bluuebunny/crossref_metadata_2025 huggingface dataset:
Constitucionalismo fuerte y democracia deliberativa: Inconsistencias en Rawls, Dworkin, y AlexyStrong constitutionalism and deliberative democracy: Inconsistencies in Rawls, Dworkin, and Alexy
Authors: Giuffré C Ignacio
Published: November 2023

In the current context, strong constitutionalism is further challenged by the objections to judicial review and the deliberative turn of democracy. Despite the potential of both caveats, the problem is that a juricentric and juristocratic constitutionalism has globally expanded. The paper’s argument is that there is an inconsistency in some theories that—at the democratic level—start from a deliberative conception, but—at the constitutional level—defend such a strong model, which hinders the inclusive dialogue ideal. This is the case of those conceptions of courts as an “exemplar of public reason” (Rawls), a “forum of principles” (Dworkin), or an “argumentative representation institution” (Alexy). To support this argument, the paper is structured as follows. First, it presents the indifference of the predominant constitutional culture to the criticisms of the judicial authority of strong constitutionalism, as well as to the deliberative turn of democracy. Then, it makes explicit the inconsistency of a group of theories which, while subscribing to a deliberative conception of democracy, subscribe to a strong model of constitutionalism. Finally, it argues that, in a context in which the objections to the judicial review and the deliberative turn of democracy have not been taken seriously, it is essential to reinforce both caveats to achieve a better constitutional model.
Strategies to improve antibiotic access and a way forward for lower middle-income countries
Authors: Wasan Himika , Reeta K H , Gupta Yogendra Kumar
Published: November 2023

Antibiotics have substantially improved life expectancy in past decades through direct control or prevention of infections. However, emerging antibiotic resistance and lack of access to effective antibiotics have significantly increased the death toll from infectious diseases, making it one of the biggest threats to global health. Addressing the antibiotic crisis to meet future needs require considerable investment in both research and development along with ensuring a viable marketplace to encourage innovation. Fortunately, there has been some improvement in the number of antibiotics approved or in different phases of development through collective global efforts. However, the universal access to these essential novel and generic antibiotics, especially in low- and middle-income countries (LMICs), is challenged by poor economic incentives, regulatory hurdles and poor health infrastructure. Recently, the agenda of securing and expanding access has gained global attention. Several mechanisms are now being proposed and implemented to improve access to essential antibiotics. This review provides an insight into the major barriers to antibiotic access as well as the models proposed and implemented to mitigate accessibility issues. These models include but are not limited to market entry rewards, subscription models and transferable exclusivity vouchers. Further, global access programmes including, Global Antibiotic Research and Development Partnership, Antimicrobial Resistance Action Fund and SECURE Platform are discussed. We also propose the way forward for improving access in LMICs with suggested measures to improve access to generic and novel antibiotics.
Distinguishing the fair use and fair dealing doctrines in copyright law—much ado about nothing?
Authors: Saw Cheng Lim
Published: November 2023

It is often assumed and taken for granted that there is a gulf separating the fair use and fair dealing doctrines in copyright law arising principally from the ‘open v closed’ distinction that is made of the statutory schemes in the respective fair use and fair dealing jurisdictions. It will be argued in this article, after a comparative and comprehensive study of the case law and of the various (overlapping) fairness factors, that this distinction merely reflects a difference as to legislative form, rather than the substance of the fairness analysis that may ultimately bear on the outcome of a fairness determination. Both doctrines, in actuality, are far more aligned than may be immediately apparent and this is where having recourse to US fair use jurisprudence—including the infamous transformative use doctrine—in appropriate cases may well assist in a court’s assessment of fairness in the fair dealing context.
Defining logical systems via algebraic constraints on proofs
Authors: Gheorghiu Alexander V , Pym David J
Published: November 2023

We present a comprehensive programme analysing the decomposition of proof systems for non-classical logics into proof systems for other logics, especially classical logic, using an algebra of constraints. That is, one recovers a proof system for a target logic by enriching a proof system for another, typically simpler, logic with an algebra of constraints that act as correctness conditions on the latter to capture the former; e.g. one may use Boolean algebra to give constraints in a sequent calculus for classical propositional logic to produce a sequent calculus for intuitionistic propositional logic. The idea behind such forms of decomposition is to obtain a tool for uniform and modular treatment of proof theory and to provide a bridge between semantics logics and their proof theory. The paper discusses the theoretical background of the project and provides several illustrations of its work in the field of intuitionistic and modal logics: including, a uniform treatment of modular and cut-free proof systems for a large class of propositional logics; a general criterion for a novel approach to soundness and completeness of a logic with respect to a model-theoretic semantics; and a case study deriving a model-theoretic semantics from a proof-theoretic specification of a logic.
GM-CSF improves endometrial receptivity in a thin endometrium rat model by upregulating HOXA10
Authors: Wei Wei , Wang Na , Zhu Yanwen , Liao Maokun , Wang Bian , Du Tong , Zhang Jie , Mao Xiaoyan
Published: November 2023

Endometrial receptivity is a prerequisite for the success of assisted reproduction. Patients with a consistently thin endometrium frequently fail to conceive, owing to low endometrial receptivity, and there are currently very few therapeutic options available. Our previous study demonstrated that intrauterine granulocyte-macrophage colony-stimulating factor (GM-CSF) administration resulted in a significant improvement in clinical pregnancy and implantation rates and was an effective means of increasing endometrial thickness on the day of embryo transfer in patients with thin endometrium. In order to explore the underlying process, an animal model with a thin endometrium was constructed, the homeobox A10 gene (HOXA10) was downregulated, and an inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway (MAPK/ERK) was employed. Our findings strongly suggest a marked decrease in GM-CSF levels in the thin endometrial rat model, and the suppression of HOXA10 impeded the therapeutic efficacy of GM-CSF in this model. Moreover, we showed that GM-CSF significantly increases endometrial receptivity in the rat model and upregulates HOXA10 via the MAPK/ERK pathway. Our data provide new molecular insights into the mechanisms underlying formation of a thin endometrium and highlight a novel, potential clinical treatment strategy as well as directions for further research.
Quantification of all 12 canonical ribonucleotides by real-time fluorogenic in vitro transcription
Authors: Purhonen Janne , Hofer Anders , Kallijärvi Jukka
Published: November 2023

Enzymatic methods to quantify deoxyribonucleoside triphosphates have existed for decades. In contrast, no general enzymatic method to quantify ribonucleoside triphosphates (rNTPs), which drive almost all cellular processes and serve as precursors of RNA, exists to date. ATP can be measured with an enzymatic luminometric method employing firefly luciferase, but the quantification of other ribonucleoside mono-, di-, and triphosphates is still a challenge for a non-specialized laboratory and practically impossible without chromatography equipment. To allow feasible quantification of ribonucleoside phosphates in any laboratory with typical molecular biology and biochemistry tools, we developed a robust microplate assay based on real-time detection of the Broccoli RNA aptamer during in vitro transcription. The assay employs the bacteriophage T7 and SP6 RNA polymerases, two oligonucleotide templates encoding the 49-nucleotide Broccoli aptamer, and a high-affinity fluorogenic aptamer-binding dye to quantify each of the four canonical rNTPs. The inclusion of nucleoside mono- and diphosphate kinases in the assay reactions enabled the quantification of the mono- and diphosphate counterparts. The assay is inherently specific and tolerates concentrated tissue and cell extracts. In summary, we describe the first chromatography-free method to quantify ATP, ADP, AMP, GTP, GDP, GMP, UTP, UDP, UMP, CTP, CDP and CMP in biological samples.
1015. A multicenter evaluation of antimicrobial utilization in hospitalized bone marrow transplant (BMT) and T-cell therapy (CAR-T) patients, and the impact on rates of C. difficile infection (CDI)
Authors: Nagel Jerod , Boeser Kimberly D , Hale Cory , Harris Alyssa , Jain Rupali , Postelnick Mike , Spivak Emily S
Published: November 2023

Background

Benchmarking antimicrobial utilization through the National Healthcare Safety Network (NHSN) will be a CMS requirement in 2024. NHSN benchmarking is available for some hospitalized populations, but there are currently no benchmarking capabilities for BMT units. Additionally, there are no published manuscripts describing antimicrobial utilization in BMT hospitals.

Intra-Hospital BMT Antimicrobial Utilization

Data from the Vizient Clinical Data Base used with permission of Vizient, Inc. All rights reserved.

Methods

This retrospective multicenter study was conducted by the Vizient Pharmacy Network AMS Committee. Antimicrobial utilization was evaluated for Vizient-member hospitals that treat at least 50 BMT patients per year. Vizient Clinical Database was used to identify patients via ICD10 codes for allogeneic transplant, autologous stem cell transplant and CAR-T therapy. Total antimicrobial days of therapy (DOTs) per 1,000 patient days was evaluated across all hospitals for each type of transplant, and for 9 different groups of antimicrobials (anti-pseudomonal beta-lactams, carbapenems, MDRO gram-negatives, fluoroquinolones, MRSA-active agents, antifungals, CMV-active agents, high-risk C. difficile agents, and C. difficile treatments). ANOVA was used to compare antimicrobial utilization across hospitals and across antimicrobial types.

Results

A total of 90 hospitals and 63,379 patient encounters were included in the analysis from 2018-2021. The median total antimicrobial utilization for allogeneic, autologous, and CAR-T patients were 2,562, 2,083, and 2,187 DOTs per 1,000 patient days, respectively. Figure 1 describes the variability in intra-hospital prescribing for 9 antimicrobial categories. Hospitals with higher antimicrobial utilization rates in allogenic transplant patients were associated with a higher incidence of CDI in this population (p=0.0368).

Conclusion

Significant variation in intra-hospital antimicrobial utilization exists for allogeneic transplant, autologous stem cell transplant, and CAR-T patients; and across 9 different categories of antimicrobials! Increasing rates of antimicrobial utilization were associated with increases in C. difficile infections in allogeneic transplants. Benchmarking antimicrobial utilization in BMT patients may help improve systematic approaches to minimize unnecessary antimicrobial exposure.

Disclosures

All Authors: No reported disclosures
1259. Successful Inpatient Penicillin Delabeling in Minimal and Low Risk Penicillin Allergic Patients
Authors: Petrak Robert , Shankaran Shivanjali , Goldenberg Benjamin , Won Sarah Y , Herald Fischer , Fayyaz Anum , Hodgson Hayley A
Published: November 2023

Background

In the US, 10% of adults report a Penicillin (PCN) allergy but true IgE-mediated or serious reactions are rare. A PCN allergy label carries risk for harm including fewer first-line treatment options, increased antimicrobial resistance, toxicities, surgical site infections, and death. The objective of this study was to identify and safely remove penicillin allergy labels in eligible hospitalized patients.

Methods

Between June 2022 - February 2023, the Antimicrobial Stewardship team electronically identified hospitalized patients with documented PCN allergy admitted to adult internal medicine wards at Rush University Medical Center (RUMC), an academic hospital in Chicago, IL. Patients with possible minimal or low risk PCN allergy reactions via chart review were administered a standardized questionnaire, followed by triage into Minimal, Low, and Moderate Risk PCN allergy categories (Figure 1). Minimal Risk patients were delabeled by history alone, or per patient request, after amoxicillin challenge. Low risk patients were offered an amoxicillin challenge with a single 500mg oral dose. Moderate or high risk patients were excluded.

Penicillin Allergy Risk Stratification

Results

Of 47 interviewed patients, 31 patients (20 minimal and 11 low risk) were appropriate for delabeling. 27 of 31 (87%) were successfully delabeled via history or amoxicillin challenge; 4 were not delabeled, due to patient discomfort or early discharge. 14 of the 31 (45%) were delabeled based on history alone; all had tolerated amoxicillin before. 13 amoxicillin challenges were administered, 9 of 11 patients in low risk, 4 of 20 in minimal risk group per patient request. 100% of amoxicillin challenges were well tolerated and patients successfully delabeled. Only 1 patient was relabeled at a subsequent hospitalization.

Penicillin Delabeling Results

Conclusion

In this proof-of-concept intervention, patients with a minimal or low risk penicillin allergy were safely delabeled as inpatients by history or amoxicillin challenge. Expanding this to a larger scale on the inpatient and outpatient settings would enable more patients with PCN allergy to be delabeled, leading to use of standard of care antibiotics and improved outcomes.

Disclosures

All Authors: No reported disclosures
1370. Prevalence and predictors of post-covid-19 (long covid) in India
Authors: Kumar Vignesh , Koshy Jency Maria , Divyashree S , Narreddy Suneetha , Rupali Priscilla , Sathyendra Sowmya
Published: November 2023

Background

Long COVID is a condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. This Indian study followed up patients after an episode of acute COVID-19 for 1 year after hospital discharge from different parts of India.

Methods

This was a multi-centric bi-directional study among patients with confirmed COVID-19 which assessed patients at different time points, i.e. 6 weeks, 3-6, 6-9 and 9-12 months. Patients aged ≥18 years with laboratory confirmed COVID-19, were recruited and followed up telephonically using standardized surveys for quality of life. Data on demographics, pre-existing co-morbidities, risk factors, signs and symptoms and hospital parameters during acute COVID-19 infection were noted. An effort was made to include people with different severity of COVID-19. Univariate and multivariate analysis were performed to determine predictors of long covid.

Results

A total of 315 patients were enrolled (Table 1). Of these, 59.4 were males and 40.6 were females. The mean age was 51.98 ± 14.619 years. At 6 weeks and 12 months, 16.5% and 24% reported continuing symptoms. While shortness of breath was common at each time point, persistent muscle pain and weakness waxed and waned (Figure 1). At 1 year of follow-up, 24% still reported at least 1 troubling symptom and 26% reported > 1 symptom that affected their quality of life i.e., nearly 8% of patients experienced problems in doing their usual activities, 11.7 % were slightly anxious or depressed and few 3.5% experienced slight pain or discomfort. In the multivariable analyses, the severity of disease at baseline (OR 2.330, 95% CI 1.080-5.027) and higher education (OR 0.437, 95% CI 0.241-1.793) seemed to be associated with long COVID.

Demographic and clinical characteristics according to the Severity of COVID

Persisting symptoms of Long COVID

Conclusion

We found that long covid symptoms may be persistent, following an initial recovery from an acute COVID-19 and may also fluctuate or relapse over time. Since symptoms persist in at least 25% of patients for at least 1 year after discharge, we urgently need therapeutic interventions which can improve the quality of life in patients after an acute episode of COVID-19 infection.

Disclosures

All Authors: No reported disclosures
1490. Predictors of Early Mortality in HIV-associated Tuberculous Meningitis
Authors: Kagimu Enock , Bangdiwala Ananta , Kasibante John , Kabahubya Mable , Gakuru Jane , Timothy Mugabi , Namombwe Suzan , Kimuda Sarah , Kasozi Derrick , Rutakingirwa Morris K , Ssebambulidde Kenneth , Tugume Lillian , Nuwagira Edwin , Okurut Samuel , Nsangi Laura , Atukunda Mucunguzi , Ellis Jayne P , Williams Darlisha A , Musubire Abdu Kisekka , Boulware David R , Meya David , Bahr Nathan C , Cresswell Fiona V
Published: November 2023

Background

Tuberculous meningitis (TBM) mortality averages at 27% but may reach 70% in HIV co-infection. High MRC severity grade, lower cerebrospinal fluid (CSF) white blood cell count (WBC) count, low weight, low CD4 and low plasma sodium were linked to mortality in Vietnam. Prognostic factors in African adults with HIV-associated TBM are unknown. We sought to determine the baseline factors predictive of death in HIV-positive Ugandan adults with TBM.

Methods

We prospectively enrolled patients who received TBM treatment and were classified as definite, probable or possible TBM by the uniform case definition from January 2019 to March 2023 in two National Referral Hospitals in Uganda. Participants received standard quadruple TB and corticosteroid therapy. We assessed association between baseline clinical and CSF characteristics (WBC< 5, 5-100, >100 cells/µl), antiretroviral therapy (ART) status and 14-day mortality.

Results

In 261 participants, median age was 36 years, 46% were women, median CD4 count was 74 cells/µl. 27% had definite, 39% probable, and 34% possible TBM. 142 (54%) had baseline CSF WBC < 5, 50 (19%) had 5-100, and 69 (27%) had >100 cells/µl.

Overall, 14-day mortality was 25.9%. Mortality was 73.6% in participants with CSF WBC count < 5, 7.5% in 5-100, and 18.9% in >100 cells/µl, p=0.0012. Factors associated with 14-day mortality were MRC severity grade, CSF WBC, CSF opening pressure (OP), CSF protein and glucose, CD4 count. ART status did not influence survival. The hazard of 14-day mortality was 4 times as high for those with CSF WBC < 5 cells/µl as for those with >100 cells/ µl (95%CI 1.47-11.5, P=0.004). However, on adjustment for Glasgow Coma Scale (GCS), CSF OP, glucose, and CD4 count the association was less significant (aHR, 2.93, 0.82-10.4, P=0.13).

Conclusion

14-day mortality varied significantly by baseline CSF WBC group, being extremely high (73.6%) in those with a paucity of CSF inflammation (WBC < 5 cells/µl). Those with intermediate inflammation (CSF WBC 5-100 cells/µl) had lowest mortality in-line with the damage response framework parabola. The association with acellular CSF and mortality was ameliorated by adjustment for CD4 count. CSF inflammation is at predictor of mortality in HIV-associated TBM and CSF WBC-directed corticosteroid therapy needs further exploration.

Disclosures

All Authors: No reported disclosures
1604. Predicted Uptake of Novel HIV Treatment Options in the United States
Authors: Russell Elizabeth S , Song Yan , Gao Yipeng , Signorovitch James
Published: November 2023

Background

People with HIV (PWH) require lifelong treatment to achieve and maintain viral suppression. The modality and frequency of dosing for chronic medications may impact adherence, quality of life, and effectiveness. Preference data reported by potential users can inform which products in development may be preferred among people with various characteristics and social determinants of health, and can inform development for which product may have the largest health impact if it were available on the market. This study used the preference results from a latent class analysis to model uptake by product of a potential future market of HIV treatment options.

Methods

Data from an online discrete choice survey among 829 US adult PWH about treatment modality (daily or weekly oral pills, 3- or 6-monthly injections by health care providers (HCP), or yearly implants) were used in a latent class model to estimate partworth utility of each product in the 4 identified classes of participants. Probabilities of product uptake were estimated based on partworth utility-predicted product use among study participants and weighted for the US population of PWH. Characteristics considered for weighting were those previously reported to be associated with HIV care and treatment outcomes; they were included in weighting if available data from representative national data sources were found through a targeted literature search.

Results

Preference data weighted for the US population of PWH predicts that if all 5 products were available, they would be used in following proportions: 23.8% yearly implants, 23.7% weekly oral pills, 23.6% 6-month HCP-injections, 18.4% daily oral pills, and 10.5% 3-month HCP-injections. Despite oversampling PWH who were < 40 years old, people with a history of food insecurity, and transgender men (Table 1), the weighted model including the characteristics in Table 1 did not alter predicted uptake by more than 2% for any product compared with the unweighted data.

Conclusion

Based on stated preference survey results, if 5 product delivery options for HIV treatment were available, product use would be broadly distributed, with weekly oral pills, yearly implant, and 6-month HCP-injections used in a similar proportion.

Disclosures

Elizabeth S. Russell, PhD, Merck & Co. Inc: Employee Yan Song, PhD, Merck & Co., Inc.: Grant/Research Support Yipeng Gao, PhD, Merck and Co.: Grant/Research Support James Signorovitch, PhD, Merck & Co., Inc.: Grant/Research Support
2126. Safety, Tolerability, and Pharmacokinetics (PK) in Healthy Participants Following Single Dose Administration of Zosurabalpin, a Novel Pathogen-Specific Antibiotic for the Treatment of Serious Acinetobacter Infections
Authors: Guenther Andreas , Millar Laurie , Messer Amanda , Giraudon Mylène , Patel Katie , Deurloo Erik J , Lobritz Michael , Gloge Andreas
Published: November 2023

Background

Zosurabalpin is the first representative of a novel class of tethered macrocyclic peptide antibiotics active against Acinetobacter spp., including carbapenem-resistant acinetobacter baumannii-calcoaceticus (ABC) complex organisms. This presentation summarizes and discusses unpublished preliminary safety and PK data of zosurabalpin from two completed Phase 1 clinical trials.

Methods

The entry-into-human study (BP41732) was a double-blind, placebo-controlled, randomized, single-and multiple ascending dose study in healthy participants. In Part 1 (SAD) of Study BP41732, participants were randomized 3:1 to receive IV zosurabalpin or placebo in sequential single ascending dose cohorts. The mass balance study (BP43532) was a non-randomized, non-controlled, open-label, single IV dose study in healthy male participants.

Results

Across these studies, 64 healthy male and female participants received a single IV dose of zosurabalpin ranging from 10 mg to 2000 mg. Participants receiving zosurabalpin, did not show any clinically significant changes compared to placebo in laboratory values, ECGs or vital signs compared to placebo.

The most common treatment-related adverse events were infusion-related reactions (IRRs), (9/64). IRR occurrence appeared to be dose-dependent, and all IRRs were fully reversible and mostly of mild intensity (7 mild/ 2 moderate).

The observed plasma exposures (Cmax and AUCinf) of zosurabalpin increased approximately dose-proportionally up to 1000 mg, and more than dose-proportionally thereafter. Total [14C]-radioactivity was approximately equally excreted in urine and feces, with on average 52.6% and 48.0% of the administered dose recovered, respectively.

Conclusion

Single IV doses of 10 mg to 2000 mg zosurabalpin were safe and overall well tolerated, and displayed a well-behaved PK profile in healthy participants. These data support evaluation of repeat dose administration in healthy participants.

Disclosures

Andreas Guenther, PhD, ​F. Hoffmann-La Roche Ltd: Employee Amanda Messer, BPharm, Roche Products Ltd: Employee Mylène Giraudon, PharmD, F. Hoffmann-La Roche Ltd: Employee Katie Patel, MSc, Roche Products Limited: Employer|Roche Products Limited: Stocks/Bonds Erik J. Deurloo, MSc, F. Hoffmann-La Roche Ltd: Salary|F. Hoffmann-La Roche Ltd: Stocks/Bonds Michael Lobritz, MD, PhD, Roche: full time employee|Roche: full time employee
2131. Activity of the Novel Antibiotic Zosurabalpin (RG6006) against Clinical Acinetobacter Isolates from China
Authors: Hawser Stephen , Kothari Nimmi , Valmont Thomas , Louvel Séverine , Zampaloni Claudia
Published: November 2023

Background

Zosurabalpin (RG6006) is the first representative of a novel class of tethered macrocyclic peptide antibiotics active against Acinetobacter spp., including carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC) organisms. In this study, the susceptibility testing of zosurabalpin was carried out against a panel of 150 randomly selected Acinetobacter spp. isolates (100 A. baumannii & 50 non-A. baumannii) representing 11 sites in China and a broad susceptibility profile (65% of which were multi-drug resistant [MDR]) collected in 2021.

Methods

MICs were performed using the Clinical Laboratory Standards Institute (CLSI) broth dilution method cation-adjusted Mueller Hinton broth (CA-MHB) supplemented with either 20% of human serum (HS) or 20% of horse serum (HoS). For a fraction of isolates (10-25%), MIC determination for zosurabalpin is affected by aberrant readings (trailing, multiple skipped wells) in CA-MHB. This effect complicates routine susceptibility testing. Supplementation of CAMHB with serum allows accurate MIC determinations without any major effects on the MIC distribution.

Results

Summary data from the study are shown in Table 1.

Zosurabalpin was active against all Acinetobacter spp., with an MIC50/90 of 0.12/0.5 μg/mL and 0.25/1 μg/mL in CA-MHB supplemented with HoS and HS, respectively (MIC range of 0.015/0.03 to 8 μg/mL). Against ABC isolates (n=133), the MIC50/90 for zosurabalpin was 0.12/0.25 μg/mL and 0.25/0.5 μg/mL, in HoS and HS, respectively (MIC range of 0.015/0.03 to 1 μg/mL). A similar activity was observed against carbapenem-resistant ABC isolates.

Conclusion

In addition to the potent activity observed against isolates from USA and Europe, zosurabalpin exhibited potent in vitro antibacterial activity against Acinetobacter clinical isolates circulating in China. These data support the continued clinical development of zosurabalpin for infections caused by ABC isolates, including difficult to treat carbapenem-resistant isolates.

Disclosures

Stephen Hawser, PhD, Allecra: study funding|Innoviva Specialty Therapeutics, Inc.: Honoraria|Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Nimmi Kothari, PhD, Allecra: Allecra (study funding)|Innoviva Specialty Therapeutics, Inc.: Honoraria|Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Thomas Valmont, BS, Roche: Honoraria|Roche: This project has been funded by BARDA (HHSO100201600038C). Séverine Louvel, PhD, F. Hoffmann-La Roche Ltd: employee of the company Claudia Zampaloni, n/a, F. Hoffmann-La Roche Ltd.: Full time employee of Roche
2941. Racial and Ethnic Disparities in the Care Cascade for Children with Perinatal Hepatitis C Virus (HCV) infection in the United States (US)
Authors: Rose Curtis Megan , Buzzee Ben , Biondi Breanne E , Linas Benjamin P , Ciaranello Andrea L , Epstein Rachel L
Published: November 2023

Background

From 2000-2019 HCV prevalence among pregnant people increased 10-fold in the US, in parallel to the opioid epidemic, with consequences for children, for whom perinatal transmission is the most common route of infection. Direct-acting antivirals (DAAs) were first approved for children ≥3 years old in 2019. The aim of this study was to characterize the care cascade among children with perinatal HCV and to examine racial and ethnic disparities in access to HCV care.

Methods

Analyzing 2014-2022 data from TriNetX, a research network of electronic health record data including 90 million individuals within US healthcare organizations, we defined a cohort of children born between 2010-2019 with a positive HCV ribonucleic acid (RNA) test. We defined linkage as: 1) HCV genotype test, 2) encounter with HCV as primary diagnosis, or 3) liver fibrosis testing. We tabulated the number of children prescribed DAAs and tested for sustained virologic response 12 weeks post-treatment (SVR12). We used logistic regression models to estimate odds of linkage and of receiving DAAs across racial and ethnic groups.

Results

Among 766 HCV RNA positive children, 211 (28%) linked to care. Only 40 children (5%; 19% of those linked) were prescribed DAAs and 15 (38% of those treated) had SVR12 assessed, all of whom achieved cure. Black and Hispanic children had 62% and 70% odds of linking (OR 0.38, 95%CI 0.19-0.76 and OR 0.30, 95%CI 0.18-0.51) when compared to White and non-Hispanic and children, respectively. Hispanic children had 72% lower odds of receiving DAAs compared with non-Hispanic children (OR 0.28, 95%CI 0.08-0.94). Disparities persisted for linkage when adjusted by region for Black and Hispanic children (OR 0.38, 95% CI 0.19-0.78 and OR 0.34, 95% CI 0.20-0.59) when compared to White and non-Hispanic children, respectively.

Conclusion

Despite DAA approvals for children ≥3 years old, most children with HCV are not yet linked or treated. This is a missed opportunity to prevent later health complications. Our study is the first to characterize the HCV care cascade in a large national cohort of children eligible for DAAs. We reveal major disparities in HCV care access for children, highlighting how infectious complications of the opioid epidemic might drive intergenerational disparities in health.

Disclosures

All Authors: No reported disclosures
2180. Pseudomonas aeruginosa epidemic high-risk clones and their association with multidrug-resistant
Authors: Zurita Jeannete , Sevillano Gabriela , Solis Maria Belen , Miño Ariane Paz y , Alves Beatriz Rizkallah
Published: November 2023

Background

Pseudomonas aeruginosa (PAE) is an opportunistic pathogen associated with a variety of hospital infections. Treatment of infections caused by PAE is challenging due to the emergence of multidrug-resistant (MDR), which is associated with increased morbidity, mortality, and healthcare costs. Clonal spread and the presence of resistance genes probably explain the successful propagation of MDR. In Ecuador, data on the molecular epidemiology, as well as circulating clones, are limited. Therefore, the objective of this study is to know the population structure of PAE by identifying clones in clinical samples in Quito-Ecuador.

Methods

A significant set (45) of randomly selected clinical PAE isolates, including multidrug and non-multidrug resistant isolates, were assigned to sequence types (STs) and compared them with their antibiotic susceptibility profile. The genetic diversity was assessed by applying the multilocus sequence typing (MLST) scheme (Figure 1) and the genetic relationships between different STs were corroborated by the phylogenetic neighbor-net network (Figure 2).Figure 1.Analysis of the allelic profiles using eBURST algorithm.Figure 2.Splits Tree showing the distribution of all the sequence types obtained for the clinical Pseudomonas aeruginosa isolates studied. The Splits Tree was based on the analysis of the allelic profiles of the acsA, aroE, guaA, mutL, nuoD, ppsA and trpE genes. Asterisk mark (*) indicates the MDR isolates

Results

The analysis of seven loci, acsA, aroE, guaA, mutL, nuoD, ppsA and trpE, identified 24 different ST and the most prevalent STs were ST-3750 and ST-253. A SplitsTree was constructed with all the isolates analyzed. The majority of the MDR isolates were included in ST-3750 and ST-253, also 3 singleton ST was identified in to MDR isolates. The 20 different ST was found to non-MDR isolates, and only 3 ST were found in more the one isolates.

Conclusion

The population structure of clinical PAE presents in these isolates indicate a significant association between MDR isolates and the clonal types: all ST-3750 and ST-253 isolates were MDR. ST-3750 is closely related strains to the ST111 (CC111), and ST-253 and ST111 are a group of successful high-risk clones and widely distributed worldwide. The multiresistant-isolates studied are grouped in the most prevalent sequence types found, and the susceptible isolates correspond mainly to singleton sequence types. Therefore, these high-risk clones and their association with multidrug resistance phenotypes are contributing to the spread of MDR in Quito-Ecuador.

Disclosures

Jeannete Zurita, n/a, Pfizer: Grant/Research Support
2515. Evaluation of the Equivalency of the Oxoid Sulbactam-Durlobactam (10/10µg) Antimicrobial Disc to the CLSI M07 Broth Microdilution Frozen Reference Method
Authors: Hajek Katie L , Lovatt Amie J , Bhalerao Shilpa , Khan Nagina , Staats Dylan T , Hendrix Megan M , Holliday Nicole M , Knapp Cindy C
Published: November 2023

Background

Sulbactam-durlobactam is an intravenous (IV) investigational drug that is a combination of an IV β-lactam antibiotic (sulbactam), and a novel broad-spectrum IV β-lactamase inhibitor (durlobactam). Sulbactam-durlobactam (SUD) is being developed for the treatment of serious infections caused by Acinetobacter spp., including multidrug-resistant (MDR) strains, and carbapenem-resistant strains. A study was conducted to evaluate the performance and reproducibility of the new Thermo Fisher™ Oxoid™ sulbactam/durlobactam 10/10 μg (SUD20) antimicrobial disc (Thermo Fisher Scientific, Basingstoke, UK) in comparison to the CLSI M07/M100 broth microdilution (BMD) frozen reference method (Thermo Fisher Scientific, Oakwood Village, OH).

Methods

Oxoid SUD20 discs were tested alongside BMD frozen reference panels for the clinical and challenge portions of this study. Two lots of SUD20 discs were utilized to show inter-lot reproducibility as read by three users over three consecutive days of testing. Isolates tested included: 227 Acinetobacter baumannii, 5 Acinetobacter calcoaceticus, 5 Acinetobacter pittii, 7 Acinetobacter nosocomialis. Quality control organisms included A. baumannii NCTC 13304, and Escherichia coli ATCC 25922 using ranges provided in the CLSI M100 document. All isolates were tested in accordance with CLSI M02/ CLSI M07/M100 and EUCAST methodologies.

Results

A categorical agreement of 98% was achieved when comparing the SUD20 disc to the BMD method. Reproducibility results showed 99.3% within-reader and between-reader agreement within 3 mm of the modal value of the combined results. QC results were within the stated limits on each day of testing for each batch, and reader.

Conclusion

The SUD20 disc, when compared to the BMD method, demonstrated an equivalent level of performance against clinical breakpoints as proposed by Entasis Therapeutics. The high categorical agreement obtained by the SUD20 disc indicates that this is an acceptable method for susceptibility testing of sulbactam-durlobactam for isolates of Acinetobacter spp.

Disclosures

All Authors: No reported disclosures
2604. Contact With School-Aged Children is a Major Risk Factor for Pneumococcal Colonization in Older Adults
Authors: Wyllie Anne L , Yolda-Carr Devyn , Hislop Maikel , Mbodj Sidiya , Kennedy Harold J , McLaughlin Molly , Wurst Loren , Waghela Pari , Peno Chikondi , Alexander-Parrish Ronika , Arguedas Adriano , Gessner Bradford D , Weinberger Daniel M
Published: November 2023

Background

Important questions remain about the role of older adults in driving transmission of pneumococcus in the community. This is a critical question for understanding the potential indirect effects of using pneumococcal conjugate vaccines (PCVs) in older adults. For non-institutionalized individuals, the most likely source of adult-to-adult transmission is in the household. The goal of this study was to characterize the dynamics and risk factors for acquisition of pneumococcus in older adults.

Methods

We designed a longitudinal study to sample adults > 60 years of age living in the same household (New Haven, CT), and without younger contacts residing in the household. Saliva samples and questionnaires regarding social behaviors and health status were obtained every 2 weeks for a period of 10 weeks. DNA extracted from culture-enriched saliva was tested using qPCR for pneumococcus genes piaB and lytA.

Results

Across the two study seasons (November 2020-August 2021, November 2021-September 2022), 184 individuals from 93 households were sampled and completed all 6 visits. Overall, 31/184 (16.8%) individuals were colonized on at least one time point based on qPCR detection of piaB. Two individuals were colonized at 6/6 time points, and two others were colonized at 5/6 time points during the 10-week sampling period. In 7/93 (7.5%) households, both members were colonized, though not necessarily at the same time point. Pneumococcal colonization was substantially higher among individuals who had contact with children < 18 years as compared to those with no recent contact with children (9.4% vs 2.3%). Participants who reported recent contact with < 5 year olds and 5-9 year olds had particularly elevated prevalence (14.3%; 13.0%, respectively).

Conclusion

Pneumococcal acquisition related to adult-to-adult transmission is low. Contact with pre-school and young school-aged children was the most important factor that influenced acquisition rates of pneumococcus among older adult households.

Disclosures

Anne L. Wyllie, PhD, Co-Diagnostics: Board Member|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support Ronika Alexander-Parrish, RN, MAEd, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Adriano Arguedas, Medical director, Pfizer: Emplyee|Pfizer: Stocks/Bonds Bradford D. Gessner, M.D., M.P.H., Pfizer: I am an employee of Pfizer|Pfizer: Stocks/Bonds Daniel M. Weinberger, PhD, GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support
2642. Multipathogen Antigen Test Kit (MAK-5) – Distribution and Frequency of Viral Respiratory Diseases in Germany among Volunteers in the VACCELERATE Registry
Authors: Nacov Julia A , Salmanton-Garcia Jon , Joisten Carolin , Többen Christina , Fleig Julian , Rochel Lisa , Cremer Louise , Pana Zoi Dorothea , Schmitt Heinz-Josef , Stemler Jannik , Cornely Oliver A
Published: November 2023

Background

Currently, SARS-CoV-2 is the predominant viral respiratory pathogen. However, during winter season other viruses may cause acute respiratory infection (ARI). Most cases of non-severe ARI are not systematically tested, thus, distribution and epidemiology of these viruses is largely unknown.

VACCELERATE is the EU funded consortium dedicated to vaccine research, running a volunteer registry and promoting clinical studies.

Methods

Adult registered subjects were invited to participate. Postal address was collected to allow sending of the MAK-5 test kit (BioTeke Corporation (Wuxi) Co., Ltd., Wuxi, Jiangsu, China). The availability of low-cost, sensitive and specific rapid tests detecting 5 pathogens (ADV, influenza viruses A and B, RSV, SARS-CoV-2) from one respiratory sample allowed us to conduct a feasibility study on their relative contribution to the burden of disease (BoD) outside any medical setting. Participants were instructed to use the test if respiratory symptoms were present for at least 24h. Test results and information on related symptoms and vaccinations were self-reported by e-mail. Underlying diseases were known from initial registration.

Results

Between 07-Dec-2022 and 01-May-2023, we processed test results from 1036 (52.1%) of 1990 participants. Including co-infections (N=18; 4.7%), we detected 384 infections: 178 (46.4%) SARS-CoV-2, 59 (32.8%) 104 (27.1%) RSV and 74 (19.3%) influenza A virus. ADV infection was detected in 10 (2.6%) volunteers and influenza B virus in 6 (1.6%). A total of 98.8% of tests yielded valid results, while 12 (1.2%) tests were invalid (negative control). While RSV was the most frequently detected virus in the first week of assessment (calendar week (CW) 49), there was a shift to Influenza A virus in CW 50, followed by a SARS-CoV-2 peaks in CW 51/22, 05/23, and 08/23.

CW49/2022-CW18/2023

Conclusion

This type of study allows assessment of the BoD by ARI pathogens before medical attention is sought and provides insights into the course of the annual (winter) infection waves down to a local level. Frequency of detected viruses varied over time. While SARS-CoV-2, RSV and influenza A virus were detected frequently, ADV and influenza B virus infections were rare.

Disclosures

Heinz-Josef Schmitt, n/a, VACCELERATE: Advisor/Consultant Jannik Stemler, -, Ministry of Education and Research (BMBF): Grant/Research Support Oliver A. Cornely, MD PhD, DZIF: Advisor/Consultant|DZIF: Board Member|DZIF: Grant/Research Support|DZIF: Honoraria|DZIF: Stocks/Bonds
2702. A Case Series of Kidney Transplant Recipients on Belatacept with CMV Infection in a Single Academic Center
Authors: Feller Fionna , Cohen Elizabeth , Marvin Jennifer , Virmani Sarthak , Malinis Maricar F
Published: November 2023

Background

Cytomegalovirus (CMV) infection has been increasingly observed among kidney transplant recipients (KTR) on belatacept for immunosuppression. Clinical outcomes of CMV infection among KTR on belatacept are not well described. We aimed to evaluate further in this case series from a single center.

Methods

We performed a retrospective study of KTR on belatacept who developed CMV infection and were hospitalized between the period of 1/1/2017-12/31/2022. Data collected were: demographics, transplant and CMV parameters, allograft outcomes, and co-infection. Descriptive statistics was performed.

Results

Of the 1,468 KTR, 387 received belatacept and have been hospitalized. Ten of the 387 (2.6%) had CMV infection. Among the 10, 60% were female and 20% were black. Median age was 59 years (range 32-78) and median time from transplant to first CMV infection was 6 months (range 1-228). Five had CMV DNAemia and 5 had CMV disease. Among the 5 with CMV DNAemia, 1 was CMV D+/R- and 4 was CMV R+. Of the 5 with CMV disease, 2 were CMV D+/R- and 3 were CMV R+. Corresponding clinical outcomes are reported in Figure 1.

Belatacept administration was uninterrupted in 7/10 KTR. Of these 7, the highest median peak and the longest duration of CMV DNAemia were seen in the CMV D+/R- only. CMV infection relapse (3/7), allograft rejection (1/7), and allograft loss (1/7) occurred in those with uninterrupted belatacept infusion. Bacterial co-infections occurred in 6/10 KTR. All survived > 90 days after CMV diagnosis. KTR with interrupted belatacept (n=3) were eventually changed to alternative regimen of azathioprine, tacrolimus, and everolimus.Table 1.Patient demographicsFigure 1.CMV clinical outcomes

Conclusion

High risk KTR who received uninterrupted belatacept at time of CMV infection were observed to have the high level and prolonged duration of CMV DNAemia. Renal allograft rejection/loss and CMV relapse were also observed with uninterrupted belatacept administration regardless of CMV donor serostatus. This limited data suggests that KTR with either CMV D+/R- or CMV R+ may have poor clinical outcomes with continued belatacept administration in the setting of CMV infection. Prospective, multi-center studies are needed to better assess the impact of belatacept management during CMV infection.

Disclosures

All Authors: No reported disclosures
2713. Risk factors and clinical presentation of Herpes Simplex Virus Encephalitis in cancer patients
Authors: Kodama Rich , Kamboj Mini
Published: November 2023

Background

Herpes Simplex Virus Encephalitis (HSVE) can have lifelong sequelae. Presentation can be nonspecific in cancer patients. Cerebrospinal fluid testing may be falsely negative early in illness [1]. New immune-based or targeted radiation (RT) modalities may change risk, incidence of HSVE in cancer patients.

Methods

Retrospective study at Memorial Sloan Kettering Cancer Center (MSK). Review of records of patients with CSF meningitis/encephalitis (ME) PCR panels from 8/1/2016 to 7/31/2022. All unique patients who received brain RT at MSK during those dates were used to calculate incidence rates.

Results

2749 patients had 5497 CSF analyses with ME panel. Of these, 12 tests from 10 patients showed HSV-1 or -2; 1 patient had relapsing HSVE and 3 positive HSV2 tests each done at least 6 months apart.

Table 1 shows 10 patients with HSVE. 8 had solid tumors, 6 with receipt of chemo- or immunotherapy within 30 days. All solid tumor patients with HSVE had brain RT; 6 received steroids. 1 patient with relapsing HSVE was on immune checkpoint inhibitor (ICI). 4/8 patients with MRIs (Table 2) lacked typical findings; 4/8 patients with EEGs had focal temporal seizure activity. CSF pleocytosis was absent in 4/10 cases. 5 patients had residual deficits. 4 died due to progression of disease.

Incidence of HSVE with brain radiation was 2.6/10,000 patient-years.

Conclusion

General population incidence of HSVE ranges from 1-4 per million population per year [2]. Those receiving cancer treatment and brain RT have elevated HSVE risk. We found the risk after brain RT is much higher: 2.6/10,000 person-years. Only 1 of 10 patients in our series made a full recovery.

Other key findings include:

Limitations:

Disclosures

Mini Kamboj, MD , ASCO: speaker fee|Medscape: speaker fee|MJH life sciences: speaker fee|Regeneron: Advisor/Consultant|Web md: speaker fee