bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient free text reporting of symptomatic adverse events in cancer clinical research using the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
Authors: Chung Arlene E , Shoenbill Kimberly , Mitchell Sandra A , Dueck Amylou C , Schrag Deborah , Bruner Deborah W , Minasian Lori M , St. Germain Diane , O’Mara Ann M , Baumgartner Paul , Rogak Lauren J , Abernethy Amy P , Griffin Ashley C , Basch Ethan M 
Published: November 2018

Abstract

Objective
The study sought to describe patient-entered supplemental information on symptomatic adverse events (AEs) in cancer clinical research reported via a National Cancer Institute software system and examine the feasibility of mapping these entries to established terminologies.

Materials and Methods
Patients in 3 multicenter trials electronically completed surveys during cancer treatment. Each survey included a prespecified subset of items from the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Upon completion of the survey items, patients could add supplemental symptomatic AE information in a free text box. As patients typed into the box, structured dropdown terms could be selected from the PRO-CTCAE item library or Medical Dictionary for Regulatory Activities (MedDRA), or patients could type unstructured free text for submission.

Results
Data were pooled from 1760 participants (48% women; 78% White) who completed 8892 surveys, of which 2387 (26.8%) included supplemental symptomatic AE information. Overall, 1024 (58%) patients entered supplemental information at least once, with an average of 2.3 per patient per study. This encompassed 1474 of 8892 (16.6%) dropdowns and 913 of 8892 (10.3%) unstructured free text entries. One-third of the unstructured free text entries (32%) could be mapped post hoc to a PRO-CTCAE term and 68% to a MedDRA term.

Discussion
Participants frequently added supplemental information beyond study-specific survey items. Almost half selected a structured dropdown term, although many opted to submit unstructured free text entries. Most free text entries could be mapped post hoc to PRO-CTCAE or MedDRA terms, suggesting opportunities to enhance the system to perform real-time mapping for AE reporting.

Conclusions
Patient reporting of symptomatic AEs using a text box functionality with mapping to existing terminologies is both feasible and informative.
Dppa3 is critical for Lin28a-regulated ES cells naïve–primed state conversion
Authors: Sang Hui , Wang Dan , Zhao Shuang , Zhang Jinxin , Zhang Yan , Xu Jia , Chen Xiaoniao , Nie Yan , Zhang Kaiyue , Zhang Shuaiqiang , Wang Yuebing , Wang Na , Ma Fengxia , Shuai Ling , Li Zongjin , Liu Na 
Published: November 2018

Abstract
Lin28a is a pluripotent factor that promotes somatic cell reprogramming. Unlike other pluripotent factors, Lin28a expression is transient and accumulated in primed embryonic stem (ES) cells, but its exact function and mechanism in the conversion of ES cells from naïve to primed state remain unclear. Here, we present evidence for Dppa3, a protein originally known for its role in germ cell development, as a downstream target of Lin28a in naïve–primed conversion. Using rescue experiment, we demonstrate that Dppa3 functions predominantly downstream of Lin28a during naïve–primed state conversion. Higher level of Lin28a prevents let-7 maturation and results in Dnmt3a/b (target of let-7) upregulation, which in turn induces hypermethylation of the Dppa3 promoter. Dppa3 demarcates naïve versus primed pluripotency states. These results emphasize that Lin28a plays an important role during the naïve–primed state conversion of ES cells, which is partially mediated by a Lin28a–let-7–Dnmt3a/b–Dppa3 axis.
The effect of maintaining high hemoglobin levels on long-term kidney function in kidney transplant recipients: a randomized controlled trial
Authors: Tsujita Makoto , Kosugi Tomoki , Goto Norihiko , Futamura Kenta , Nishihira Morikuni , Okada Manabu , Hiramitsu Takahisa , Narumi Shunji , Uchida Kazuharu , Takeda Asami , Morozumi Kunio , Maruyama Shoichi , Watarai Yoshihiko 
Published: November 2018

AbstractBackgroundPosttransplant anemia may be a major determinant of chronic allograft nephropathy. However, the impact of correcting anemia on graft function remains controversial.MethodsA 3-year follow-up of an open-label, multicenter, randomized controlled trial involving kidney transplantation recipients examined whether sustained maintenance of target hemoglobin (Hb) concentrations at a high level (12.5–13.5 g/dL, n = 64) with either darbepoetin alfa or epoetin beta pegol would slow the graft function decline rate as the primary efficacy endpoint, compared with maintenance of a low Hb concentration (10.5–11.5 g/dL, n = 63).ResultsThe mean blood pressures in the two groups were well controlled throughout the study. In the high Hb group, mean Hb concentrations increased to >12 g/dL at 3 months, reaching the target range at 18 months. At the end of this study (36 months), the mean Hb concentration was 12.8 ± 0.7 g/dL in the high Hb group and 11.5 ± 1.2 g/dL in the low Hb group. The decline rate of the estimated glomerular filtration (eGFR) rate was considerably greater in the low Hb group (ΔeGFR, −5.1 ± 9.5 mL/min/1.73 m2) than in the high Hb group (−1.0 ± 8.4 mL/min/1.73 m2) (P = 0.02). Of note, only a few high Hb patients developed cardiovascular events and returned to hemodialysis, but the low Hb patients did not.ConclusionThis prospective study suggests that correcting anemia to the target Hb level range (12.5–13.5 g/dL) slows renal function deterioration by >3 years in the chronic phase of allograft nephropathy.
111. Increasing Duration of Surgical Prophylaxis Increases Antimicrobial-Associated Adverse Events but Does Not Decrease Surgical Site Infections: An Opportunity for Stewardship
Authors: Strymish Judith M , Branch-Elliman Westyn , O’Brien William , Itani Kamal , Gupta Kalpana 
Published: November 2018

Abstract

Background
The benefits of surgical antimicrobial prophylaxis are limited to the first 24 hours postoperatively. However, little is known about the harms associated with prophylaxis lasting for greater than 24 hours. Thus, we sought to characterize the relationship between duration of prophylaxis and key post-operative outcomes, including surgical site infections (SSI), acute kidney injuries (AKI), and C. difficile infections (CDI) using a large, multi-center national cohort.

Methods
All patients who underwent cardiac, orthopedic total joint, vascular, and colorectal procedures and who received planned manual review by a trained nurse reviewer for type and duration of surgical prophylaxis and for SSI within the national VA healthcare system during the period from FY08 to FY13 were included. The primary exposure variable of interest was duration of postoperative prophylaxis (&lt;24 hours, 24–48 hours, and 48+ hours). Outcomes evaluated included SSI, AKI, and CDI. ORs were calculated using log binomial regression models adjusted for known risk factors for each clinical syndrome selected a priori.

Results
Out of a total cohort of 79,092, all patients had SSI and C. difficile outcomes available and 67,729 patients had AKI outcome available. After stratification by type of surgery and adjusting for age, sex, race, diabetes, smoking, pre-operative MRSA colonization status, mupirocin receipt, and type of prophylaxis, there was no significant association between SSI and duration of prophylaxis; longer durations did not lead to additional SSI reduction. Odds of AKI increased with each additional day of prophylaxis among cardiac and noncardiac surgeries. Similarly, the odds of C. difficile increased with each additional day of prophylaxis across all types of surgery (P &lt; 0.01) (see figure).

Conclusion
Increasing duration of postoperative antimicrobial prophylaxis is associated with higher odds of AKI and C. difficile infection in a dose-dependent manner. Additional days of prophylaxis are not associated with reduced odds of SSI. These findings suggest that stewardship efforts to limit duration have the potential to reduce antimicrobial-associated adverse events without leading to increases in SSI.

Disclosures
K. Itani, sanofi: Grant Investigator, Grant recipient. Pfizer: Grant Investigator, Grant recipient.
117. Effect of Nasopharyngeal Pneumococcal Carriage on RSV and hMPV Illness Severity in Infants in Nepal
Authors: Murray Alastair , Englund Janet , Kuypers Jane , Tielsch James , Katz Joanne , Shrestha Laxman , Khatry Subarna , Leclerq Steven C , Steinhoff Mark C , Chu Helen Y 
Published: November 2018

Abstract

Background
Pneumococcal pneumonia after a preceding respiratory viral illness is associated with morbidity and mortality in infants. Our study sought to determine how pneumococcal carriage impacted illness severity due to respiratory syncytial virus (RSV) or human metapneumovirus (hMPV) in infants 0–6 months in a low resource setting in South Asia without pneumococcal vaccination. Previous studies in this population found an overall 79.4% prevalence of pneumococcal carriage in ages 1–36 months with higher rates of carriage among healthy controls when compared with those with respiratory illness.

Methods
Infants were enrolled at the time of birth in a maternal influenza immunization trial conducted in rural Nepal from 2011 to 2014. Weekly household-based active surveillance was performed from birth to 6 months to assess for infant respiratory illness, defined as fever, cough, difficulty breathing, wheeze, or otorrhea. Mid-nasal swabs were collected and tested by PCR for RSV, hMPV, and streptococcus pneumoniae with inclusion of first illness episode in the surveillance period. Disease severity was defined using the World Health Organization Integrated Management of Childhood Illness criteria.

Results
Altogether, 247 (73.5%) of 336 infants with RSV and 154 (83.7%) of 184 infants with hMPV had S. pneumoniae detected. Mean age at RSV illness with concurrent pneumococcal carriage was 97.0 days (91.3–102.6) versus 72.8 days (63.3–82.4) for infants without carriage (P &lt; 0.001). Mean age at hMPV illness with concurrent pneumococcal carriage was 101.3 days (93.9–108.7) versus 77.2 days (56.5–98.0) for infants without carriage (P = 0.01). Frequency of reported lower respiratory tract infection did not differ with or without carriage (RSV: 64.4% vs. 65.2% respectively; P = 0.89, hMPV: 52.6% vs. 50.0% P = 0.79). S. pneumoniae PCR cycle threshold value did not differ by duration or severity of RSV or hMPV illness episode.

Conclusion
High rates of pneumococcal carriage were observed with RSV and hMPV illness episodes in a birth cohort of infants in rural Nepal. The majority of infants with RSV or hMPV illness had pneumococcus detected at the time of first observed illness. However, no increase in RSV or hMPV illness severity or duration was seen with pneumococcal carriage.

Disclosures
H. Y. Chu, sanofi pasteur: Grant Investigator, Grant recipient. Novavax: Grant Investigator, Grant to co-investigator’s institution.
121. Improving Predictive Value of Phase 2a TB Drug Development Models Through PET/CT Imaging (NexGen EBA)
Authors: Xie Yingda , Via Laura , Chen Ray , Dodd Lori , Cai Ying , Paripati Paveen , Goldfeder Lisa , Winter Jill , Arora Kriti , Wang Jing , De Jagar Veronique , Malherbe Stephanus , Song Taeksun , Walzl Gerhard , Diacon Andreas , III Clifton Barry 
Published: November 2018

Abstract

Background
Current Phase 2a methods in tuberculosis (TB) drug development are severely limited in capturing a drug candidate’s sterilizing activity (ability to prevent TB relapse). We hypothesize that sputum-based measurements of current methods fail to capture drug activity in deep TB lesion compartments, where recalcitrant TB populations are sequestered. In our recent marmoset study, we found complementary 14-day PET/CT delta signatures across different TB lesion compartments that distinguish drugs with long-term sterilizing activity (e.g., rifampin and pyrazinamide) versus drugs with primarily early bactericidal activity (e.g., isoniazid) (Figure 1). We proceeded to evaluate this novel PET/CT Phase 2a approach among TB patients, benchmarked by drugs that are well-characterized clinically and pharmacokinetically.

Methods
HIV-negative patients with smear-positive pulmonary tuberculosis from Cape Town, South Africa were enrolled and randomized to receive a single drug [isoniazid (H), rifampin (R), pyrazinamide (Z), moxifloxacin (M)], a 2-drug regimen (HZ, RZ), or a 4-drug regimen (HRZE, MRZE) for 14 days in an inpatient facility. Primary data points were PET/CT scans evaluated at pretreatment baseline and treatment day 14 (and day 28 in the HRZE arm), and daily overnight sputum for early bactericidal activity measurements.

Results
From December 2015 to September 2017, 160 participants completed the study, from whom 340 PET/CT scans and 2,238 overnight sputum samples were collected. PET/CT scans from participants demonstrate diversity of lesion architecture and inter-individual variation in PET/CT changes over 14 days of treatment (Figure 2). A preliminary computational algorithm and first- and second-order PET/CT statistics have been developed for initial segmentation and TB lesion categorization of all study scans. Derivation of radiologic signatures by analysis of 14-day PET/CT changes across each lesion type is ongoing; blinded prediction of each participant’s treatment arm based on these signatures is expected by third-quarter 2018.

Conclusion
If successful, these signatures may be applied within a 14-day Phase 2a framework to evaluate new TB drug candidates and construct TB drug regimens with complementary lesion pharmacokinetics.

Disclosures
All authors: No reported disclosures.
151. Evaluation of Pneumococcal Vaccine Effectiveness Against Invasive Pneumococcal Disease Among US Medicare Beneficiaries ≥65 Years Old
Authors: Pilishvili Tamara , Almendares Olivia M , Nanduri Srinivas , Warnock Rob , Wu Xiyuan , McKean Stephen , Kelman Jeffrey , Farley Monica M , Schaffner William , Thomas Ann , Reingold Arthur , Harrison Lee H , Holtzman Corinne , Rowlands Jemma V , Petit Susan , Barnes Meghan , Torres Salina , Beall Bernard , Whitney Cynthia 
Published: November 2018

Abstract

Background
Pneumococcal conjugate vaccine (PCV13) was recommended in series with PPSV23 for all US adults ≥65 years in late 2014. We evaluated effectiveness of PCV13 against invasive pneumococcal disease (IPD) among Medicare beneficiaries ≥65 years old to assess this new policy.

Methods
We linked records for IPD cases (pneumococcus isolated from sterile sites) in persons ≥65 years old identified through Active Bacterial Core surveillance with those of Medicare beneficiaries. Isolates were serotyped and classified as PCV13 (with or without cross-reacting type 6C), and nonvaccine types. We selected Medicare beneficiaries with no record of IPD or pneumonia as controls, and matched to cases on age, residence census tract, and length of Medicare enrollment; we included all eligible controls. Vaccination and medical histories were obtained through Medicare. We estimated vaccine effectiveness (VE) as 1 minus the IPD odds ratio for vaccinated (PCV13) vs. unvaccinated (no PCV13 or PPSV23) persons using conditional logistic regression, adjusted for sex and underlying conditions.

Results
From 2,246 IPD cases identified in 2015–2016, 1,017 (45%) were matched to Medicare beneficiaries. After excluding cases in persons residing in long-term care facilities or with &lt;1 year of Medicare enrollment, we included 699 eligible cases and 10,152 controls in our analysis. PCV13-types (+6C) accounted for 164 (23%) cases, and serotype 3 was the most common PCV13-type. Case patients were more likely than controls to have one or more chronic (88% vs. 58%) or immunocompromising (54% vs. 32%) conditions present. Fourteen percent, 22%, and 8% of case patients, and 18%, 21%, and 8% of controls received PCV13 only, PPSV23 only, or both vaccines, respectively. PCV13-only VE against PCV13-types was 36% (95% CI −18, 65%). When we included type 6C with PCV13-types, VE was 67% (95% CI 11, 88%). PCV13 showed similar effectiveness against PCV13 type (+6C) IPD among adults &gt;75 years of age (VE 61%, 95% CI 14, 82). VE was 26% (95% CI −58, 65%) against serotype 3 and 67% (95% CI 11, 88%) against other PCV13-types (+6C). PCV13 was not effective against nonvaccine types.

Conclusion
PCV13 was effective in preventing IPD caused by PCV13 types when excluding type 3; no effectiveness was demonstrated against serotype 3.

Disclosures
W. Schaffner, Merck: Member, Data Safety Monitoring Board, Consulting fee. Pfizer: Member, Data Safety Monitoring Board, Consulting fee. Dynavax: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. SutroVax: Consultant, Consulting fee. Shionogi: Consultant, Consulting fee.
159. Genomic Epidemiology of MRSA at Intake to a Large Inner-City Jail: Evidence for Community Transmission Networks?
Authors: Popovich Kyle J , Snitkin Evan S , Green Stefan J , Aroutcheva Alla , Schoeny Michael , Payne Darjai , Thiede Stephanie , Zawitz Chad , Hota Bala , Hayden Mary K , Weinstein Robert A 
Published: November 2018

Abstract

Background
USA300 is endemic in the community, with congregate settings potentially facilitating spread. The impact of community MRSA transmission networks on importation of MRSA into urban jails is unknown. We examined MRSA colonization isolates entering the jail and determined whether there are community transmission networks for MRSA that precede incarceration.

Methods
HIV-infected and HIV-negative males incarcerated at the Cook County Jail were enrolled within 72 hours of intake. Surveillance cultures (nares, throat, and groin) were collected to determine prevalence of MRSA colonization. A survey was administered to identify predictors of colonization. Whole-genome sequencing (WGS) and phylogenetic analysis were integrated with epidemiologic data to identify community transmission networks.

Results
A total of 800 males were enrolled (83% AA and 9% Hispanic); 58% were HIV-infected. The prevalence of MRSA colonization at intake was 19%. In multivariate analysis, methamphetamine use (METH), unstable housing, and prior jail incarceration were significant predictors of MRSA. Among HIV patients, injection drug use and HIV care at outpatient Clinic A that emphasize comprehensive care to the LGBTQ community were significant predictors of MRSA. Of the 31 (45%) patients with care at Clinic A, 14 had MRSA colonization. We sequenced 145 isolates from unique individuals, with 102 and 13 closely related to USA300 and USA500 reference genomes, respectively. USA300 strains from intake were diverse (median pairwise SNV distance = 109), with several small clusters noted. WGS revealed the high prevalence of MRSA in Clinic A was not due to clonal spread but rather an intermingling of distinct community transmission networks (strains were highly diverse; median pairwise SNV distance = 410). We did identify a 13-member community transmission network underlying spread of USA500 (figure). Members of this network were more likely to be HIV-infected (P &lt; 0.004), MSM (P &lt; 0.001), and METH (P &lt; 0.001).

Conclusion
A high proportion of individuals enter jail already colonized with MRSA and colonization risk factors provide clues to community reservoirs for MRSA. WGS extended epidemiologic analysis and revealed community transmission networks that could be a potential focus for an intervention.

Disclosures
All authors: No reported disclosures.
164. Reporting the High-resolution Structure of the Enterococcal Ribosome: A New Template for Antibiotic Discovery
Authors: Jogl Gerwald , Khayat Reza , Murphy Eileen , Kleffmann Torsten , Singh Kavindra , Murray Barbara , Krause Kurt 
Published: November 2018

Abstract

Background
The ribosome is a rich target for antibiotic design and its structural secrets have been described at the atomic level over the past 2 decades. However, most bacterial ribosome structures come from nonpathogenic species of Archaea or thermophilic bacteria. To aid in the development of modern antibiotics against the enterococcus, we report the structure of the ribosome from Enterococcus faecalis at 3.5 Å resolution using cryo-electron microscopy.

Methods
E. faecalis strain OG1 was grown in liquid culture, collected and lysed using a French press. 70S ribosomes were purified using centrifugation through a sucrose cushion followed by column chromatography and sucrose gradient centrifugation. 70S particles were diluted in buffer and applied to a holey carbon grid and using an FEI vitrobot were flash-frozen in liquid ethane. Data were collected on an FEI Titan Krios operating at 300 kV acceleration voltage. The particles classified into 6 distinct structures based on their composition. Completed maps were utilized for structure modelling using Coot and were then refined using real space refinement within Phenix.

Results
High-quality maps of the 70S ribosome were obtained at up to 3.5 Å resolution in several distinct conformations. The 23S, 16S, and 5S RNA structures were almost completely built into maps with clear density. All but 2 ribosome proteins L25 and L33 have been placed in density. The A, P, and E sites were built into unambiguous density and found to be consistent with other bacterial structures. Notably, 1 EM density map contains an uncharged t-RNA molecule in the E site. The sites identified for current antibiotics are also well defined and interpretable. This 70S structural platform is suitable for structural analysis of antibiotic binding sites, especially for those antibiotics directed specifically against the enterococcal ribosome.

Conclusion
For the first time, the structure of the ribosome from the important human pathogen Enterococcus faecalis has been determined. The maps were obtained at high resolution and found to be suitable for antibiotic design. It is anticipated that the continued determination of the structures of ribosomes from pathogens will aid in the discovery of new treatments for infectious diseases.

Disclosures
All authors: No reported disclosures.