bluuebunny/crossref_metadata_2025_split huggingface dataset:
962. Trends in Cervical Pre-cancers by Race and Ethnicity During the Human Papillomavirus Vaccine Era, HPV Vaccine Impact Monitoring Project (HPV-IMPACT), United States, 2008–2016
Authors: Gargano Julia , Lewis Rayleen , Hunt Hillary , McClung Nancy , Bennett Nancy M , Griffin Marie , Niccolai Linda , Park Ina , Powell Melissa , Brackney Monica , Scahill Mary , Pemmaraju Manideepthi , Fink Deanna , Ehlers Sara , Cleveland Angela , Unger Elizabeth R , Markowitz Lauri 
Published: October 2019

Abstract

Background
Since human papillomavirus (HPV) vaccine introduction in the United States in 2006, cervical pre-cancer incidence has declined in young women, but pre-cancer trends have not been reported by race/ethnicity. We evaluated trends in cervical pre-cancers from 2008 to 2016 in non-Hispanic (NH) white, NH black, NH Asian, and Hispanic women identified through active population-based surveillance in the 5-site Human Papillomavirus Vaccine Impact Monitoring Project (HPV-IMPACT).

Methods
We analyzed data on cervical intraepithelial neoplasia (CIN) grades 2–3 and adenocarcinoma in situ (CIN2+) cases aged 20–39 years. Annual CIN2+ rates per 100,000 women were calculated stratified by race/ethnicity in 5-year age groups, using multiple imputation to account for 10% missing race/ethnicity data. Rates were also calculated using estimated numbers screened for cervical cancer to control for known declines in screening. Trends, evaluated using JoinPoint software, are presented as average annual percentage changes (AAPC) with 95% confidence intervals (CI).

Results
A total of 18,222 CIN2+ cases (62% NH white, 16% NH black, 16% Hispanic, 6% Asian) were reported from 2008 to 2016. CIN2+ rates among 20–24 year-olds declined significantly in all groups: NH white, AAPC: −14.2 (95% CI: −16.3, −12.1); NH black, AAPC: −15.5 (−19.5, −11.4); Asian, AAPC: −14.8 (−20.5, −8.8); Hispanic, AAPC: −14.3 (−17.9, −10.5). In 25–29 year olds, a significant decline was observed for NH whites only (AAPC: −2.4, [−4.0, −0.8]). No declines were seen in 30–34 or 35–39 year olds. Among screened 20–24 year-olds, significant but smaller declines were observed (AAPC: −9.8 to −8.4); no declines were observed in screened 25–29 year olds or older groups.

Conclusion
In this evaluation of CIN2+ trends by race/ethnicity during the HPV vaccine era, the significant declines in 20–24 year olds across all groups, including among screened women, is consistent with equitable vaccine impact on CIN2+.

Disclosures
All Authors: No reported Disclosures.
971. The Role of Inflammation and Innate Effectors in Passive Immunization for Acinetobacter baumannii Infections
Authors: Nielsen Travis B , Yan Jun , Luna Brian M , Talyansky Yuli , Bonomo Robert A , Spellberg Brad 
Published: October 2019

Abstract

Background
We have previously demonstrated that A. baumannii virulence is driven by avoidance of innate effector clearance, resulting in LPS-TLR4 triggering of excess inflammation in the host. We also raised a monoclonal antibody (MAb) that improved survival of mice lethally infected with A. baumannii.

Methods
Mice were selectively depleted of innate effectors (macrophages with liposomal clodronate, neutrophils with cyclophosphamide, and/or complement with cobra venom factor), infected with an XDR clinical blood isolate of A. baumannii, and treated with placebo or anti-A. baumannii MAb.

Results
Single disruption of macrophages or neutrophils did not enhance lethality but complement deficiency did. In contrast, singly disrupting complement or neutrophils did not impact bacterial density but macrophage disruption markedly increased it. Thus, a dissociation of bacterial density and survival was observed. MAb therapy was completely protective in mice depleted of a single effector. While dual depletion resulted in diminished MAb efficacy in terms of survival, mice retaining neutrophils had marked improvements in survival with MAb therapy compared with other dual-depletion groups. The dissociation of bacterial density and survival suggested that inflammation was a primary driver of host outcome. Levels of IL-10 and TNFα had a reciprocal relationship in mice across effector depletion groups and were lower in mouse groups with higher survival when adjusted for bacterial density. IL-10 disruption completely abrogated the survival benefit of MAb therapy without altering bacterial clearance mediated by MAb. In contrast, TNFα disruption enhanced MAb efficacy for survival, and the presence of TNFα was antagonistic to MAb efficacy.

Conclusion
These results confirm that host outcomes from A. baumannii infection are driven by host inflammatory response rather than bacterial density alone. Furthermore, novel therapeutic approaches seeking to improve outcomes from such infections must seek to shift the balance of pro-/anti-inflammatory cytokines to favor a down-modulated inflammatory response.

Disclosures
All Authors: No reported Disclosures.
972. A Mycobacterium tuberculosis Secreted Lipid Triggers Cough Through a Neuronal Cough Receptor
Authors: Cruz Paxton , Ruhl Cody , Shiloh Michael 
Published: October 2019

Abstract

Background
A hallmark symptom of active pulmonary tuberculosis vital for disease transmission is cough. The current paradigm for tuberculosis-related cough is that it results from airway damage or irritation. However, there is limited experimental data to support this theory, and whether Mycobacterium tuberculosis (Mtb) induces cough to facilitate its own transmission has not been explored. The cough reflex is a complex and coordinated event involving both the nervous and musculoskeletal systems initiated by particulate or chemical molecules activating nociceptive neurons, which sense pain or irritation. This activation induces a signaling cascade ultimately resulting in a cough. Respiratory nociceptive neurons innervate the airway of humans and most mammals and thus are poised to respond to noxious molecules to help protect the lung from damage. Because Mtb is a lung pathogen, cough is a primary mechanism of Mtb transmission, and respiratory nociceptive neurons activate cough, we hypothesized that Mtb produces molecules that stimulate cough thereby facilitating its spread from infected to uninfected individuals. We previously identified a cough molecule produced by Mtb, and in this work characterize its neuronal receptor using genetics, biochemistry, and pharmacology.

Methods
We used an in vitro neuronal activation bioassay to study Mtb cough-inducing molecules. We also used a biochemical assay to identify the cough receptor. Finally, we used gene silencing, biochemistry, and pharmacologic inhibition to validate and characterize the activity of the newly discovered cough receptor.

Results
We isolated a complex lipid produced by Mtb that activates nociceptive neurons. Both an organic Mtb extract and the purified molecule alone were sufficient to induce cough in a conscious guinea pig cough model and guinea pigs infected with wild-type Mtb cough much more frequently than guinea pigs infected with Mtb strains unable to produce nociceptive molecules. Using genetics, biochemistry, and pharmacology techniques, we identified and validated a cough receptor for the Mtb lipid expressed on nociceptive neurons.

Conclusion
We conclude that Mtb produces a molecule that activates nociceptive neurons and induces cough through a specific neuronal receptor. These findings have significant implications for our understanding of Mtb transmission.

Disclosures
All Authors: No reported Disclosures.
1828. Bedaquiline Resistance in Mycobacterium intracellulare Is Mediated by the Transcriptional Repressor MmpT5
Authors: Alexander David , Yoneda Joshua , Bhat Supriya , Oleksyn Teagan , Chen Jeffrey , Andrew Cameron 
Published: October 2019

Abstract

Background
Bedaquiline (BDQ) is an FDA approved antibiotic with antimycobacterial activity. BDQ resistance has been observed in several Mycobacterium species. High-level resistance is due to mutations in ATP synthase. Low -level resistance is attributed to drug efflux. Previously, we suggested that the MmpSL5 efflux system mediates BDQ resistance in M. intracellulare. Here, we examine the role of MmpT5 in transcriptional regulation of mmpSL5 and BDQ resistance.

Methods
In this study, mmpSL5-mmpT5 genes were cloned from 2 pre-treatment (wild-type mmpT5) and 2 relapse (mutant mmpT5) isolates of M. intracellulare and transformed into M. smegmatis. BDQ MICs were determined as well as cell survival after 24 hours exposure to an inhibitory concentration (0.07 µg/mL) of BDQ. Transcription of the M. intracellulare mmpT5 and mmpSL5 promoters was monitored with luciferase reporter gene fusions in the presence of wild-type and mutant alleles of mmpT5. Single and multigene constructs were created using the MoClo system, and transformed into E. coli DH5α. Constructs containing the M. tuberculosis rv0678 gene, which mediates low-level BDQ resistance in M. tuberculosis, were also examined.

Results
The BDQ MIC for the M. smegmatis control strain, and all strains containing mmpSL5-mmpT5 constructs, was 0.007 µg/mL. Even so, strains containing mutant mmpT5 alleles showed enhanced survival after 24 hours exposure to 0.007 µg/mL BDQ. Bacterial colonies associated with mutant mmpT5 alleles exhibited altered morphology relative to wild-type strains. Transcription of mmpSL5 was repressed by wild-type mmpT5, but neither mutant mmpT5 nor rv0678 repressed transcription. The mmpT5 luciferase reporter was not active.

Conclusion
MmpT5 represses transcription of mmpSL5 whereas the operon is dysregulated by mmpT5 mutations. Although Rv0678 regulates mmpSL expression in M. tuberculosis, it cannot repress the M. intracellulare mmpSL5 genes. The mmpSL5-mmpT5 genes have no impact on the BDQ MIC for M. smegmatis, but constructs containing mutant mmpT5 alleles do enhance bacterial survival. The altered morphology of these colonies suggests that BDQ resistance is mediated by cell wall changes in combination with drug efflux.

Disclosures
All Authors: No reported Disclosures.
1879. A 20/20 Vision: Successful Integration of a Prescribing Dashboard for Outpatient Antimicrobial Stewardship to Target 20% Reduction by the Year 2020
Authors: Gentry Erin , Kowalkowski Marc , Burns Ryan , Sweeney Chloe , Collins Cliff , Ann Medaris Leigh , Spencer Melanie , Handy Elizabeth , Davidson Lisa 
Published: October 2019

Abstract

Background
At least 30% of antibiotics prescribed in the ambulatory setting are unnecessary, including high rates of overuse for acute respiratory infections (ARI). We designed and evaluated whether a multifaceted outpatient stewardship program leveraging multidisciplinary stakeholder engagement, education tools, and an innovative prescribing dashboard decreased antibiotic prescribing in ARI.

Methods
In November 2017, the Carolinas HealthCare Outpatient Antimicrobial Stewardship Empowerment Network (CHOSEN) launched an antibiotic awareness campaign in over 150 ambulatory practices in the Charlotte metropolitan area, reaching over one million patients. The campaign included online and in-person tools for patients and providers, targeted education at meetings, and social and mass media exposure. In March 2018, a provider level prescribing dashboard was introduced to target inappropriate antibiotic prescribing in ARI (acute sinusitis, nonsuppurative otitis media, nonbacterial pharyngitis, URI, cough, allergy, and influenza). Data were collected for family medicine (FM), internal medicine (IM), urgent care (UC) and pediatric medicine (PM); 10% and 20% relative reduction targets (years 2019 and 2020, respectively) were set for each service line. We compared pre (April 2016–March 2018) vs. post (April 2018–March 2019) intervention prescribing rates (calculated as the number of encounters with antibiotics vs. total) as rate ratios and used segmented regression models to assess change over time.

Results
There were 1,001,335 pre and 448,390 post-intervention encounters. Postintervention prescribing rates (antibiotics per 100 encounters) decreased for all service lines, FM (49.4 to 39.3), IM (49.7 to 41.2), UC (49.8 to 44.4), and PM (40.6 to 36.1) vs. pre-intervention (all rate ratios, P ≤ 0.01). All service lines met the target 2019 10% reduction goals. Post-implementation, FM and IM showed immediate decreases in prescribing (figure). After an initial increase, UC showed a significant month-to-month decrease (figure).

Conclusion
Integration of a prescribing dashboard within a multifaceted antibiotic awareness campaign reduced inappropriate outpatient antibiotic prescribing for ARI and achieved interim targets consistent with 2020 reduction goals.

Disclosures
All Authors: No reported Disclosures.
1882. Tuberculosis in the Department of Veterans Affairs: Missed Opportunities for Prevention
Authors: Oda Gina , Lucero-Obusan Cynthia , Schirmer Patricia , Holodniy Mark 
Published: October 2019

Abstract

Background
US and global elimination of tuberculosis (TB) is an important goal. Despite decreased incidence, CDC predicts elimination of TB in the US will not occur in the 21st century without improved detection and treatment of latent TB infection (LTBI). We describe the current burden of active TB infection and LTBI testing and treatment among patients within the Department of Veterans Affairs (VA).

Methods
Using the 2009 CDC case definition for laboratory-confirmed TB, we queried VA data sources from January 2010 to December 2018 for Mycobacterium tuberculosis detected via culture or nucleic acid amplification test (NAAT) from specimens from all body sites. For all TB patients, we extracted demographic, ICD-9 and ICD-10 risk factor, and LTBI testing and treatment data.

Results
Between 2010 and 2018, the average annual incidence of TB was 1.7 cases per 100,000 unique users of VA care (ranging from a high of 2.8 in 2010 to low of 0.8 in 2018). For 899 identified cases, demographic factors associated with highest TB rates were age between 45 and 64, Asian race, and residence in District of Columbia (Table 1). The most frequently occurring risk factors were substance abuse, diabetes, and homelessness. Of 90 patients with susceptibility documentation, 14 (15%) had resistance to 1 or more anti-TB drug (1 with multi-drug-resistant TB). Fifteen patients (1.7%) died within 7 days of their TB diagnosis; in all but 2 cases, TB was the primary cause of death (Table 2). Figure 1 depicts screening and treatment for LTBI among patients with TB. Only 228/899 (25.4%) TB patients had LTBI screening ≥ 3 months prior to diagnosis. Of the 347 TB patients never screened for LTBI, 264 (76%) had ≥ 1 documented TB risk factor. Among 228 patients screened for LTBI >3 months prior to active disease, 69 (30%) screened positive; however, only 24 (35%) had LTBI treatment initiated.

Conclusion
Although rates of TB infection are decreasing, VHA providers would benefit from education on recognizing patients with risk factors which place them at high risk for TB who should be screened for LTBI. CDC recommends preventive treatment of patients who screen positive for LTBI, and provider collaboration with local public health departments to provide directly observed therapy in cases where adherence may be in question.

Disclosures
All Authors: No reported Disclosures.
1887. Estimating the Burden of Waterborne Disease in the United States
Authors: Collier Sarah , Benedict Katharine , Fullerton Kathleen , Deng Li , Cope Jennifer R , Yoder Jonathan , Hill Vincent 
Published: October 2019

Abstract

Background
Treatment of drinking water is one of the greatest US public health achievements of the twentieth century and provides a safe, reliable water supply. However, waterborne disease and outbreaks continue to occur, and are associated with a variety of water sources and exposure routes. New estimates of the burden of waterborne disease in the United States will direct prevention activities and set public health goals.

Methods
We chose 17 waterborne diseases for which domestic waterborne transmission was plausible, substantial burden of illness or death was likely, and data were available. Diseases included were campylobacteriosis, cryptosporidiosis, giardiasis, Legionnaires’ disease, norovirus infection, nontuberculous mycobacteria [NTM] infection, otitis externa, Pseudomonas pneumonia and septicemia, salmonellosis, Shiga toxin-producing E. coli infection, shigellosis, and vibriosis. Adapting previously used methods, disease-specific multipliers were used to adjust the reported/documented number of cases of each disease for under-reporting, under-diagnosis, proportion domestically acquired, and proportion transmitted via water, to generate point estimates with 95% credible intervals (CrI). Data sources included surveillance data, population studies, and expert judgment if no other data were available. We estimated the number of illnesses, ED visits, hospitalizations, and deaths, and costs of ED visits and hospitalizations due to waterborne disease in the United States in 2014.

Results
7.2 million waterborne illnesses (CrI 3.9–12.0 million) from the selected diseases occur annually, including 600,000 (CrI 365,000–865,000) ED visits, 120,000 (CrI 85,000–150,000) hospitalizations, and 6,500 deaths (CrI 4,300–8,900) deaths, incurring US$3.2 billion (2014 dollars) in direct healthcare costs. Hospitalizations and deaths were predominantly caused by environmental pathogens commonly associated with biofilm in plumbing systems (NTM, Pseudomonas, Legionella) costing US$2 billion annually.

Conclusion
Millions of domestically acquired waterborne illnesses from these 17 infections occur in the United States each year, and incur billions of dollars in healthcare costs.

Disclosures
All Authors: No reported Disclosures.
1949. Putting Out Fires: Assessing Burnout within an Infectious Diseases Fellowship at an Academic Medical Center
Authors: Alexander Leslie-Ann , Blair Barbra M , Stead Wendy 
Published: October 2019

Abstract

Background
Burnout, “a psychological syndrome of emotional exhaustion (EE), depersonalization (DP), and reduced personal accomplishment (PA),” is a well-described problem in the medical community. National surveys report 45% of practicing physicians and 60% of residents and fellows are burnt out. A longitudinal study of medical students and residents reported 45% burnout, as well as career choice regret in 14% of trainees. There are little data about burnout in Infectious Diseases (ID) physicians, including fellows. We sought to measure burnout prevalence in an academic ID Division, identify factors that modified the risk of burnout, and assess knowledge and attitudes about fellow and faculty burnout in the division.

Methods
The study population included 33 ID physicians (10 fellows, 23 faculties). Level of burnout was assessed via the Maslach Burnout Inventory (MBI), a validated 22-item tool. An additional survey was distributed as a needs assessment to determine participant understanding of “burnout” and “wellness,” ability to recognize burnout in colleagues, attitudes about the scope of the problem, and specific programmatic and personal factors felt to contribute to burnout.

Results
The MBI was completed by 10 fellows and 16 faculties (76%). A high score in ≥ 1 domain of burnout was reported in 50% of respondents, and 19% received a high score in both EE and DP. Fellows had moderate to high levels of EE (90%) and DP (70%), though all fellows reported at least a moderate sense of PA.
The survey needs assessment was completed by 9 fellows and 17 faculties (79%). In a hypothetical case, 100% and 58% of participants correctly identified elements of DP and EE, respectively. Respondents identified several factors contributing to burnout risk, most commonly being lack of schedule autonomy (100%), increasing patient load (96%), and inability to attend teaching conferences (88%). Fellows felt burnt out when seeing ≥ 4 new consults per day and/or carrying a census of 10–11 patients.

Conclusion
ID fellows at an academic medical center recognize burnout and report levels on par with national data. Fellows and faculty can identify personal and programmatic factors that increase and decrease their risk of burnout. These data can guide programmatic and divisional interventions to improve trainee wellness.

Disclosures
All Authors: No reported Disclosures.
1963. PrEP Significantly Reduces the Rate of New HIV Diagnoses in US Metropolitan Statistical Areas Independent of Treatment as Prevention (2012–2017)
Authors: Mera-Giler Robertino M , Das Moupali , Hawkins Trevor , Magnuson David , Asubonteng Julius , McCallister Scott 
Published: October 2019

Abstract

Background
Tenofovir/Emtricitabine (TVD) was approved for a Pre-exposure Prophylaxis (PrEP) indication in the United States in July 2012. Biomedical HIV prevention tools can impact the rate of new HIV diagnoses but their relative contributions have not been described.

Methods
The analysis utilized CDC published data on HIV diagnoses in 105 US metropolitan statistical areas (MSAs), a Treatment as Prevention (TasP) proxy of HIV suppressed individuals from 38 US states and DC, and a national pharmacy and medical claims databases to track TVD PrEP use from 2012 to 2017. The calculation of person time at risk excluded time of those taking PrEP as well as those who became HIV positive. TVD PrEP use was categorized in quintiles. A multilevel Poisson regression model which considers changes over time of each MSA was utilized. Rates and rate ratios plus corresponding 95% confidence intervals were obtained for quintiles of PrEP utilization after adjusting for the effect of treatment as prevention and calendar time.

Results
The US MSA rate of HIV diagnoses decreased significantly at a rate of 5.1% (95% CI −4.8 to −5.3%) per year in the period 2012–2017. PrEP use increased from an average of 1.64+1.3 per 100 subjects with a PrEP indication in 2012 to 15.4 + 3.2 in 2017. HIV viral suppression also increased by 1.3% per year (95% CI 1.1 to 1.6%) during the same period among HIV treated subjects. A multivariate model showed that PrEP use was significantly associated with the decline in the rate of new HIV cases, independent of a significant TasP effect. During the period of observation, the lowest quintile of PrEP utilization saw a decline of −0.23% (95% CI −0.2 to −0.43%), while the highest quintile of PrEP utilization showed a statistically significant decline of −4.24% (95% CI −0.39 to −8.01%) per year. Treatment as prevention had a significant and independent effect of- 1.56% (−1.1 to −2.1%) per each percent increase of the proportion of HIV subjects with suppression.

Conclusion
From 2012 to 2017, HIV diagnoses declined most steeply in MSAs where PrEP use was the highest. The effect of PrEP use was significantly associated with this decline and was independent of treatment as prevention.

Disclosures
All Authors: No reported Disclosures.