bluuebunny/crossref_metadata_2025_split huggingface dataset:
An evolved, orthogonal ssDNA generator for targeted hypermutation of multiple genomic loci
Authors: Chu Weiran , Tian Rongzhen , Guo Yaxin , Wu Yaokang , Rehm Fabian B H , Liu Long , Li Jianghua , Du Guocheng , Chen Jian , Liu Yanfeng 
Published: January 2025

Abstract
Achieving targeted hypermutation of specific genomic sequences without affecting other regions remains a key challenge in continuous evolution. To address this, we evolved a T7 RNA polymerase (RNAP) mutant that synthesizes single-stranded DNA (ssDNA) instead of RNA in vivo, while still exclusively recognizing the T7 promoter. By increasing the error rate of the T7 RNAP mutant, it generates mutated ssDNA that recombines with homologous sequences in the genome, leading to targeted genomic hypermutation. This approach, termed T7 RNAP mutant-assisted continuous evolution (T7ACE), functions effectively in both typical prokaryotic and eukaryotic microorganisms (Escherichia coli and Saccharomyces cerevisiae), achieving targeted hypermutations at rates 2800- and 1200-fold higher than the genomic mutation rates, respectively. Using T7ACE, we successfully evolved an eight-fold increase in tigecycline resistance within 7 days and doubled the efficiency of a xylose utilization pathway in 10 days, demonstrating the efficiency and broad applicability of this single-component tool for continuous evolution.
The role of nutritional vitamin D in CKD-MBD in children and adults with CKD, on dialysis and after kidney transplantation – a European consensus statement
Authors: Jørgensen Hanne Skou , Vervloet Marc , Cavalier Etienne , Bacchetta Justine , de Borst Martin H , Bover Jordi , Cozzolino Mario , Ferreira Ana Carina , Hansen Ditte , Herrmann Markus , de Jongh Renate , Mazzaferro Sandro , Wan Mandy , Shroff Rukshana , Evenepoel Pieter 
Published: January 2025

Abstract
Vitamin D deficiency is common in patients with chronic kidney disease (CKD) and associates with poor outcomes. Current clinical practice guidelines recommend supplementation with nutritional vitamin D as for the general population. However, recent large-scale, clinical trials in the general population failed to demonstrate a benefit of vitamin D supplementation on skeletal or non-skeletal outcomes, fueling a debate on the rationale for screening for and correcting vitamin D deficiency, both in non-CKD and CKD populations. In a collaboration between the European Renal Osteodystrophy initiative of the European Renal Association (ERA) and the European Society for Paediatric Nephrology (ESPN), an expert panel performed an extensive literature review and formulated clinical practice points on vitamin D supplementation in children and adults with CKD and after kidney transplantation. These were reviewed by a Delphi panel of members from relevant working groups of the ERA and ESPN. Key clinical practice points include recommendations to monitor for, and correct, vitamin D deficiency in children and adults with CKD and after kidney transplantation, targeting 25-hydroxyvitamin D levels &gt;75 nmol/L (&gt;30 ng/mL). While vitamin D supplementation appears well-tolerated and safe, it is recommended to avoid mega-doses (≥100 000 IU) and very high levels of 25 hydroxyvitamin D (&gt;150-200 nmol/L, or 60-80 ng/mL) to reduce the risk of toxicity. Future clinical trials should investigate the benefit of vitamin D supplementation on patient-relevant outcomes in the setting of vitamin D deficiency across different stages of CKD.
DSCT: A novel deep learning framework for rapid and accurate spatial transcriptomic cell typing
Authors: Xu Yiheng , Yu Bin , Chen Xuan , Peng Aibing , Tao Quyuan , He Youzhe , Wang Yueming , Li Xiao-Ming 
Published: January 2025

Abstract
Unraveling the complex cell-type composition and gene expression patterns at the cellular spatial resolution is crucial for understanding intricate cell functions in the brain. In this study, we developed Deep Neural Network-based Spatial Cell Typing (DSCT), an innovative framework for spatial cell typing within spatial transcriptomic datasets. This approach utilizes a synergistic integration of an enhanced gene selection strategy and a lightweight deep neural network for data training, offering a more rapid and accurate solution for the analysis of spatial transcriptomic data. Based on comprehensive analysis, DSCT achieved exceptional accuracy in cell-type identification across various brain regions, species, and spatial transcriptomic platforms. It also performed well in mapping finer cell types, thereby showcasing its versatility and adaptability across diverse datasets. Strikingly, DSCT exhibited high efficiency and remarkable processing speed, with fewer computational resource demands. As such, this novel approach opens new avenues for exploring the spatial organization of cell types and gene expression patterns, advancing our understanding of biological functions and pathologies within the nervous system.
88. Efficacy of nirmatrelvir-ritonavir in high-risk trial participants with prior SARS-CoV-2 infection or vaccination: a pooled analysis
Authors: McLaughlin John M , Leister-Tebbe Heidi , Bao Weihang , Quercia Romina , Hammond Jennifer 
Published: January 2025

Abstract

Background
EPIC-HR, a trial conducted early-on in the COVID-19 pandemic, showed &gt; 85% efficacy of oral nirmatrelvir-ritonavir (NMV/r) for preventing COVID-19 hospitalization and all-cause death in unvaccinated high-risk patients (≥ 1 risk factor for severe COVID-19). The applicability of these findings to current settings of high population-level immunity, however, are not well understood. We evaluated efficacy of NMV/r in a subset of high-risk trial participants with pre-existing SARS-CoV-2 immunity from either prior infection or vaccination.
Efficacy of NMR-r by outcome in high-risk EPIC-HR and EPIC-SR mITT patients with prior SARS-CoV-2 infection or vaccination (n=1600)

Methods
Efficacy of NMV/r received within 5 days of COVID-19 symptom onset was assessed vs placebo through 28 days against a range of pre-specified outcomes. Data were pooled from two Phase 2/3 RCT modified intention-to-treat populations: (1) high-risk EPIC-HR patients who were unvaccinated and SARS-CoV-2 seropositive at baseline, and (2) high-risk EPIC-SR patients who previously received COVID-19 vaccine.

Results
1600 participants were included, of whom 969 (60.6%) were high-risk and SARS-CoV-2 seropositive from EPIC-HR and 631 (39.4%) were high-risk and vaccinated against COVID-19 from EPIC-SR. Overall, 807/1600 (50.4%) received NMV/r and 793/1600 (49.6%) placebo. Compared to placebo, NMV/r reduced the risk of COVID-19 hospitalization and all-cause death by 73.7% (95% confidence interval: 21.4–91.3%; absolute rate reduction: 1.40% [0.33–2.47%; P=.010]), any COVID-19 medical visit by 65.0% (24.4–83.8%; P=.008), and having severe COVID-19 symptoms by 22.1% (0.66–38.9%; P=.044) and 46.6% (22.1–63.4%; P=.001) in the 2–6 and 7–28 days following treatment initiation, respectively (Table). Median time to sustained symptom alleviation was 2 days shorter (12 vs 14 days; P=.047) for those who received NMV/r vs placebo.

Conclusion
In a subset of RCT participants with pre-existing natural or vaccine-derived SARS-CoV-2 immunity, treatment with NMV/r significantly reduced the risk of COVID-19 hospitalization and all-cause death, with a number-needed-to-treat of 71. Treated patients also had fewer COVID-19-related medical encounters, lower risk of having severe COVID-19 symptoms, and shorter time to symptom alleviation. These data underscore the utility of NMV/r in high-risk patients with baseline SARS-CoV-2 immunity.

Disclosures
John M. McLaughlin, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds (Public Company) Heidi Leister-Tebbe, BSN, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds (Public Company) Weihang Bao, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds (Public Company) Romina Quercia, M.D., Ph.D., Pfizer: Employee|Pfizer: Stocks/Bonds (Public Company) Jennifer Hammond, PhD, Pfizer, Inc: Employee|Pfizer, Inc: Stocks/Bonds (Public Company)
100. Genomic epidemiology of carbapenemase-producing Enterobacter species in Toronto, Canada, 2007-2021
Authors: Izydorczyk Conrad , Lee Robyn , Mataseje Laura , Golding George , Braukmann Tom , Carroll Amanda C , Katz Kevin , Kozak Robert , Jamal Alainna J , MacFadden Derek , Mazzulli Tony , Melano Roberto , Patel Samir , Poutanen Susan M , Richardson David , Waglechner Nicholas , McGeer Allison 
Published: January 2025

Abstract

Background
Identification of transmission networks of carbapenemase-producing organisms (CPO) is critical to identifying their reservoirs and limiting their spread. This study aimed to use whole-genome sequencing to identify genomic relationships between CP Enterobacter (CP-Ent) in Ontario, Canada over a 15-year period.

Methods
All CP-Ent cases identified by prospective population-based surveillance in the Toronto/Peel Region from first isolate in 2007 to 2021, from hospital sinks (2016-2019), and wastewater treatment plants and surface water sites (2015-2017) were included. CPO isolates were identified by phenotypic screening (ertapenem MIC &gt; 1mg/L or meropenem disc diffusion diameter ≤ 25mm), confirmed as Enterobacter by MALDI-TOF MS and as positive for carbapenemase genes by PCR, and sequenced by Illumina. Genomics analysis utilized a custom pipeline combining Snippy, IQ-Tree, and ClonalFrameML.

Results
Overall, 182 isolates from 127 patients, 61 isolates from 40 sinks, and 155 isolates from 9 wastewater plants/surface water sites were available (Table 1). Thirty-one of 127 (24%) patients had &gt; 1 sequenced isolate: in 29 patients all isolates were highly related (median SNV distance 3.5, range 0-13); one patient had two CP-Ent species ∼1.5 years apart, and one had 2 sequence types (STs) 86 days apart. Of 12 (30%) sinks with &gt; 1 isolate, 5 had 2 STs recovered at different times (4 with different carbapenemases). Multiple species, STs, and carbapenemases were recovered from sewage trunks and surface water. Using a ≤ 20 SNV threshold between any one pair of isolates, 14 multi-patient putative clusters involving 39 patients were identified; 1 added cluster was identified and 4 expanded when the threshold was increased to 40 SNVs (Table 2). At the 40 SNV threshold, the median number of patients per cluster was 2 (range 2-9), and the median number of hospitals with at least one first identified patient in each cluster was 1.5 (range 1-4). In total, 35% (45/127) patients were part of a cluster.

Conclusion
CP-Ent in Ontario are diverse, but a significant minority of affected patients are part of genomically-defined clusters. Genomic clusters may reflect undetected transmission of CP-Ent in healthcare, exposure to water, or other as yet unidentified sources.

Disclosures
Allison McGeer, MD, AstraZeneca: Honoraria|GSK: Honoraria|Merck: Honoraria|Moderna: Honoraria|Novavax: Honoraria|Pfizer: Grant/Research Support|Pfizer: Honoraria|Roche: Honoraria|Seqirus: Grant/Research Support|Seqirus: Honoraria
157. Long-Acting Injectable HIV Treatment in Individuals with Adherence Challenges: Real-World Insights from Southern California
Authors: Hastie Elizabeth , Hill Lucas , Bamford laura , CS Martin Thomas 
Published: January 2025

Abstract

Background
Long-acting injectable antiretroviral therapy with cabotegravir and rilpivirine (LAI CAB/RPV) showed superiority over daily oral ART among persons with HIV (PWH) with adherence challenges in the LATITUDE study. This trial included conditional economic incentives (CEI) and compensation, which may limit generalizability. We aimed to assess real-world outcomes of LAI CAB/RPV among a similar population in a Ryan White funded primary care HIV clinic.

Methods
PWH with adherence challenges who initiated LAI CAB/RPV at the UCSD Owen Clinic were included. Adherence challenges were defined as at least one HIV viral load (VL) &gt; 200 copies/mL in the previous 12-months, along with either poor response to oral ART (two HIV VLs &gt; 200 copies/mL separated by ≥ 4-weeks in the prior 18-months despite being prescribed oral ART) or being lost to clinical follow-up (no contact with an HIV provider for ≥ 6-months and non-adherence to ART for ≥ 7-days). The primary outcome was discontinuation of LAI CAB/RPV or VL ≥ 200 copies/mL within 48-weeks of initiation. Secondary outcome was confirmed virologic failure with resistance-associated mutations (RAMs).

Results
63 PWH fulfilled the inclusion criteria: 71% male, 27% female and 2% non-binary, with a median age of 43 years. 46% were white, 16% black, and 38% Hispanic. 41% reported current or prior injection drug use, 40% had active substance use, and 57% had a psychiatric diagnosis. At LAI CAB/RPV initiation, 43% had a VL ≥ 50 copies/mL and 11% had a VL &gt; 10,000 copies/ml. 14 (22%) participants, including all those with a detectable VL at baseline, were prescribed an additional ART for at least part of the 48-weeks. Of the 50 participants with virologic data to 48-weeks, 10 (20%) discontinued LAI CAB/RPV: 4 (8%) had virologic failure (VL ≥ 200 copies/mL) with RAMs and 6 (12%) discontinued for other reasons including participant preference and one participant death.

Conclusion
This observational, real-world study demonstrated that PWH with adherence challenges experienced similar outcomes to those in clinical trials with CEI (20% with VL ≥ 200 copies/mL or LAI CAB/RPV discontinuation vs 24.1% in LATITUDE at 48-weeks). Our study’s lower primary outcome rate may be due to a higher-risk population being referred to LATITUDE to take advantage of CEI and compensation.

Disclosures
Lucas Hill, PharmD, AAHIVP, ViiV Healthcare: Honoraria Thomas CS Martin, MD, Gilead Sciences: Grant/Research Support
305. Hospitalized Patients with Community-Acquired Pneumonia and Structural Lung Disease: A Multicenter Analysis
Authors: Doumat Geroge , Nielsen Daniel , Ratz David , Horowitz Jennifer , McLaughlin Elizabeth , Czilok Tawny , Malani Anurag , Osterholzer Danielle , Gupta Ashwin , Gandhi Tejal N , Petty Lindsay A , Saravolatz Louis , Flanders Scott A , Vaughn Valerie 
Published: January 2025

Abstract

Background
Patients with structural lung disease (SLD) are more susceptible to community-acquired pneumonia (CAP) and are at higher risk for resistant organisms. CAP studies often exclude patients with SLD making it difficult to determine when to treat patients empirically with broad-spectrum antibiotics (BSA). Here, we describe the epidemiology of CAP in inpatients with moderate to severe SLD.

Methods
Between 1/2017 and 12/2023, we analyzed data from inpatients with CAP in 68 Michigan hospitals. SLD was defined as documented moderate or severe chronic obstructive pulmonary disease, bronchiectasis, pulmonary fibrosis, or interstitial lung disease. BSA use was defined as therapy covering methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas and was considered appropriate if recommended by IDSA/ATS CAP guidelines. General estimating equation models, adjusted for variables known to be associated with outcomes, were used to compare 30-day outcomes between SLD and non-SLD CAP inpatients. Logistic or Poisson models, as appropriate, were adjusted for variables known to be associated with the outcomes.

Results
Of 51,953 patients with CAP across 68 hospitals, 18.2% (n=9,447) had documented SLD. Compared to patients without SLD, patients with SLD were sicker at baseline (see Table 1 for details) and, despite lacking traditional risk factors, were more often found to have MRSA (1.4% vs. 0.8%, p&lt; 0.01) or Pseudomonas aeruginosa (4.7% vs. 1.7% p&lt; 0.01) in their respiratory cultures (Table 2). While 42.2% of patients with SLD (vs. 35.5% without SLD) received broad-spectrum antibiotics, only 16.1% (vs. 10% without SLD) of such therapy was recommended by guidelines. Compared to patients without SLD, those with SLD had higher odds of mortality (aOR=1.31, p&lt; 0.01 ) and hospital readmission (aOR = 1.19, p&lt; 0.01; Table 3).

Conclusion
Patients with CAP and underlying SLD had more severe disease and experienced worse clinical outcomes. Though they were more likely to grow MRSA or Pseudomonas than patients without SLD, patients with SLD were far more likely to have non-guideline concordant empiric BSA use. New models may be needed to identify the risk of resistant pathogens in SLD and support better selection of empiric therapy.

Disclosures
Elizabeth McLaughlin, MS, RN, Blue Cross Blue Shield of Michigan: Salary Support
310. A comparative study on the effectiveness and safety between colistin-based and high-dose ampicillin/sulbactam-based combination therapy for nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii
Authors: Lee Jaehoon T , Lee Imchang , Lee Ki-Byung , Soon Lee Seung 
Published: January 2025

Abstract

Background
There are differences between IDSA guidance and ESCMID guideline in the treatment of nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). We compared differences in treatment outcomes between the colistin-based and high-dose ampicillin/sulbactam-based regimen in CRAB pneumonia.

Methods
A retrospective cohort study was conducted on adult patients diagnosed with nosocomial pneumonia (clinically defined pneumonia or pneumonia with specific laboratory findings according to the CDC/NHSN surveillance definition) by CRAB (with a meropenem MIC ≥16ug/ml, colistin MIC 1 ≤ug/ml, and ampicillin/sulbactam MIC ≥4ug/ml) in a university-affiliated hospital in Korea. The study enrolled those who received colistin-based regimen using a loading dose of colistin followed by a maintenance dose (June 2021 to May 2022) and high-dose ampicillin/sulbactam-based regimen using sulbactam 9g/day (October 2022 to September 2023). The primary outcome (all-cause mortality within 28 days) and secondary outcomes (including 14-day/28-day clinical success rates and 14-day/28-day kidney injury -RIFLE score) between the two groups were compared using a Log-binomial regression.

Results
A total of 170 CRAB pneumonia patients were enrolled in the study, including 87 patients receiving colistin-based regimen and 83 patients receiving high-dose ampicillin/sulbactam-based regimen. The 28-day mortality rate in the ampicillin/sulbactam group (27.7%) was significantly lower than the colistin group (57.5%) (adjusted RR = 0.48, 95% CI 0.33-0.71). The 14-day and 28-day clinical success rates of the ampicillin/sulbactam group (50.6% and 68.7%) were both significantly higher than those of the colistin group (23.0% and 32.2%) (aRR = 2.20, 95% CI 1.42-3.42 and aRR = 2.13, 95% CI 1.52-2.99). Also, both 14-day and 28-day kidney injury in the ampicillin/sulbactam group (0.6 ± 1.2 and 0.7 ± 1.4) were significantly lower than those in the colistin group (0.9 ± 1.2 and 1.0 ± 1.3) (aRR = 0.69, 95% CI 0.52-0.91 and aRR = 0.68, 95% CI 0.47-0.99).

Conclusion
In patients with CRAB nosocomial pneumonia, High-dose ampicillin/sulbactam-based combination therapy is a better treatment option because of its lower mortality, higher clinical success rate, and lower risk of kidney injury.

Disclosures
All Authors: No reported disclosures
P-819. Epidemiology of Serratia marcescens Bloodstream Infections in a Hospital System in the Southeast U.S
Authors: Niravath Marilyn , Axell-House Dierdre B 
Published: January 2025

Abstract

Background
Serratia marcescens (Sm) is an environmental gram-negative bacilli that can cause a variety of serious human infections. Sm is frequently attributed as a hospital acquired infection. However, there is not extensive documentation as to the common etiologies of Serratia bloodstream infections (BSI), frequency of antibiotic resistance, and risk factors for recurrent infection or mortality.

Methods
We conducted a retrospective chart review of a cohort of patients (pts) ≥ 18 years old with Serratia marcescens BSI from 5/2016 to 10/2022 at our hospital system. Sm BSI was defined as ≥ 1 blood culture positive for Sm. Multidrug resistance was defined according to Centers for Disease Control (CDC) criteria. Patients were assessed for outcomes of recurrence of bacteremia (positive blood culture with same isolate within 3 months of clearance) and 30-day mortality.

Results
A total of 243 patients had Sm BSI during the study period. The most frequent etiology was central line-associated BSI (38%) followed by skin and soft tissue infection (12%). The majority (96%) of isolates were not multidrug resistant. Most patients had a repeat blood culture (67%), and of these patients, 15% had recurrence of bacteremia. A total of 44 patients (18%) died within 30 days. Echocardiogram was performed in 60% of our patients, with 7 patients diagnosed as having endocarditis or device endocarditis. Current active or history of injection drug use occurred in 7.5% of patients.

Conclusion
Our retrospective study demonstrates a low burden of antibiotic resistance in Sm at our hospital system. Similar to prior studies, CLABSI is a frequent cause of Sm BSI, and foreign materials/devices are common in patients with Sm BSI. Our patient population has a lower rate of IVDU compared to other studies of Sm BSI, and endocarditis is not common. Further analysis is needed to evaluate treatment regimens and other risk factors for recurrent BSI and mortality.

Disclosures
All Authors: No reported disclosures
P-826. Impact of Antimicrobial Stewardship Prospective Audit on the Treatment of Staphylococcus aureus Bloodstream Infections
Authors: Kim Eunice , Chapin Ryan W , McCoy Christopher 
Published: January 2025

Abstract

Background
Staphylococcus aureus (SA) is a serious cause of bloodstream infection (BSI) associated with significant morbidity and mortality. Empiric treatment of Gram-positive cocci (GPC) BSIs varies across institutions. Vancomycin, compared to beta-lactams for the treatment of MSSA, is associated with longer durations of bacteremia and higher relapse rates. At our center, a lack of rapid phenotypic diagnostics technology (RPDT) limits prompt optimization. A pre- and post- implementation analysis was performed to assess the impact of a guideline driven stewardship pharmacist intervention on GPC BSI treatment.

Methods
Patients with GPCs in blood cultures were identified using a third-party pharmacovigilance platform. Patients were included for if they grew SA in at least 1 blood culture bottle and excluded if they had polymicrobial infections or if they were placed on comfort measures before antimicrobial therapy was tailored. The primary endpoint was time to optimal therapy, defined as the narrowest effective therapy. Secondary endpoints included time to Infectious Diseases (ID) consultation after GPC identification, duration of BSI, and rate of stepdown to oral antimicrobials for patients with uncomplicated BSI.

Results
From June 2023 to April 2024, 136 patients were identified. Eighty-one patients were included in the pre-guideline group (before December of 2023), and 55 patients were included in the prospective review. Baseline demographics were similar between the two groups (table 1). Patients receiving optimal therapy within 24 hours was 70.9% in the pre-guideline group and 75% in the post-guideline group. Step-down to oral therapy occurred in 66.7% and 23.5% patients, respectively.

Conclusion
We found implementation of a SA BSI guideline with steward follow up did not significantly alter time to empiric therapy, ID consults, or number of patients on tailored therapy within 24h of susceptibilities. Since most patients in our analysis received an infectious diseases consult, fewer opportunities for independent stewardship intervention existed. RPTD may play a potential role to decrease time to optimal therapy at our institution, results will be shared to support the onboarding of this stewardship tool.

Disclosures
All Authors: No reported disclosures