registry at the time of admission to assess patients’ prior colonization status. A subset of facilities, mainly hospitals, participate in the registry’s automated querying process; alerts are generated automatically and sent via email, page, or text to infection preventionists at the time of patient admission.

Methods

We assessed counts of XDRO report submissions and total queries (manual and automated) over time, by organism. Facilities achieved automated alerts by sending a near-real-time feed of inpatient admission data (patient name and date of birth) to Illinois Department of Public Health (IDPH) via one of the three connection types: direct (data sent directly to IDPH), vendor (data sent via vendor software), and syndromic surveillance (existing syndromic surveillance data adapted for registry).

Results

In total, 6,445 unique patients (11,258 total reports) from 213 facilities have been reported to the XDRO registry (counts by organism type, Table). The registry has been manually queried 39,678 times by 232 facilities. Seventy-five facilities have achieved automation of alerting; the types of data connections used were direct (N = 56), vendor (N = 18), and syndromic surveillance (N = 1). In total, 5,344 automated alerts have been sent for 1,555 unique patients. Automated alerts per month have increased over time (P < 0.001, Figure). Infection preventionists reported feedback on 3,008 CRE alerts via a website questionnaire; among 1176 first alerts/patient/facility, 49% of patients’ XDRO status were previously unknown to the facility, and 33% were not in contact precautions at the time of alert.

Conclusion

The XDRO registry, originally focused on CRE, successfully expanded to include emerging XDRO threats such as Candida auris and is poised for rapid response to emerging threats. The registry’s adaptable reporting structure and expanding automation have enabled it to deliver an increasing number of actionable infection-control alerts over time.

Disclosures

All Authors: No reported Disclosures.
88. Public Health Service (PHS) Increased-Risk Factors in Organ Donors: A Review of the OPTN Ad hoc Disease Transmission Advisory Committee (DTAC)
Authors: Vece Gabe , La Hoz Ricardo M , Wolfe Cameron R , Ward Emily G , Wood R Patrick , Strasfeld Lynne , Sawyer Rob , Rana Meenakshi , Marboe Charles , Malinis Maricar , Liliy Kathleen , Ho Sam , Florescu Diana F , Danziger-Isakov Lara , Bucio Jamie , Berry Gerald , Bag Remzi , Aslam Saima , Michaels Marian G
Published: October 2019

Background

In the United States, all deceased donors (DD) are evaluated for behavioral risk factors for human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C (HCV) infection during the past 12 months. DD with behavioral risk factors or hemodilution are designated as PHS increased risk donors (IRD). Since 2013, the number of IRD has increased from 13.4% of DD to 27% in 2018. Despite a low residual risk of disease transmission after a negative nucleic acid test for HIV/HBV/HCV, the considerable underutilization of IRD has driven an interest in revising the PHS IRD 2013 guidelines. The objective of this study was to describe the epidemiology of IRD with the goal of guiding policy change and maximize organ use.

Methods

This is a retrospective cohort study of DD during 2018. Characteristics of IRD were compared with non-IRD. A random 10% sample of IRD was selected for manual review of text narratives and donor questionnaires submitted by organ procurement organizations to determine specific PHS IRD factors. Categorical variables were compared using the χ 2 test and continuous variables were compared using a 2-sample t-test for independent samples.

Results

Among 10,721 DD in 2018, 2,904 were designated IRD (27.1%) with regional variability noted (Figure). Compared with non-IRD, IRD were younger (median age 35 vs. 45 years, P < 0.001) and more often died from drug intoxication (33.2 vs. 5.6%, P < 0.001). Hemodilution was found in 6.8% of all IRD and was the only factor for IRD designation in 60% of pediatric donors <12 years old. The random sample of IRD (N = 288) was similar to IRD population for age, gender, ethnicity, cause of death, and region of recovery (table). Descriptive analysis of the random sample showed that intravenous drug use was the most common behavioral risk factor (N = 124, 43.1%), followed by incarceration (N = 108, 37.5%). Most DD met only 1 criterion (N = 179, 62%); 21% met 2 criteria; and 17% had >3 criteria.

Conclusion

This study represents the most detailed description of PHS IRD factors since the adoption of the new guidelines in 2013. Understanding the prevalence of factors that lead to IRD designation will help inform future policy development, optimize safe DD use, and increase the number of transplants.

Disclosures

All Authors: No reported Disclosures.
842. Social Resistance Fuels Ebola Transmission in the Eastern Democratic Republic of Congo
Authors: Mian Qaasim , Masumbuko Claude Kasereka , Underschultz Jack , Hawkes Michael
Published: October 2019

Background

The second largest Ebola epidemic in history is currently raging in Eastern Democratic Republic of Congo (DRC). Stubbornly persistent Ebola transmission has been associated with social resistance, ranging from passive noncompliance to overt acts of aggression toward Ebola response teams.

Methods

We explored community resistance using focus group discussions and assessed the prevalence of resistant views using standardized questionnaires.

Results

Despite being generally cooperative and appreciative of the foreign-led Ebola response, focus group participants provided eyewitness accounts of aggressive resistance to control efforts, consistent with recent media reports. Mistrust of Ebola response teams was fueled by perceived inadequacies of the response effort (“herd medicine”), suspicion of mercenary motives, and violation of cultural burial mores (“makeshift plastic morgue”). Survey questionnaires found that the majority of respondents had compliant attitudes with respect to Ebola control. Nonetheless, 78/630 (12%) respondents believed that Ebola was fabricated and did not exist in the area, 482/630 (72%) were dissatisfied with or mistrustful of the Ebola response, 60/630 (9%) sympathized with perpetrators of overt hostility, and 102/630 (15%) expressed noncompliant intentions in the case of Ebola illness or death in a family member, including hiding from the health authorities, touching the body, or refusing an official burial team. Denial of the biomedical discourse and dissatisfaction/mistrust of the Ebola response were statistically significantly associated with indicators of social resistance.

Conclusion

We concluded that social resistance to Ebola control efforts was prevalent among focus group and survey participants. Mistrust, with deep political and historical roots in this area besieged by chronic violence and neglected by the outside world, may fuel social resistance. Resistant attitudes may be refractory to short-lived community engagement efforts targeting the epidemic but not the broader humanitarian crisis in Eastern DRC.

Disclosures

All Authors: No reported Disclosures.
855. Evolution of Group B Streptococcal Capsular Type V Invasive Infections in Neonates and Young Infants: A Whole Genome Sequencing Study
Authors: Flores Anthony R , Sanson Misu A , Shah Brittany J , Rench Marcia , Shelburne Samuel A , Shelburne Samuel A , Baker Carol J
Published: October 2019

Background

Since 1970 group B Streptococcus (GBS) has been a frequent cause of sepsis or meningitis in young infants. Capsular polysaccharide type V was first recognized in 1990 and has increased to the point where it now causes ~15% of GBS infections. GBS type V strains are almost entirely sequence type 1 (ST1) in adult infections. To understand the emergence of type V GBS, we compared infant strains before 1990 to more contemporary isolates from young infants and adults.

Methods

Thirty-five strains isolated from blood or CSF of infants <90 days of age (Houston, 1979–1996) were compared with the following previously sequenced type V, ST1 strains: (1) 14 from infant blood or CSF from Center for Disease Control and Prevention (CDC) (2015–2017), (2) 193 blood ST1 isolates from adults (Houston, 1992–2013), and (3) 516 invasive isolates from the CDC (2015–2017). Isolates were sequenced using an Illumina MiSeq instrument followed by molecular typing, antimicrobial resistance gene determination, and phylogenetic analysis. Antimicrobial susceptibility testing (AST) was performed using disk diffusion and E-test.

Results

The majority (29/35) of Houston young infant strains were ST1. Type V GBS strains isolated prior to 1990 were more likely to be of ST-2 or ST-26 (5/10) compared with those from 1990 or later (24/25 and 14/14 CDC infant invasive type V). Tetracycline resistance was identified in 83% (29/35) while macrolide resistance (MR) occurred in only 23% (8/35) of the strains. Compared with early neonatal isolates, MR was significantly more frequent among contemporary neonatal (12/14, 86%, P < 0.0001) and adult (502/710, 71%, P < 0.0001) ST1 GBS. Phylogenetic analysis showed two distinct clades defined, in part, by MR. A high-frequency MR (340/360, 94%) clade was defined by the presence of erm(B) on Tn3872 while the low-frequency MR clade (159/350, 45%) was more diverse in mobile elements contributing to MR. The majority (27/29) of early neonatal ST1 GBS strains were observed in the low-frequency MR clade.

Conclusion

Infant invasive disease due to type V GBS before 1990 consisted of more diverse STs but is now almost exclusively ST1. Differences in the frequency of MR between early neonatal and contemporary type V ST1 GBS suggest MR may, at least in part, have driven the expansion of type V ST1 GBS.

Disclosures

All Authors: No reported Disclosures.
883. Evidence from a Multistate Cohort: Enrollment in Affordable Care Act Qualified Health Plans Results in Viral Suppression
Authors: McManus Kathleen A , Christensen Bianca B , Nagraj V P , Rogawski McQuade Elizabeth T , Furl Renae , Yerkes Lauren , Swindells Susan , Weissman Sharon , Rhodes Anne , Targonski Paul V , Dillingham Rebecca
Published: October 2019

Background

In individual states, the Patient Protection and Affordable Care Act has been associated with improved viral suppression (VS) rates for AIDS Drug Assistance Program (ADAP) clients or low-income people living with HIV (PLWH). This study aims to assess whether this association is consistent in multiple states (Nebraska, South Carolina, Virginia).

Methods

The multistate cohort included ADAP clients who were eligible for ADAP-funded Qualified Health Plans (QHPs). Data were collected from 2014 through 2015. A log-binomial model was used to estimate the association of demographics (age, race/ethnicity, sex, AIDS, rurality, HIV risk factor, previous VS) and healthcare delivery factors (income, previous ADAP plan, previous HIV care engagement) with QHP enrollment prevalence and 1-year risk of VS.

Results

For the cohort (n = 7,800; 5% NE, 36% SC, 59% VA), 52% enrolled in ADAP-funded QHPs with enrollment ranging from 35% to 63% by state. Enrollment in ADAP-funded QHPs in 2015 was higher for those who had ADAP-funded QHPs in 2014 (adjusted prevalence ratio [aPR] 3.28; 95% confidence interval [CI] 3.21–3.35) and those who were engaged in care in 2014 (aPR 1.16; 95% CI 1.05–1.27), and it was lower for those with a rural residence (aPR 0.91; 95% CI 0.81–1.00). Of those who were consistently engaged in care (n = 4,597), as defined by one viral load in 2014 and one viral load in 2015 separated by at least 180 days, those who received medications from Direct ADAP had a VS rate of 80.2% and those with ADAP-funded QHPs had a VS rate of 86.0%. The number needed to enroll in ADAP-funded QHPs for an additional PLWH to achieve VS is 18. Those who achieved VS in 2014 (adjusted risk ratio [aRR] 1.39, 95% CI 1.30–1.48) and those who enrolled in QHPs in 2015 (aRR 1.06, 95% CI 0.99–1.13) were more likely to achieve/maintain VS.

Conclusion

Additional efforts should be made to reach rural PLWH for QHP enrollment. State ADAPs, especially those in the South and those in states without Medicaid expansion, should consider investing in purchasing QHPs for PLWH because increased enrollment could improve VS rates. This evidence-based intervention could be a part of “Ending the HIV Epidemic.” Once ADAP clients are enrolled in ADAP-funded QHPs, they stay enrolled, and QHP enrollment is associated with VS across states and demographic groups.

Disclosures

All Authors: No reported Disclosures.
884. Patient Adherence to Long-Acting Injectable Cabotegravir + Rilpivirine Through 48 Weeks of Maintenance Therapy in the Phase 3 ATLAS and FLAIR Studies
Authors: Teichner Paula , Cutrell Amy , D’Amico Ronald , Dorey David , Griffith Sandy , Harrington Conn M , Huang Jenny , Hudson Krischan J , Margolis David , Mrus Joseph , Polli Joseph , Spreen William , Williams Peter , Van Solingen-Ristea Rodica , Shaefer Mark S
Published: October 2019

Background

Cabotegravir (CAB) and rilpivirine (RPV) are under development as a novel long-acting (LA) regimen for maintenance of HIV virologic suppression. Pooled Week 48 data from pivotal Phase 3 trials demonstrated noninferiority of CAB LA + RPV LA vs. current antiretroviral regimen (CAR) on the primary endpoint, proportion of subjects with HIV-1 RNA ≥50 c/mL (1.9% and 1.7%, respectively). Adherence to dosing visits, use of oral dosing (bridging) to cover planned missed injections and injection tolerability were examined for subjects in the ATLAS and FLAIR studies.

Methods

Virologically suppressed subjects (HIV-1 RNA < 50 c/mL) were randomized to switch to CAB LA + RPV LA or to continue CAR. On-time injections occurred Q4 weeks within a +7-day dosing window of the projected dosing date. Adherence to LA therapy was calculated as the number of on-time injection visits divided by the number of expected dosing visits through Week 48. Injection visits outside the pre-specified window and missed injection visits with/without the use of oral dosing were quantified. Injection tolerability was assessed via adverse event reporting.

Results

A total of 14,682 injections of CAB and RPV were administered to 581 subjects during 6,920 injection visits. 98% of injection visits took place within the allowed ±7-day dosing window with 3,194 (46%) on the projected dosing date. Forty-six (<1%) injection visits were early and 106 (2%) were late. Oral bridging was used in 16 subjects overall; 8 planned missed injection visits were successfully covered, with no change to virologic suppression status. No subject with HIV-1 RNA ≥ 50 c/mL at Week 48 had missed/late injection visits. 25% (3,663/14,682) of injections were associated with local injection site reactions (ISRs). The most common ISR was pain (3,087/3,663 = 84%). Most ISRs were grade 1–2 (99%), short duration (median 3 days), with few associated discontinuations (<1%).

Conclusion

Subjects receiving CAB LA + RPV LA demonstrated high rates of adherence to injection visits through week 48, with 98% of injections occurring within the ±7-day dosing window. Oral bridging with CAB and RPV was an effective strategy for maintaining viral load suppression to cover missed injection visits. Injections were well-tolerated with few associated discontinuations.

Disclosures

All Authors: No reported Disclosures.
886. Pregnancy Outcomes Following Raltegravir Exposure
Authors: Shamsuddin Hala , Raudenbush Casey , Sciba Brittany , Gooch Erica N , Greaves Wayne , Leong Ronald W , Straus Walter
Published: October 2019

Background

Safety data are needed regarding HIV treatment in women of reproductive potential and during pregnancy. This review is to evaluate pregnancy outcomes following prospective exposures (exposure report prior to knowledge of pregnancy outcome) to raltegravir during pregnancy.

Methods

Exposures to raltegravir during pregnancy reported cumulatively through March 26, 2019 to the internal safety database at Merck & Co., Inc. were reviewed. This database includes all reports of pregnancy from clinical trials sponsored by the company, spontaneous post-marketing reports, and noninterventional data sources. Prospective pregnancy reports were evaluated to determine rates of spontaneous abortion, stillbirth, and congenital anomalies, including neural tube defects. Data from two ongoing cohorts of pregnant women with HIV-1 infection, not included in the internal safety database, were also reviewed.

Results

A total of 2,508 prospective pregnancy reports with reported outcomes were identified among women exposed to raltegravir: 919 from the internal safety database (Table 1) and 1,589 from the UK/Ireland and French pregnancy cohorts. Among the 2,508 prospective pregnancy exposures, 945 were in the first trimester, of which 757 were within the periconception period (within 28 days of conception). Of the 471 documented first trimester exposures identified in the internal safety database, the rates of spontaneous abortion (6.9%), stillbirth (1%), and congenital anomalies (1.5% per live births) were similar to the rates observed in the background populations of the United States Among outcomes following any exposure, the rate of congenital anomalies was 3.4% per live births. There were no reports of neural tube defects identified within the internal safety database or among the cohort data.

Conclusion

Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure and spontaneous abortion, stillbirth, or congenital anomalies, including neural tube defects. These data support the current HIV treatment recommendations for the use of raltegravir 400 mg twice daily in women of reproductive potential and during pregnancy.

Disclosures

All Authors: No reported Disclosures.
901. MEDI8897 Prevents Serious RSV Disease in Healthy Preterm Infants
Authors: Pamela Griffin Mary , Yuan Yuan , Takas Therese , DeVincenzo John , Domachowske Joseph B , Simoes Eric A , Khan Anis , Esser Mark T , Dubovsky Filip , Villafana Tonya L
Published: October 2019

Background

RSV is the principal cause of lower respiratory tract infection (LRTI) among infants, and a significant unmet need exists for RSV prevention in healthy infants. We have developed a highly potent, extended half-life monoclonal antibody (mAb), to protect infants for an entire RSV season using a single IM dose. Here we report the efficacy, safety, pharmacokinetics, and anti-drug antibody (ADA) responses for MEDI8897 in palivizumab-ineligible preterm infants born between 29 and 35 weeks gestation.

Methods

A total of 1,453 Infants were randomized 2:1 to receive a single 50 mg IM injection of MEDI8897 (n = 969) or placebo (n = 484) and followed for 360 days. Enrollment occurred just prior to the 2016 and 2017 RSV seasons in 23 northern and southern hemisphere countries. Blood was collected periodically. Infants with a medically attended (MA) LRTI (outpatient or inpatient) had nasal swabs obtained for central RSV testing by RT-PCR. Predefined clinical criteria were used for the case definition.

Results

A total of 1,417 (97.5%) subjects completed the 150-day efficacy follow-up period and 1,367 (94.1%) completed the study. In the MEDI8897 group, a 70.1% (95% CI: 52.3%, 81.2%; P < 0.0001) reduction in the incidence of medically attended RSV LRTI and a 78.4% (95% CI: 51.9%, 90.3%; P = 0.0002) reduction in the incidence of RSV LRTI hospitalization was achieved. These efficacy results were consistent when analyzed by hemisphere, RSV subtype, and subject demographics. Similar proportions of adverse events (86.8% placebo; 86.2% MEDI8897) and serious adverse events (16.9% placebo; 11.2% MEDI8897) were reported in study subjects. There were no significant hypersensitivity reactions with similar proportions reported for both groups (0.6% placebo; 0.5% MEDI8897). The incidence of ADA detected any time post baseline was low (3.8% placebo; 5.6% MEDI8897) with no impact on PK or safety. The occurrence of non-RSV LRTIs was similar for both groups indicating no replacement by other pathogens.

Conclusion

In this large randomized study of RSV prophylaxis in healthy preterm infants, MEDI8897 immunoprophylaxis provided a significant reduction in RSV MA-LRTI and hospitalization. These results have promising implications for the future of RSV prophylaxis for all infants.

This study was funded by AstraZeneca and sanofi pasteur.

Disclosures

All Authors: No reported Disclosures.
975. Roles of Type I and III Interferon in Severe Pathogenesis of Human Metapneumovirus
Authors: Williams John V , Zhang Yu , Xu Jiuyang , Miranda-Katz Margot , Rich Helen , Manni Michelle , Tollefson Sharon , Sarkar Saumendra , Alcorn John
Published: October 2019

Background

Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in children and adults. However, mechanisms of pathogenesis are not fully understood.

Methods

We tested HMPV clinical and laboratory isolates in an established C57BL/6 mouse model and measured weight loss, airway function, and viral titers. Immune responses were determined using cytokine quantitation and flow cytometry.

Results

HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Laboratory strain TN/94-49 did not cause weight loss, but mice infected with clinical isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection (Figure 1). These findings were confirmed in other inbred mouse strains. C2-202-infected mice also suffered from impaired pulmonary function post-recovery. Lung viral titer did not correlate with disease severity, suggesting immune-mediated pathogenesis. C2-202-infected mice exhibited increased production of type I and III interferons (IFN) and pro-inflammatory cytokines, and lung neutrophil infiltration. However, neutrophil depletion or inflammasome inactivation did not reduce disease. Stat1/Stat2 double knockout (KO) mice lacking type I and III IFN signaling exhibited reduced weight loss but increased lung viral titer after C2-202 infection (Figure 2). Type I IFN receptor (IFNAR) KO mice infected with C2-202 had reduced weight loss but unchanged lung viral titer (Figure 3), while the addition of type III IFN blockade to C2-202-infected IFNAR mice had no effect on disease but increased lung viral titer (Figure 4).

Conclusion

These results suggest that severe disease caused by virulent HMPV was due to exuberant IFN response. Moreover, type I IFN was primarily associated with disease, while type III IFN was associated with viral clearance. These data suggest that IFN signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target.

Disclosures

All Authors: No reported Disclosures.
1836. Genomic Epidemiology of Methicillin-Susceptible Staphylococcus aureus Colonization and Infection among US Army Trainees at Fort Benning, Georgia
Authors: Millar Eugene V , McGann Patrick , Ellis Michael , Tribble David , Jones Anthony , Bennett Jason
Published: October 2019

Background

Methicillin-susceptible Staphylococcus aureus (MSSA) is a common cause of skin and soft-tissue infection (SSTI). MSSA genomic epidemiology data are limited. We used whole-genome sequencing (WGS) to examine MSSA strain diversity among military trainees, a group known to be at high risk for S. aureus infection and carriage.

Methods

From July 2012 to December 2014, we conducted a prospective SSTI case–control study among US Army trainees at Fort Benning, GA. Thereafter, we identified MSSA SSTI clusters within select military training classes and performed WGS on clinical and colonizing isolates. We analyzed epidemiologic, clinical, genomic, and phylogenetic data in order to evaluate MSSA strain diversity and patterns of disease transmission.

Results

A total of 67 SSTI cases from 15 training classes were identified. The median (range) number of cases per class was 4 (3–10). Cases presented for care after a median of 39 (6–101) days of training. Of the 67 cases, 42 (63%) were colonized with MSSA at ≥1 anatomic site. A total of 78 MSSA colonizing isolates were identified at the time trainees presented for clinical care; colonizing isolates were found in the nares (37%), throat (31%), inguinal region (21%), and perianal region (12%). Multilocus sequence typing (MLST) assigned 128 (88%) isolates to 20 known types and 17 isolates to novel types. Among clinical isolates, 60 (90%) were assigned to known types. Sequence Type (ST) 8 was the most frequent type, accounting for 45% and 35% of clinical and colonizing isolates, respectively. The phylogenetic tree of isolates revealed seven major clusters, some of which were composed of a diversity of training classes, specimen types, and STs. These major clusters were further segregated into 15 sub-clusters where there was considerable diversity in intrahost variation.

Conclusion

Genomic characterization of MSSA infection and colonization isolates among congregate military trainees revealed a broad diversity of strains. There was a clear clonal origin and dissemination of MSSA isolates among close contacts within the ST-8 cluster but this transmission pattern was less apparent for MSSAs from other STs.

Disclosures

All Authors: No reported Disclosures.
1878. Title: Impact of Antibiotic Stewardship Rounds in the Intensive Care Setting: A Prospective Cluster-Randomized Crossover Study
Authors: Seidelman Jessica , Turner Nicholas A , Wrenn Rebekah , Sarubbi Christina , Anderson Deverick J , Sexton Daniel J , Moehring Rebekah W
Published: October 2019

Background

The impact of formalized, interdisciplinary antimicrobial stewardship program (ASP) rounds in the intensive care unit (ICU) setting has not been well described.

Methods

We performed a two-arm, cluster-randomized, crossover quality improvement study over 8 months to compare the impact of weekly ICU rounds with an ASP team vs. usual care. The primary outcome was antibiotic use (AU) in days of therapy (DOT) per 1,000 days present during and following ICU exposure. Our cohort consisted of ICU patients in 5 ICUs in Duke University Hospital. The unit of randomization was rounding team, which corresponded to half of the ICU beds in each unit. Each team was randomized to the intervention for 4 months followed by usual care for 4 months (or vice versa). The intervention involved multidisciplinary review of eligible patients to discuss antibiotic optimization. Patients not on antibiotics, followed by infectious diseases, post-transplant, on ECMO, or with a ventricular assist device were excluded from review. Intervention impact was assessed with multivariable negative binomial regression rate ratios (RR). AU was assessed over time before and after the study period to assess global and unit-level trends.

Results

We had 4,683 ICU-exposed patients. Intervention effect was not significant for the primary outcome (table). The intervention order was not significant in the model. Eligible patients were lower in the cardiothoracic ICU (CTICU) compared with other units (table); the intervention led to a significant decrease in AU when the CTICU was removed (RR = 0.93 [0.89–0.98], P = 0.0025). Intervention impact was differential among ICUs, with the greatest effect in surgical and least in CTICU (table). nit-level AU decreased in all ICUs, driven by 4 of the 5 ICUs (table, figure).

Conclusion

The effect of ASP rounds on AU was mixed for different types of ICUs. The direct effect on AU (intervention vs. control) was small because the analysis addressed the whole ICU population and thus was subject to biases from exposures after an ICU stay, ineligible patients, and lack of blinding. However, we observed an overall decline in AU during the study period, which we believe represents indirect effects of increased ASP activity and awareness. Additional ASP resources to round more than weekly may result in greater effect.

Disclosures

All Authors: No reported Disclosures.
1888. A Nationwide Outbreak of Invasive Pneumococcal Disease (IPD) Caused by a Novel Streptococcus Pneumoniae Serotype 2 (SP2) Clone in the PCV13 Era, in Israel
Authors: Dagan Ron , Ben-Shimol Shalom , Benisty Rachel , Regev-Yochay Gili , Ron Merav , Givon-Lavi Noga , Rokney Assaf
Published: October 2019

Background

IPD caused by Sp2 (non-PCV13 serotype) is relatively rare. However, Sp2 has a high potential for causing IPD including meningitis. Large-scale outbreaks of Sp2 IPD are rare and were not reported post-PCV implementation. We describe Sp2 IPD outbreak in Israel, in the PCV13 era, caused by a novel clone. Additionally, we analyzed the population structure and evolutionary dynamics of Sp2 during 2006–2018.

Methods

An ongoing, population-based, nationwide active surveillance, conducted since July 2009. PCV7/PCV13 were implemented in Israel in July 2009 and November 2010, respectively. All isolates were tested for antimicrobial susceptibility, PFGE, MLST and whole-genome sequencing (WGS). Results. Overall, 173 Sp2 IPD cases were identified; all isolates were analyzed by MLST (Figure 1). During 2016–2017, Sp2 caused 7.6% of all-IPD, a 7-fold increase compared with 2006–2015, and ranked second (after serotype 12F causing 12%) among IPD isolates. During 2006–2015, 98% (40/41) Sp2 IPD were caused by the previously reported global ST-1504 clone. The outbreak was caused by a novel clone ST-13578, not previously reported (Figure 2). WGS analysis confirmed that ST-13578 was related, but genetically distinct from ST-1504, observed exclusively before the outbreak. A single strain of clone ST-74 previously globally reported was identified in 2017–2018. An additional case was identified in an adult in the UK, following a family visit from Israel. The ST-13578 clone was identified only in the Jewish population and was mainly distributed in 3 of the 7 Israeli districts. All tested strains were penicillin-susceptible (MIC < 0.06 μg/mL).

Conclusion

To the best of our knowledge, this is the first widespread Sp2 outbreak since PCV13 introduction worldwide, caused by a novel clone ST-13578. The outbreak is still ongoing, although a declining trend was noted since 2017.

Disclosures

All Authors: No reported Disclosures.
1956. Reduction in Endotracheal Aspirate Cultures after Implementation of a Diagnostic Stewardship Intervention in a Pediatric Intensive Care Unit
Authors: Sick-Samuels Anna , Bergmann Jules , Linz Matthew , Fackler James , Berenholtz Sean , Dwyer Joe , Hoops Katherine , Colantuoni Elizabeth , Milstone Aaron
Published: October 2019

Background

Clinicians obtain endotracheal aspirate (ETA) cultures from mechanically ventilated patients in the pediatric intensive care unit (PICU) for the evaluation of ventilator-associated infection (i.e., tracheitis or pneumonia). Positive cultures prompt clinicians to treat with antibiotics even though ETA cultures cannot distinguish bacterial colonization from infection. We undertook a quality improvement initiative to standardize the use of endotracheal cultures in the evaluation of ventilator-associated infections among hospitalized children.

Methods

A multidisciplinary team developed a clinical decision support algorithm to guide when to obtain ETA cultures from patients admitted to the PICU and ventilated for >1 day. We disseminated the algorithm to all bedside providers in the PICU in April 2018 and compared the rate of cultures one year before and after the intervention using Poisson regression and a quasi-experimental interrupted time-series models. Charge savings were estimated based on $220 average charge for one ETA culture.

Results

In the pre-intervention period, there was an average of 46 ETA cultures per month, a total of 557 cultures over 5,092 ventilator-days; after introduction of the algorithm, there were 19 cultures obtained per month, a total of 231 cultures over 3,554 ventilator-days (incident rate 10.9 vs. 6.5 per 100 ventilator-days, Figure 1). There was a 43% decrease in the monthly rate of cultures (IRR 0.57, 95% CI 0.50–0.67, P < 0.001). The ITSA revealed a pre-existing 2% decline in the monthly culture rate (IRR 0.98, 95% CI 0.97–1.00, P = 0.01), an immediate 44% drop (IRR 0.56, 95% CI 0.45–0.69, P = 0.02) and a stable rate in the post-intervention period (IRR 1.03, 95% CI 0.99–1.07, P = 0.09). The intervention led to an estimated $6000 in monthly charge savings.

Conclusion

Introduction of a clinical decision support algorithm to standardize the obtainment of ETA cultures from ventilated children was associated with a significant decline in the rate of ETA cultures. Additional investigation will assess the impact on balancing measures and secondary outcomes including mortality, duration of ventilation, duration of admission, readmissions, and antibiotic prescribing.

Disclosures

All Authors: No reported Disclosures.
1965. PrEP On the Go! Implementation Mobile PrEP, STI, and HIV Prevention Services in South Florida
Authors: Doblecki-Lewis Susanne , Kobetz Erin , Byrne2; Stefani Butts John , Torrealba Marco , Klose Katie , McGaugh Angela , Shatz Connor , Scaramutti Carolina , Baez Leon Brian , Narcisse Gilianne , Morel Jessica , Whiteside Patrick , Cardenas Gabriel , Feaster Daniel , Stevenson Mario
Published: October 2019

Background

Pre-Exposure Prophylaxis (PrEP) can reduce HIV incidence when implemented effectively for people who are at highest risk of HIV infection. However, access to and uptake of PrEP remains suboptimal among priority populations such as black and Hispanic/Latino men who have sex with men (MSM). We established mobile HIV prevention/PrEP services delivered with cancer screening services through the Sylvester Gamechanger vehicle. We describe demographics, utilization, and early retention in PrEP care delivered through this model.

Methods

We selected four local HIV high-incidence areas where PrEP services were lacking, to locate the clinic. The vehicle, staffed by a medical provider, HIV/PrEP counselor, and cancer educator, returned to each site regularly. In addition to self-referrals, Prevention305, a community-based organization, developed focused patient recruitment through social media. Services were provided at no cost. Normative demographics, risk behavior, sexually transmitted infections (STIs), and early-maintenance-in-care data were collected. Descriptive statistics were compiled using SPSS.

Results

From October 2018 to April 2019 services were provided to 229 clients. Of these, 168 (73.7%) sought PrEP. Of PrEP clients, 125 (74.4%) identified as White/Hispanic, 6 (3.5%) as Black/Hispanic, 6 (3.5%) as White/non-Hispanic, 11 (6.5%) as Black/non-Hispanic, and 19 (11.3%) as other; 124 (73.8%) were foreign-born; 159 (94.9%) of PrEP clients identified as MSM. Six (3.5%) PrEP-seeking clients were HIV positive at baseline. Of these, 2 were identified as acute/early infections. An initial PrEP prescription was filled by 166 (98.8%). Of the 77 clients seen within the initial 3 months of operation and due for follow-up assessment, 55 (71.4%) completed a follow-up visit. Overall, 45 (26.6%) PrEP clients had positive STI results (gonorrhea, chlamydia, or syphilis) at baseline. Nine (16.3%) clients returned positive STI results at their follow-up visit.

Conclusion

Implementation of mobile HIV prevention services including PrEP is feasible and is effective in engaging Hispanic/Latino immigrant MSM. High demand for services is noted and plans are underway to increase capacity and outreach to other highly affected groups.

Disclosures

All Authors: No reported Disclosures.
2840. Long-term Efficacy, Safety, and Durability of CAB and RPV as Two Drug Oral Maintenance Therapy: LATTE Week 312 Results
Authors: Margolis David , Sutton Kenneth , De Vente Jerome , LeBlanc Roger , DeJesus Edwin , Smith Graham , Mills Anthony , Baril Jean-Guy , St. Clair Marty , Stancil Britt , Williams Peter , Spreen William
Published: October 2019

Background

Cabotegravir (CAB), an INI, is under development in both oral and long-acting (LA) injectable formulations. LATTE (NCT01641809) was designed to select a daily oral dose of CAB and evaluate a two-drug ART regimen with rilpivirine (RPV), as suppressive maintenance therapy. Results enabled the LATTE-2 (NCT02120352) study to evaluate CAB LA + RPV LA dosed once every 1 or 2 months.

Methods

Phase 2b, multicentre, partially blinded dose-ranging study in ART-naïve HIV infected adults, randomized 1:1:1:1 to the induction regimen of once-daily oral CAB 10, 30, or 60 mg or efavirenz (EFV) 600 mg with TDF/FTC or ABC/3TC through W24. CAB patients with VL <50 c/mL immediately prior to W24 discontinued NRTIs and began RPV 25 mg as a two-drug oral maintenance regimen through W96. No change was made to the EFV arm. After W96, at the start of the open-label (OL) phase, all patients randomized to CAB were given the option to continue and switch to the sponsor-selected dose of oral CAB 30 mg. EFV patients completed the study at W96. The OL phase was completed at W312 (288 weeks on CAB + RPV). Successful CAB + RPV patients transitioned to the POLAR study (NCT03639311).

Results

A total of 243 patients were randomized and initiated treatment (ITT-E). Of those randomized to CAB (n = 181), 160 patients began CAB + RPV (W24) and 138 continued into OL phase (W96). One hundred and ten patients successfully completed the study (W312). Among patients who began CAB + RPV at W24, 66% maintained <50 c/mL, 9% had HIV-1 RNA ≥ 50 c/mL, and 25% were categorized as “No Virologic Data” by Snapshot at W312 (ITT-ME). There were 11 protocol-defined virologic failures (PDVF) on CAB; only 2 occurring after W144. Six patients developed treatment emergent (TE) resistance to one or both agents during the study; of which 4 patients developed TE major INI resistance mutations, 3 after W96. The median increase in CD4+ cell count from Baseline was 393 cells/mm3 (−174 to 1118). During the maintenance and OL phases, 4% of CAB patients reported drug-related AEs ≥ Grade 2; SAEs occurred in 9% of CAB patients (none drug related); 3% of CAB patients withdrew due to AEs. 43% of CAB patients who entered maintenance phase reported TE lab abnormalities ≥ Grade 3.

Conclusion

As maintenance therapy in virologically suppressed patients, the 2DR CAB + RPV provided durable viral suppression through W312. Through 7 years of study, CAB + RPV continues to be generally safe and well tolerated.

Disclosures

All Authors: No reported Disclosures.