bluuebunny/crossref_metadata_2025_split huggingface dataset:
23. Regional Variation in Outpatient Antibiotic Prescribing in a Commercially-insured Population, United States, 2017
Authors: Bizune Destani J , Palms Danielle , King Laura M , Bartoces Monina , Link-Gelles Ruth , Hicks Lauri , Fleming-Dutra Katherine E 
Published: January 2021

Abstract

Background
Studies have shown that the Southern United States has higher rates of outpatient antibiotic prescribing compared to other regions in the country, but reasons for this variation are unclear. We aimed to determine whether the regional variability in outpatient antibiotic prescribing for respiratory diagnoses can be explained by differences in patient age, care setting, comorbidities, and diagnosis in a commercially-insured population.

Methods
We analyzed the 2017 IBM® MarketScan® Commercial Database of commercially-insured individuals aged &lt; 65 years. We included visits with acute respiratory tract infection (ARTI) diagnoses from retail clinics, urgent care centers, emergency departments, and physician offices. ARTI diagnoses were categorized as: Tier 1, antibiotics are almost always indicated (pneumonia); Tier 2, antibiotics are sometimes indicated (sinusitis, acute otitis media, pharyngitis); and Tier 3, antibiotics are not indicated (asthma, allergy, bronchitis, bronchiolitis, influenza, nonsuppurative otitis media, viral upper respiratory infections, viral pneumonia). We calculated risk ratios and 95% confidence intervals (CI) stratified by US Census region and ARTI tier using log-binomial models controlling for patient age, comorbidities (Elixhauser and Complex Chronic Conditions for Children), and setting of care, with Tier 3 visits in the West, the strata with the lowest antibiotic prescription rate, as the reference for all strata.

Results
A total of 100,104,860 visits were analyzed. In multivariable modeling, ARTI visits in the South and Midwest were highly associated with receiving an antibiotic for Tier 2 conditions vs. patients in other regions (Figure 1).
Figure 1. Multivariable model comparing risk of receiving an antibiotic for an ARTI by region and diagnostic tier in urgent care, retail health, emergency department, and office visits, MarketScan® 2017, United States

Conclusion
Regional variability in outpatient antibiotic prescribing for Tier 2 and 3 ARTIs remained even after controlling for patient age, comorbidities, and setting of care. It is likely that this variability is in part due to non-clinical factors such as regional differences in clinicians’ prescribing habits and patient expectations. Targeted and enhanced public health stewardship interventions are needed to address cultural factors that affect antibiotic prescribing in outpatient settings.

Disclosures
All Authors: No reported disclosures
27. The Membrane Antimicrobial Peptide Defense (MadRS) System Orchestrates Resistance Against Antibiotics and Host Innate Immune Peptides in enterococcus Faecalis
Authors: Miller William R , Khan Ayesha , Erickson Samuel G , Pettaway Cedric H , Rios Rafael , Cruz Melissa R , Dinh An Q , Diaz Lorena , Garsin Danielle A , Arias Cesar A 
Published: January 2021

Abstract

Background
Enterococci have evolved a network of two component-signaling systems (TCS) to evade killing by cationic antimicrobial peptides (AP) of the host innate immune response. Activation of these pathways can also lead to cross-resistance to AP-like antibiotics such as daptomycin (DAP), complicating treatment of severe enterococcal infections. Our previous work implicated the MadRS (formerly YxdJK) TCS in resistance to DAP. In this work, we show that the MadRS system regulates a network of membrane defense proteins that provide targeted resistance to killing by LL-37.

Methods
We performed a global transcriptional analysis comparing wild type (WT) E. faecalis OG1RF and an OG1RF derivative possessing a mutated allele of the madS gene that activates the MadRS system (OG1RFmadSA202E). Selected genes identified in this analysis were knocked out using a CRISPR-cas9 gene editing system and confirmed by sequencing. Antibiotic minimum inhibitory concentrations (MIC) were determined using gradient diffusion strips. LL-37 killing assays were performed in triplicate in RPMI+5% LB broth. Caenorhabditis elegans assays were performed in triplicate, and representative results are shown.

Results
Analysis of the MadRS regulon revealed a significant upregulation of a network of gene targets, including madLM (formerly yxdLM, involved in bacitracin resistance), madEFG, the dlt operon, salA, and EF2211 (Fig 1). The madSA202E allele was associated with increased bacterial survival on exposure to LL-37, while the madEFG deletion mutant was more susceptible to killing (Fig 2A). Deletion of madLM decreased bacitracin MICs, but did not alter survival on exposure to LL-37. In C. elegans, inactivation of the MadRS system by deletion of the madR response regulator resulted in attenuation as compared to WT OG1RF. The effect was reversed by complementing with wild-type madR on a plasmid (Fig 2B). The attenuation effect of the mutant was abolished in pmk-1 knockout worms, which lack the ability to produce innate immune peptides (Fig 2C).
Figure 1

Figure 2

Conclusion
The MadRS system plays an important role in mediating resistance to AP both in vitro and in vivo. The novel ABC-transporter MadEFG is likely to play a major role in preventing enterococcal killing by the human cathelicidin LL-37.

Disclosures
William R. Miller, MD, Entasis Therapeutics (Scientific Research Study Investigator)Merck (Grant/Research Support)Shionogi (Advisor or Review Panel member) Cesar A. Arias, M.D., MSc, Ph.D., FIDSA, Entasis Therapeutics (Scientific Research Study Investigator)MeMed (Scientific Research Study Investigator)Merck (Grant/Research Support)
31. Post-ebola Syndrome Presents with Multiple Overlapping Symptom Clusters: Evidence from an Ongoing Cohort Study in Eastern Sierra Leone
Authors: Himmelfarb Sarah Talia , Bond Nell , Okoli Adaora , Schieffelin John , Shaffer Jeffrey , Samuels Robert J , Engel Emily J 
Published: January 2021

Abstract

Background
Since the outbreak of Ebola Virus Disease (EVD) in West Africa from 2013–2016, a large cohort of survivors with persistent health complaints has emerged. This constellation of issues is termed post-Ebola syndrome. Here we characterize the symptoms and physical exam findings of this syndrome in a cohort of survivors from Sierra Leone 2.6 years after resolution of disease.
Ebola survivors present with clusters of symptoms that represent sub phenotypes of post-Ebola syndrome

Methods
Potential survivor participants in Eastern Sierra Leone were identified and recruited through the Sierra Leone Association of Ebola Survivors. Household contacts of survivors were identified by enrolled survivors. Both groups were administered a questionnaire assessing self-reported symptoms. A physical exam was performed by a limited number of trained providers. Symptoms were then compared using hierarchical clustering. Statistical analysis of the correlations between clusters was conducted using conditional logistic regression. Both SPICE and principal component (PCA) analyses were performed to explore the relationships between symptom clusters.

Results
Between March 2016 and January 2019, 375 Ebola survivors and 1040 contacts were enrolled. At enrollment, Ebola survivors of all age groups reported significantly more symptoms than their contacts in all categories. Six symptom clusters were identified representing distinct organ systems. SPICE revealed 2 general phenotypes: with or without rheumatologic symptoms. Clusters including rheumatologic symptoms were correlated with one another (r = 0.63) but not with other clusters (r &lt; 0.35). Ophthalmologic/auditory symptoms were moderately correlated with the non-rheumatologic clusters (r &gt; 0.5). Interestingly, psychologic/neurologic, cardiac/GI and constitutional clusters correlated with one another (r &gt; 0.6) p &lt; 0.0001 in all cases. The symptom clusters were then mapped onto a PCA. Each symptom cluster separated from the remainder along PC1, particularly the phenotypes with rheumatologic symptoms.

Conclusion
This study presents an in-depth characterization of post-Ebola syndrome in Sierra Leonean survivors. The interrelationship between symptom clusters indicates that post-Ebola syndrome is a heterogeneous disease. The phenotypes identified may have unique mechanisms of pathogenesis, and require distinct therapies.

Disclosures
John Schieffelin, MD, MSPH, Wolters-Kluwer (Independent Contractor)
33. Concerning Trends of Pediatric Leprosy in Minas Gerais, Brazil and Associations with Number of Municipality Medical Facilities
Authors: Landay Taylor , Clennon Julie A , Ferreira José A , Fraga Lucia A , Grossi Maria Aparecida F , Fairley Jessica K 
Published: January 2021

Abstract

Background
Leprosy in children under 15 years of age, and in particular, the presence of leprosy grade 2 disability (G2D) in children, signifies ongoing transmission and the need for improved surveillance. Our objective was to describe the epidemiology of pediatric leprosy in Minas Gerais, Brazil and to explore associations with access to medical facilities.

Methods
A cross-sectional study was conducted using data from the Brazilian Notifiable Diseases Surveillance System (SINAN) from 2002–2017. Incident cases were included if they resided in a municipality with both adult and pediatric cases. Municipalities were divided by the number of medical facilities per municipality: &lt; 5, 5–17, and 18 or higher. Analyses compared pediatric cases across two time periods (2002–2009 and 2010–2017) and number of medical facilities / municipality using chi-square, t-tests, and logistic regression.

Results
A total of 27,725 cases were reported with 1,611 under 15 years of age. Overall incidence declined from 34.8 per 100,000 to 13.6 per 100,000 during the study period with pediatric incidence declining from 2.6 per 100,000 to 0.8 per 100,000. Time period 2 (TP2) showed an increase in the proportion of pediatric G2D (2.58% vs 1.91%, p &lt; 0.0001) when compared to time period 1 (TP1). Mean age of diagnosis in children was younger in TP2 then in TP1 (10.06 vs 10.43, p=0.02). In 2017, the pediatric incidence in municipalities with the fewest medical facilities was 0.95 per 100,000 compared to 0.23 per 100,000 in municipalities with &gt; 5 facilities (p=0.009). There was significantly higher odds of disability at diagnosis (grades 1 and 2) in pediatric cases residing in municipalities with &lt; 5 medical facilities (aOR 1.88; 95% CI 1.37–2.59), adjusted for age and sex. See map (Fig 1).
Figure 1. Cases of Pediatric Disability By Number of Municipality Medical Facilities from 2002–2017 (White areas without reported pediatric leprosy)

Conclusion
The increasing proportion of G2D in children in the second half of the study period despite declining incidence suggest occult infections among children and adults alike in Minas Gerais. Furthermore, the average age of diagnosis in children should increase, not decrease, if M. leprae transmission was truly declining. Lastly, the association between fewer municipality health facilities and increased disability suggest barriers to timely diagnosis and a critical area of focus for research into access to healthcare and leprosy risk.

Disclosures
All Authors: No reported disclosures
38. Predicting stenotrophomonas Maltophilia bloodstream Infections (BSI) in the Hematologic Malignancy Population
Authors: Karaba Sara M , Amoah Joe , Cosgrove Sara E , Tamma Pranita D 
Published: January 2021

Abstract

Background
Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred treatment for S. maltophilia BSI. Hematologic malignancy patients are at increased risk of S. maltophilia BSI but because of the TMP-SMX adverse event profile, this agent is not routinely included in empiric treatment regimens. We sought to identify risk factors for S. maltophilia BSI in hematologic malignancy patients to guide empiric treatment decisions in this population.

Methods
Inpatients ≥ 12 years at Johns Hopkins Health System hospitals between 7/1/16-12/1/19 with a hematologic malignancy and/or stem cell transplant (SCT) within 12 months were included. Cases were patients with S. maltophilia BSI and controls were patients with BSI from Gram-negative organisms other than S. maltophilia. Demographics, pre-existing medical conditions, antibiotic use (including prophylaxis) in the previous 3 months, and hospitalization in the previous 3 months were compared between cases and controls using non-parametric methods and multivariable logistic regression.

Results
There were 20 cases and 105 controls. Cases and controls were similar in terms of age, sex, type of underlying malignancy, proportion with recent SCT, absolute neutrophil count, (ANC), central venous catheter, and severity of illness. Cases were more likely to have received ≥ 72 hours of a carbapenem within the preceding 3 months, controlling for age, recent SCT, ANC, and central venous catheter (OR=3.11, 95% 1.05–9.16, p=0.04). There were no significant differences in prior cefepime or piperacillin/tazobactam use in the preceding 3 months between cases and controls.

Conclusion
Hematologic malignancy patients who received ≥ 72 hours of carbapenem therapy, but not other broad spectrum antibiotic use within the previous 3 months were more likely to be infected with S. maltophilia BSI. Identifying patients at high risk for S. maltophilia BSI can ensure early, appropriate empiric therapy – ultimately improving clinical outcomes.

Disclosures
All Authors: No reported disclosures
39. Comparative One-year Outcomes of Invasive staphylococcus Aureus infections Among Persons with and Without Drug Use in an Urban West Coast Cohort
Authors: Appa Ayesha Ashley , Adamo Meredith , Le Stephenie , Davis Jennifer , Winston Lisa Gail , Doernberg Sarah B , Chambers Henry , Martin Marlene , Coffin Phillip , Jain Vivek 
Published: January 2021

Abstract

Background
Persons who use drugs (PWUD) face substantial risk from invasive Staphylococcus aureus infections but have important demographic and clinical differences from persons without drug use (non-PWUD). Despite this, limited data exist comparing S. aureus infection outcomes in PWUD vs. non-PWUD; these data are needed to inform interventions to optimize care for this vulnerable population.

Methods
We identified adults hospitalized from 2013–2018 at two academic hospitals in San Francisco with S. aureus bacteremia or ICD-coded diagnoses of endocarditis, epidural abscess, or vertebral osteomyelitis with compatible S. aureus culture. Via structured chart review, we compared the following among PWUD vs. non-PWUD: clinical and substance use features, adjusted odds of antibiotic completion, and one-year infection-free survival using a multivariate Cox proportional hazards model adjusted for age/race, housing, comorbidities, and MRSA.

Results
Of 963 hospitalizations for invasive S. aureus infections in 946 patients, 372/963 (39%) occurred in PWUD. Among PWUD, heroin (198/372, 53%) and methamphetamine use (185/372, 50%) were common (Table 1). Bacteremia occurred in 82% of hospitalizations. PWUD vs. non-PWUD had higher proportions of MRSA (48% vs. 31%) and invasive infections: 20% vs. 12% with endocarditis, 25% vs. 11% with epidural abscess, and 28% vs. 13% with vertebral osteomyelitis (all p&lt; 0.001). PWUD had more self-directed (“AMA”) discharges, and most using opioids did not receive methadone or buprenorphine (Table 2). PWUD completed antibiotic courses less often (70% vs. 87%; p&lt; 0.001) and had 2.9-fold higher adjusted odds of incomplete treatment (95% CI:1.7–5.0). One-year mortality was lower in PWUD (18% vs. 30%), but one-year readmission for ongoing/recurrent infection was far higher (28% vs. 14%; HR 1.9 [95% CI:1.3–2.9], Figure 1).
Table 1: Demographic, Clinical, and Substance Use Characteristics

Table 2: Care Delivery, PWUD vs. non-PWUD

Figure 1: One-year Infection-free survival in persons who use drugs (PWUD) vs. non-PWUD

Conclusion
PWUD had higher proportions of S. aureus vertebral osteomyelitis, epidural abscess, and endocarditis than non-PWUD, lower odds of treatment completion, and greater risk of infection persistence/recurrence at one year. Among PWUD, opioid and stimulant use were common and undertreated. New patient centered models of care that deliver synchronized S. aureus infection and substance use disorder therapy are urgently needed.

Disclosures
All Authors: No reported disclosures
46. Tacrolimus Increases Susceptibility to Secondary Infection in a Mouse Model
Authors: Miller-Handley Hilary , Kinder Jeremy , Pham Giang , Way Sing Sing 
Published: January 2021

Abstract

Background
Transplant acceptance requires life-long pharmacological intervention that broadly suppresses recipients’ immunity in order to prevent rejection of foreign graft. In turn, non-specific immune-suppression in these patients is also associated with increased risk of infection from opportunistic pathogens. Currently our knowledge on the effects immune suppressive therapies on adaptive immune components response in patients is limited

Methods
To investigate this we established a mouse model of post-transplant immune suppression therapy, using tacrolimus. To dissect the effects of tacrolimus on infection susceptibility, tacrolimus-treated mice were infected with a virulent strain of recombinant Listeria monocytogenes (Lm) expressing model antigens. Infection with this transgenic strain of Lm transforms these model antigens into surrogate Lm antigens and allows tracking of pathogen-specific T-cells using MHC tetramer staining.

Results
Here we show, tacrolimus treatment triggered increased susceptibility to secondary, but not primary Lm infection with increased bacterial burden in the liver and spleen tissues. Increased susceptibility during secondary infection paralleled dampened functional activation of Lm-specific CD8+ T cells as indicated by diminished in vivo cytolytic activity. Interestingly, when tacrolimus treatment was initiated only during primary or during secondary infection susceptibility to infection was overturned as both groups of mice had lower bacterial burden in target tissues. This suggests that while tacrolimus treatment does not negatively impact primary immune response, it may dampen the formation of CD8+ T cell memory.

Conclusion
Further studies will investigate the long-term durability of blunted pathogen-specific memory and CTL activity triggered by tacrolimus treatment after cessation of therapy. These findings will allow more defined prediction of patient risk of infection allowing for a personalized prophylaxis regimen.

Disclosures
All Authors: No reported disclosures
3. A Review of the Clinical Development of MenACWY-TT, a Quadrivalent Meningococcal Vaccine Conjugated to Tetanus Toxoid, in Adolescents
Authors: Peyrani Paula , Webber Chris , Burman Cindy , Balmer Paul , Perez John L 
Published: January 2021

Abstract

Background
As a peak in meningococcal disease often occurs during adolescence, meningococcal vaccination programs are available for this age group in various regions across the globe. Quadrivalent meningococcal (MenACWY) conjugate vaccines are being incorporated in an increasing number of programs in response to changing meningococcal serogroup epidemiology. MenACWY-TT (Nimenrix®) is a MenACWY conjugate vaccine available in the European Union and 50 other countries for preventive vaccination of serogroup A, C, W, and Y disease (Figure 1). MenACWY-TT is licensed in some countries as a 2-dose primary series in individuals as young as 6 weeks of age, while a single dose may be given to previously unvaccinated individuals ≥ 6 months of age, adolescents, and adults. Here, we provide an overview of the 3 primary and 5 extension studies evaluating the clinical development of MenACWY-TT in adolescents (Table 1).
Figure 1. Global Registration Status of MenACWY-TT (Nimenrix®) in Adolescents

Table 1. Pivotal Clinical Studies of MenACWY-TT (Nimenrix®) Supporting Licensure in Adolescents

Methods
Immunogenicity and safety data from these 8 clinical studies are summarized.

Results
Across studies, MenACWY-TT antibody responses against all vaccine serogroups were comparable to those of other MenACWY vaccines 1 month post vaccination (Table 1). Antibody responses to MenACWY-TT persisted for up to 10 years in those vaccinated during adolescence. A MenACWY-TT booster given 10 years after primary meningococcal vaccination in early childhood or adolescence elicited robust antibody responses. MenACWY-TT had an acceptable safety profile, with reactogenicity events most commonly reported. Reactogenicity profiles with MenACWY-TT booster were similar to those seen after primary MenACWY-TT.

Conclusion
The MenACWY-TT clinical study program demonstrated the immunogenicity and safety of primary and booster dosing in adolescents. Immune responses persisted through 10 years after primary vaccination.

Funding
Pfizer.

Disclosures
Paula Peyrani, MD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Paul Balmer, PhD, Pfizer Inc (Employee, Shareholder) John L. Perez, MD, MA, Pfizer Inc (Employee, Shareholder)
5. Observational Study of Routine Use of 9-Valent Human Papillomavirus Vaccine: Safe in More Than 140,000 Individuals
Authors: Hansen John , Yee Arnold , Lewis Ned , Li Se , Velicer Christine , Saddier Patricia , Klein Nicola P 
Published: January 2021

Abstract

Background
Nine-valent human papillomavirus (HPV) vaccine (9vHPV vaccine, Gardasil®9) was licensed in the US in Dec-2014. Using a self-controlled risk interval design, we conducted a post-licensure retrospective cohort study within Kaiser Permanente in Northern California (KPNC) to assess 9vHPV safety following routine administration.

Methods
We included KPNC members 9-years or older who received 9vHPV as their first dose of HPV vaccine between Oct-2015 and Sep-2017. Post-vaccination emergency and hospitalization events were compared during risk intervals (days 1–60 and 0–14) with later self-comparison intervals using conditional logistic regression, following all 9vHPV vaccine doses combined, and by dose. We investigated significant findings by assessing post-vaccination timing and medical record reviews. We evaluated and reviewed medical records for all day 0 allergic reaction and syncope events, and all deaths during the study. An independent Safety Review Committee reviewed potential safety signals.

Results
We studied 140,628 9vHPV-vaccinated individuals, including 69,027 (49%) who received 2 doses and 29,901 (21%) 3 doses, totaling 239,556 doses. Eight categories were significantly increased in at least one analysis (Table). On review, most findings were previously known, preceded vaccination, or were better explained by other medical history. Some day 0 allergic reactions and syncope were potentially related to vaccination. None of the 20 deaths were considered related to 9vHPV.
Table. Elevated diagnosis categories comparing risk and self-comparison intervals.

Conclusion
This large study of individuals who received only 9vHPV vaccine did not identify any new safety events related to 9vHPV administration and provides reassuring evidence of the favorable safety profile of the 9vHPV vaccine.

Disclosures
Se Li, PhD, Merck & Co., Inc. (Employee, Shareholder) Christine Velicer, PhD, Merck & Co., Inc. (Employee, Shareholder) Patricia Saddier, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Nicola P. Klein, MD, PhD, GSK group of companies (Research Grant or Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Protein Science (now SP) (Grant/Research Support)Sanofi Pasteur (Grant/Research Support)