bluuebunny/crossref_metadata_2025_split huggingface dataset:
163. Enhancing the Immunogenicity of a Novel, Low-cost Ebola Vaccine
Authors: Stampfer Samuel D , Jin Rui , Yang Chinglai 
Published: January 2021

Abstract

Background
Ebolaviruses cause viral hemorrhagic fever with high mortality rates. Nearly all Ebola vaccines in development use Ebola glycoprotein (GP) as the immunizing antigen. GP is present on the viral membrane and functions in cell entry by binding the cellular receptor and mediating membrane fusion; antibodies to GP induce protective immunity. Ebola also produces sGP: a smaller, secreted form of GP containing the receptor-binding domain; it is also able to induce protective immunity. sGP naturally refolds after thermal denaturation and thus may be more stable than GP, and may also be more cost effective as it is produced easily in high quantities. sGP is a homodimer that is covalently linked by a cysteine near its C-terminus. In this work, we explored how modifications to sGP that affect its ability to dimerize also alter its immunogenicity.

Methods
sGP mutants were generated in the pCAGGS mammalian expression plasmid, and injected into mice as a DNA vaccine. Mouse sera was tested by ELISA against sGP and GP proteins, and in a neutralization assay against GP-typed pseudovirions.

Results
We generated 4 different mutants of sGP that had altered abilities to form inter-protomer disulfide bonds. All had a mutated or deleted cysteine at position 306; two had disulfide-bonding restored by introduction of an engineered inter-protomer disulfide bond. Mice were immunized with a DNA vaccine encoding either an sGP mutant or wild-type sGP, and sera were collected. We found that sera from sGP mutants with reduced interprotomer disulfide bonds had significantly higher antibody titers to sGP and GP than sera from our wild-type sGP and engineered-disulfide sGP immunized mice. Antibody titers were similar between sGP and GP; these titers correlated with neutralization ability.

Relative binding to sGP & GP (by ELISA OD) & relative % neutralization of pseudovirions at 1:10 dilution

Conclusion
Immunogenicity of Ebola sGP was enhanced significantly when mutations were introduced to reduce its ability to covalently dimerize. Immunogenicity correlated with induction of neutralizing antibodies, implying that our mutants may outperform wild-type sGP when used as a vaccine in vivo. This work helps paves the way for an alternative Ebola vaccine that has the potential to be more cost-effective and heat-stable than the currently-licensed vaccine.

Disclosures
Samuel D. Stampfer, MD/PhD, Gilead (Shareholder)
164. in Vitro Antibacterial Activity of Cefiderocol Against Non-fermenter Clinical Strains Collected in North America and Europe from Multinational Surveillance Studies SIDERO-WT-2014–2018
Authors: Ukai Yuuta , Nakamura Rio , Oota Merime , Hackel Meredith , Echols Roger , Takemura Miki , Yamano Yoshinori , Sahm Daniel F 
Published: January 2021

Abstract

Background
Non-fermenting Gram-negative bacilli (NFGNB), such as Pseudomonas aeruginosa, Acinetobacter baumannii-complex (ABC), Stenotrophomonas maltophilia, and Burkholderia cepacia-complex (BCC), are recognized as difficult-to-treat organisms due to acquired and intrinsic antimicrobial resistance. This study evaluated the in vitro activity of cefiderocol (CFDC), a novel parenteral siderophore cephalosporin, and comparator agents against NFGNB clinical isolates collected in 2014–2018 as part of the multinational SIDERO-WT surveillance program.

Methods
12,293 non-fermenter clinical isolates, including 5310 from North America and 6983 from Europe, were tested for antimicrobial susceptibility. Minimum inhibitory concentrations (MICs) were determined for CFDC, cefepime (FEP), ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), meropenem-vaborbactam (MVB), meropenem (MEM), ciprofloxacin (CIP), colistin (CST), and trimethoprim-sulfamethoxazole (SXT) by broth microdilution according to Clinical Laboratory and Standards Institute (CLSI) guidelines. MICs for aztreonam-avibactam (ATM/AVI; ATM in the presence of 4 μg/mL AVI), MVB, and SXT were determined only for SIDERO-WT 2018 strains. As per CLSI guidelines, CFDC was tested in iron-depleted media, and carbapenem-non-susceptible (CarbNS) isolates were defined as non-susceptible to MEM.

Results
CFDC demonstrated in vitro activity with MIC90s of 0.25–2 µg/mL against clinical isolates of P. aeruginosa, ABC, S. maltophilia, and BCC, including CarbNS subsets. MIC90s of CFDC against CarbNS P. aeruginosa (N=1416), CarbNS ABC (N=2274), S. maltophilia (N=1565), and CarbNS BCC (N=80) were 1, 2, 0.5, and 2 μg/mL, respectively, which were the lowest among the tested compounds (Table). The MIC90 differences between all isolates and CarbNS subsets were ≤2-fold for P. aeruginosa and ABC, showing that CFDC is active against CarbNS subsets as well as carbapenem-susceptible isolates. However, an 8-fold MIC90 difference between all isolates and CarbNS subsets was observed for BCC.

Conclusion
In 4 years of consecutive multinational surveillance studies, CFDC was the most active agent among antimicrobials tested against a wide range of NFGNB, including CarbNS strains.

Disclosures
Yuuta Ukai, MSc, Shionogi & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi & Co., Ltd. (Employee) Merime Oota, BSc, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)
170. Acute Flaccid Myelitis: Patient Characteristics and Prospective Follow-up Study at Children’s National Hospital, 2013–2019
Authors: Yonts Alexandra B , Harik Nada , Doslea Alyssa , Murnick Jonathan , Carpenter Jessica , Wells Elizabeth , DeBiasi Roberta L 
Published: January 2021

Abstract

Background
Acute Flaccid Myelitis (AFM), diagnosed almost exclusively in children, is characterized by sudden onset flaccid weakness in one or more extremities with distinct gray matter spinal cord lesions on magnetic resonance imaging (MRI), with or without cerebrospinal fluid (CSF) pleocytosis. Outbreaks of AFM have occurred biennially since 2014. Although the definitive causative agent(s) remain unknown, current data support an association with Enteroviruses D68 and A71. Treatment is supportive and long-term prognosis is variable, with many children having persistent motor deficits.

Methods
In this prospective cohort study, we identified patients with clinical and radiographic presentation consistent with AFM at Children’s National Hospital (CNH) from 2013–2019. Medical records and MRIs of identified patients were then reviewed by members of the multidisciplinary CNH AFM Task Force to identify those meeting diagnostic criteria for AFM. Identified patients had follow-up arranged in the multidisciplinary AFM clinic for exam, functional motor assessment and quality of life questionnaires (Peds QL, PROMIS and NeuroQoL).

Results
Since 2013, we identified 22 patients meeting criteria for AFM at CNH. The average age of our patients was 7.25 years (range 6 months to 16 years); almost 2/3 of patients had CSF pleocytosis. Half of patients presented with initial neurologic complaint of single limb weakness. Other presenting neurological symptoms included ataxia, bilateral lower extremity weakness and ophthalmoplegia. A potential infectious cause was identified in the CSF, blood, nasopharynx or stool of 9 patients. As of November 2019, 7 of 21 patients have had follow-up evaluation; 1 had no improvement, 4 had partial improvement but with persistent motor deficits, and 2 had complete resolution. Two patients/families have completed quality of life questionnaires to date.
CNH AFM Patient Characteristics and Results

Conclusion
Similar to other centers, the majority of CNH AFM patients with follow-up to date have persistent and significant long term motor deficits. Assessment of quality of life is an important aspect that has not yet been formally assessed in other studies and will provide useful information regarding the experience of these patients and help identify goals for optimizing care in the future.

Disclosures
All Authors: No reported disclosures
177. Safety of Measles and Pertussis-containing Vaccines in School-age Children Previously Diagnosed with Autism Spectrum Disorders
Authors: Zerbo Ousseny , Modaressi Sharareh , Goddard Kristin , Lewis Ned , Fireman Bruce , Jackson Lisa , Irving Stephanie , Daley Matthew F , Gethaun Darios , Qian Lei , Donahue James , Klein Nicola P 
Published: January 2021

Abstract

Background
Some parents, especially those of children with autism spectrum disorders (ASD), are uncertain about the safety of childhood immunization. We compared rates of fever, febrile seizure and emergency room (ER) visits following measles and pertussis-containing vaccines recommended between ages 4–6 years among children with and without ASD.

Methods
The study included children who were born between 1995–2012, aged 4–7 years at vaccination, and members of six integrated healthcare delivery systems within the Vaccine Safety Datalink. Children with ASD were defined based on receipt of two separate International Classification of Diseases (ICD)-9 or 10 codes. Outcomes (fever, febrile seizures, and ER visits) were identified in electronic health records. To minimize confounding by unmeasured factors related both to avoidance of vaccination and to outcomes of interest, we compared rates of each outcome between children with and without ASD, in risk and control intervals, by estimating the difference-in-differences on a log scale (i.e. the ratio of rate ratios) using logistic regressions. We also conducted risk interval analyses comparing rates of outcomes in risk intervals and control intervals within each group.

Results
The study included 14,947 children with ASD and 1,650,041 children without ASD. After measles or pertussis-containing vaccination, there were no differences in association between the two groups for fever or ER visits (Table). There were no febrile seizures identified among children with ASD. Within the ASD group, rates of fever, seizure or ER visits did not differ significantly between the risk and control intervals after vaccination. However, among the non-ASD group, measles and pertussis-containing vaccines were associated with higher rates of fever and seizure in risk intervals compared to controls intervals. Pertussis-containing vaccines were associated with increased risk of ER visits in risk interval compared to control interval (Table).

Conclusion
We found no difference in the risk of fever, and ER visits comparing children with autism to children without autism after measles or pertussis-containing vaccines. The study provides some reassurance that these vaccines are not less safe in children with ASD.

Disclosures
Lei Qian, PhD, GlaxoSmithKlein (Research Grant or Support) 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)
183. chlamydia Trachomatis Seroprevalence with a pgp3 Serologic Assay and Association with Pelvic Inflammatory Disease Among Women, United States, 2013–2016
Authors: Anyalechi Gloria E , Danavall Damien , Raphael Brian H , Bowden Katherine E , Hong Jaeyoung , Gwyn Sarah , Martin Diana , Kersh Ellen , Kirkcaldy Robert D 
Published: January 2021

Abstract

Background
Chlamydia trachomatis (CT) causes pelvic inflammatory disease (PID) and other sequelae; however, these associations are not fully characterized. CT serologic assays including Pgp3 ELISA may detect prior CT infection and may better elucidate these associations. We used a serologic Pgp3 multiplex bead array assay (Pgp3MBA) to measure CT seroprevalence in reproductive-age US women and assess the association with PID.

Methods
We performed CT Pgp3MBA on sera collected from women 18–39 years old during the 2013–2016 cycles of the National Health and Nutrition Examination Survey (NHANES) who had available urine CT nucleic acid amplification test results. Weighted Pgp3MBA CT seroprevalence and 95% confidence intervals (95% CI) were calculated. We also determined weighted prevalence ratios (PRs) and 95% CIs of self-reported lifetime PID among women with and without detectable Pgp3MBA and other characteristics to estimate these US national statistics.

Results
Among 2,339 women, 1,725 (73.7%) had available sera. Of these women, 1,425 (or 93.4% of those with data) were sexually experienced and had a CT seroprevalence of 35.9% (95% CI 33.4–38.4). When weighted for US women, CT seroprevalence was 30.5% (95% CI 26.6–34.4%), ranging from 16.9% (95% CI 11.0–22.8%) among non-Hispanic Asian women to 70.2% (95% CI 62.4–78.0%) among non-Hispanic black women.
PID was reported by 4.2% (95% CI 3.1–5.2) of 1,413 sexually-experienced women with PID data or an estimated 3.8% (95% CI 2.6–5.0) of US women. Among US women, estimated PID varied by Pgp3MBA status; 7.3% (95% CI 4.3–10.2) of Pgp3MBA-positive women were estimated to report PID versus 2.3% (95% CI 1.3–3.4) of Pgp3MBA-negative women (PR 3.1; 95% CI 1.7–5.9). PID prevalence did not vary by age, nor self-reported recent sexually transmitted disease among US women, but was higher among non-Hispanic black women compared to non-Hispanic white women (PR 2.2; 95% CI 1.4–3.5).

Conclusion
Nearly one-third of US women have had CT by Pgp3MBA, with differences by race/ethnicity. Women with prior CT had three times the reported PID prevalence of women without CT. Further serologic research may refine the population-level impact of CT prevention activities, such as recommended annual CT screening, on PID incidence, particularly among non-Hispanic black women.

Disclosures
All Authors: No reported disclosures
186. A Systematic Literature Review on the Economic Burden of Illness in Gonorrhea
Authors: Martin Amber , Mitrani-Gold Fanny S , Turner Monica , Schiller Emma , Joshi Ashish V 
Published: January 2021

Abstract

Background
In 2016, the World Health Organization estimated the global incidence of gonorrhea (GC) to be 86.9 million, and the reported incidence of GC in 2017 was 145.8 cases per 100,000 females and 212.8 cases per 100,000 males in the US. GC therefore represents a significant global healthcare burden; as the infection can be recurrent, overall costs can accumulate. We undertook a systematic literature review (SLR) to examine the economic burden of illness for GC in key countries.

Methods
Systematic searches were conducted in MEDLINE, EMBASE, and Cochrane databases to identify English-language articles published from January 1, 2009–December 1, 2019 reporting data on the economic burden of uncomplicated urogenital GC (uuGC) in the US, the UK, Germany, Japan and China. The SLR was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (2009). Articles were evaluated for eligibility using population, intervention, comparison, outcome, study design and time period criteria (Table). Dual-independent screening was used at both the abstract and full-text levels; data were captured by a single reviewer with validation by a second reviewer.
Table. PICOS-T Study Selection Criteria

Results
The SLR identified 27 eligible articles (Figure), of which 17 studies (16 US, 1 UK) reported the economic burden of uuGC. The studies primarily reported cost data, with a subset reporting limited resource use. Lifetime costs for uuGC, when elaborated upon, considered the potential for pelvic inflammatory disease among women, and epididymitis in men, as well as lifetime medical costs associated with human immunodeficiency virus. Among the 16 studies reporting costs, the total estimated lifetime cost of uuGC in the US reached as high as $162.1 million. Costs varied vastly based on sex, with one study reporting lifetime estimates up to $163,433 for men but $7,534,692 for women in 2005. Nine studies described costs per patient/infection and found average costs ranging from $26.92–$438.46, though most fell in the range of $79–$354.
Figure. PRISMA flow diagram of study inclusion and exclusion

Conclusion
We identified a large body of evidence detailing the economic burden of GC. The cost burden varied by sex and was higher for females. However, the vast majority of the evidence came from the US, highlighting the need for more global research.

Disclosures
Amber Martin, BS, Evidera (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Fanny S. Mitrani-Gold, MPH, GlaxoSmithKline plc. (Employee, Shareholder) Monica Turner, MPH, Evidera (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Emma Schiller, BA, Evidera (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Ashish V. Joshi, PhD, GlaxoSmithKline plc. (Employee, Shareholder)
188. The Role of Bone Pathology in the Management of Residual Osteomyelitis After Amputation for Diabetic Foot Infections
Authors: Lee Eugene , Pupaibool Jakrapun , Certain Laura 
Published: January 2021

Abstract

Background
Diabetic foot osteomyelitis is a common infection often treated by a combination of antibiotic therapy and limb-sparing amputation. During amputation, IDSA guidelines recommend histopathological analysis of the proximal resection margin, but there are few studies evaluating the prognostic value of such analysis. We did a retrospective cohort study to evaluate whether histopathologic findings predict the clinical outcomes of further proximal amputation or death.

Methods
We conducted a retrospective cohort study at a VA hospital reviewing 84 patients. We evaluated patients who had a diagnosis of diabetes mellitus with diabetic foot osteomyelitis who were treated with limb-sparing amputations. All cases that were included had adequate histopathological description of the proximal margin of the amputation site. We also collected relevant clinical data including comorbidities, labs, culture data and pre-op and post-op antibiotics. The primary outcome was defined as the need for further proximal resection at the amputation site within six months of the original amputation or death from all causes within three months of the original amputation. Categorical variables were compared using Fischer’s exact test or the Chi-Square test. Continuous variables were compared using the t-test.

Results
We found a statistically significant difference (p=0.0003) of the primary outcome with 10 of 19 (53%) patients with positive margins needing further surgical resection and 1 of 19 (5%) patients dying. Of the patients with negative margins, 9 of 55 (14%) patients needed further surgery and none died.

Conclusion
Our study showed that patients with residual osteomyelitis at the proximal margin were more likely to need further proximal amputation or die. We did not have adequate power to assess whether extended antibiotic therapy improved outcomes for patients with positive margins, but there was no suggestion that it did. Further research will be needed to elucidate what the ideal duration of antibiotic therapy is for residual osteomyelitis after amputation for diabetic foot osteomyelitis.

Disclosures
All Authors: No reported disclosures
190. Osteomyelitis Following Mandibular Reconstruction with Free Fibula Flap: A Cohort Study of an Emerging and Complex Bone and Joint Infection
Authors: javaux Clément , Daveau Clémentine , Bettinger Clothilde , Bourlet jérôme , Dupieux-Chabert Céline , craighero Fabien , Fuchsmann Carine , Céruse Philippe , Sigaux Nicolas , Ferry Tristan , Valour Florent 
Published: January 2021

Abstract

Background
Free fibular flap (FFF) mandible reconstruction is at high risk of complications due to patient comorbidities, microvascular surgery after neck irradiation and intrabuccal exposure. We aimed to describe clinical and microbiological features, management and outcome of osteomyelitis following mandibular reconstruction with FFF.

Methods
Patients referred to our reference center for an osteomyelitis following FFF reconstruction of the mandible were included in a retrospective cohort. Microbiology was described based on gold-standard samples. Risk factors for treatment failure (infection persistence or relapse, need for additional surgery for septic reason, infection-related death) were assessed by logistic regression and Kaplan-Meier survival curve analysis.

Results
48 patients (age, 60.5 [IQR, 52.4–66.6]; 30 males; 62.5%; modified Charlson comorbidity index, 4 [3–5]) were included. Indications for FFF mandible reconstruction were mostly carcinoma (n=27; 56.3%) and osteoradionecrosis (n=12; 25.0%), with 44 (82.9%) previous neck irradiation. FFF osteomyelitis were mostly early (≤ 3 months post-surgery; n=43; 89.6%). Main symptoms were local inflammation (n=28; 59.6%), ununion or sinus tract (n=28; 59.6%), bone or device exposure (n=21; 44.7%), and were associated with radiological signs for infection in 33 (75.0%) cases. Microbiological documentation highlighted Enterobacteriaceae (n=25; 61.0%), Streptococcus spp. (n=22; 53.7%), S. aureus (n=10; 24.4%), anaerobes (n=10, 24.4%), Enterococcus spp. (n=9; 22.0%) and non-fermenting Gram negative bacilli (GNB; n=8; 19.5%). Thirty-nine (81.3%) required surgery, consisting in debridement with implant retention in 25 (64.1%) cases, associated with a 93 (64–128) day course of antibiotherapy. After a follow-up of 18 (11–31) months, 24 (50.0%) treatment failure were observed. An early ID-specialist referral was the only significant predictor of favorable outcome (OR, 0.167; p=0.005). Non-fermenting GNB infections tended to be associated with a higher risk of failure (OR, 8.4; p=0.058).
Probability of treatment failure of osteomyelitis following FFF mandible reconstruction according to ID-referral (A), CRP level 2 weeks after surgery (B) and presence of non-fermenting GNB

Conclusion
Osteomyelitis following mandibular reconstruction with FFF represent difficult-to-treat infections. Our results advocate for a multidisciplinary management, including an early ID-specialist referral.

Disclosures
All Authors: No reported disclosures