Citations

AbstractBackgroundPreviously, we found that female sex is associated with greater pathology burden in early‐onset Alzheimer’s disease (EOAD) in the Longitudinal EOAD Study (LEADS). Here, we have expanded our analyses by adding APOE‐ε4 carrier status as a further predictor of EOAD pathologic burden.MethodWe included 180 EOAD LEADS participants with available APOE genotype, Flortaucipir PET, Florbetaben PET, and MRI data. Demographic and biomarker differences were analyzed using ANOVA. EOAD participants were split by sex and APOE‐ε4 carrier status. Box plots were created in R and a voxel‐wise multiple linear regression in SPM12 yielded statistical brain maps of gray matter density (GMD), amyloid and tau burden.ResultCompared to males, EOAD females showed significantly greater global amyloid uptake (mean SUVR, p=0.002) and greater tau SUVR in the MetaROI, Braak 3&4 and 5&6 regions (p=0.0007, p=0.001, p=0.01, resp., Table 1). Female APOE‐ε4 carriers showed greater tau SUVR in Braak regions 1&2 than female non‐carriers (p<0.01, Figure 2B). Male APOE‐ε4 carriers showed trend‐level thinner entorhinal cortex than male non‐carriers (p=0.06, Figure 1). Interestingly however, femaleAPOE‐ε4 non‐carriers showed greater global amyloid SUVR than female carriers (p<0.01, Figure 2A). Further, APOE‐ε4 non‐carriers showed significantly thinner medial temporal cortices than carriers in both sexes (M, p<0.05; F, p<0.01). Male APOE‐ε4 non‐carriers also showed significantly lower mean cortical thickness than male carriers (p<0.05, Figure 1). Female APOE‐ε4 non‐carriers showed trend‐level lower mean cortical thickness than female carriers (p=0.06, Figure 1). The FWE corrected SPM12 maps showed significantly greater GM atrophy in the right temporal lobe and greater amyloid burden in a right lateralized occipitoparietal pattern in female APOE‐ε4 non‐carriers compared to female carriers. Further, male APOE‐ε4 non‐carriers showed greater tau uptake in the left frontal lobe than male carriers (Figure 3).ConclusionThese results suggest that APOE‐ε4 non‐carrier status is associated with greater atrophy, amyloid and tau deposition in EOAD. This might be due to the presence of other strong genetic drivers of disease pathology in EOAD.

AbstractBackgroundTo gather user input iteratively to develop a matching algorithm for peer‐to‐peer support and to assess the feasibility and usability of a web‐based program to conduct matching.Method32 caregivers of persons with dementia (PwD) participated in semi‐structured focus groups and completed surveys to provide input regarding characteristics deemed valuable in someone they would choose to be connected with for emotional support. Through an iterative process as new information emerged, a web‐based prototype and matching algorithm were developed. Caregivers interacted with the prototype and provided feedback indicating ease of accessibility and use, initial impression, and comfort/satisfaction with profile content.ResultAll 32 caregivers (age 40‐90, education 12/GED‐20, sex 88% female, 31% Black/African‐American) completed online profiles. Of those who interacted with the prototype, 23 completed the feedback survey, on which 87% had no or only mild difficulty accessing the site, 91% had no difficulty with technology once there, 86% had a very or quite positive initial impression, 91% found it very or quite easy to navigate, 87% rated a very or quite high level of comfort with completing the personal profile questions, and 82% felt very or quite confident the questions asked would lead to a good match.ConclusionA large majority of caregivers of PwD demonstrated the web‐based platform was easy to access and navigate, provided a positive experience, and gathered information that would lead to a good supportive relationship with another caregiver. Phase II will optimize the design and algorithm and evaluate the matching process in 350 caregivers.

Epithelial-to-mesenchymal transition (EMT) is key to tumor aggressiveness, therapy resistance, and immune escape in breast cancer. Because metabolic traits might be involved along the EMT continuum, we investigated whether human breast epithelial cells engineered to stably acquire a mesenchymal phenotype in non-tumorigenic and H-RasV12-driven tumorigenic backgrounds possess unique metabolic fingerprints. We profiled mitochondrial–cytosolic bioenergetic and one-carbon (1C) metabolites by metabolomic analysis, and then questioned the utilization of different mitochondrial substrates by EMT mitochondria and their sensitivity to mitochondria-centered inhibitors. “Upper” and “lower” glycolysis were the preferred glucose fluxes activated by EMT in non-tumorigenic and tumorigenic backgrounds, respectively. EMT in non-tumorigenic and tumorigenic backgrounds could be distinguished by the differential contribution of the homocysteine-methionine 1C cycle to the transsulfuration pathway. Both non-tumorigenic and tumorigenic EMT-activated cells showed elevated mitochondrial utilization of glycolysis end-products such as lactic acid, β-oxidation substrates including palmitoyl–carnitine, and tricarboxylic acid pathway substrates such as succinic acid. Notably, mitochondria in tumorigenic EMT cells distinctively exhibited a significant alteration in the electron flow intensity from succinate to mitochondrial complex III as they were highly refractory to the inhibitory effects of antimycin A and myxothiazol. Our results show that the bioenergetic/1C metabolic signature, the utilization rates of preferred mitochondrial substrates, and sensitivity to mitochondrial drugs significantly differs upon execution of EMT in non-tumorigenic and tumorigenic backgrounds, which could help to resolve the relationship between EMT, malignancy, and therapeutic resistance in breast cancer.

Abstract Background URIs are the most common indication for outpatient antibiotic prescribing. Given high rates of unnecessary prescribing, these indications have been identified as a high-priority target for outpatient antimicrobial stewardship programs (ASP). Our primary objective was to evaluate the impact of a system-wide, multifaceted, outpatient ASP intervention bundle on unnecessary antibiotic prescribing for URI. Methods This quasi-experimental study was conducted from 2019 to 2021. ICD-10 codes for URIs were grouped into 3 tiers (i.e., tier I = antibiotics always indicated, tier II = sometimes, tier III = never). Encounters from 5 care specialties (i.e., family medicine, community internal medicine, express care, pediatrics, and emergency department) with a tier III URI primary ICD-10 code but without a secondary tier I or tier II code were included. COVID-19 ICD-10 codes were excluded. Interventions included construction of a prescribing data model, dissemination of clinician prescribing data and education, promotion of symptom management strategies, a patient-facing commitment poster, and a pre-populated URI order panel. Tools were designed at a system level and implemented by regional champions beginning in the 3rd quarter of 2020. The primary outcome was the rate of antibiotic prescribing, and the secondary outcome and counterbalance measure was the rate of repeat URI-related healthcare contact within 14 days. Outcomes were analyzed with chi-square with an α level of 0.05. Results A total of 147403 encounters were included. The overall antibiotic prescribing rate decreased from 24.1% to 12.3% between 2019 and 2021 (p&lt; 0.01). Significant reductions in tier III antibiotic prescribing were demonstrated for each region, care specialty, and syndrome evaluated (Table 1). A reduction in repeat healthcare contact was seen across the total cohort (9.5% in 2019 vs. 8.3% in 2021, p&lt; 0.01); decreases in repeat contact rates were observed in those not initially receiving an antibiotic (10.3% vs. 8.6%, p&lt; 0.01), but not in those who initially received an antibiotic (6.8% vs. 6.8%, p = 0.94). Tier III URI encounter level antimicrobial prescribing rates by region, care specialty, and syndrome Conclusion A multifaceted, outpatient ASP intervention bundle decreased rates of unnecessary antimicrobial prescribing without increasing rates of 14-day repeat URI-related healthcare contact. Disclosures Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support Evan Draper, PharmD, Gilead Foundation: Grant/Research Support Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.

Abstract Background Multi-drug resistant (MDR) pathogens are a continuously evolving threat for which there are limited effective treatment modalities. Omadacycline (OMC) is a novel oral and intravenously administered aminomethylcycline with potent in-vitro activity against MDR gram-negative and gram-positive pathogens. Post-marketing data investigating its potential place in the antibiotic armamentarium is limited. This study aimed at describing the clinical success and tolerability of patients receiving OMC for various infections. Methods This was a multicenter, retrospective, observational study conducted from January 2020 to March 30, 2022. We included all patients ≥ 18 years of age that received OMC for any infection not related to Mycobacterium spp. for ≥72 hours. The primary outcome was clinical success at 30 days, defined as survival, the absence of persistence or re-emergence of infection during or after therapy, and the absence of escalation or alteration of OMC. Incidence of adverse effects while on OMC and reasons for OMC utilization were also analyzed. Results This analysis included 19 patients from 10 distinct academic centers. The median age was 50 years (IQR, 37-63), 58% were male, 63% were Caucasian, and the median APACHE II, Charlson and SOFA scores were 10 (IQR 5-12.5), 4 (IQR 2-6.3), and 1 (IQR 0 – 2.25), respectively. Most patients had a bone and joint (8/19, 42.1%) or intra-abdominal infections (4/19, 21.1%), all with positive cultures. Eight patients (44.1%) had a polymicrobial infection and 4 (22.2%) had bacteremia. The most common pathogens encountered were Carbapenem-resistant A. baumannii (5/19, 27.8%), E. coli (5/19, 27.8%), Vancomycin-resistant Enterococcus spp. (4/19, 22.2%), and K. pneumoniae (3/19, 16.7%). Clinical success was observed in 14 patients (74%) and 7 (36.8%) received combination therapy. Adverse drug reactions were reported in 3 patients (15.8%) and of those patients, none discontinued therapy. Reasons for prescribing OMC were mostly attributed to oral availability (12/14, 85.7%) and resistance to other agents (7/14, 50%). Conclusion OMC demonstrated clinical effectiveness and safety against a large number of MDR pathogens. More robust, prospective, comparative studies are needed to confirm our preliminary findings. Disclosures P. Brandon Bookstaver, PharmD, Spero Therapeutics: Advisor/Consultant.

Abstract Background Beta-lactam therapeutic drug monitoring (BL TDM; drug level testing) can facilitate improved outcomes in critically ill patients. Yet less than 20% of hospitals have implemented BL TDM. The purpose of this study was to characterize provider perceptions and key considerations for successful implementation of BL TDM. Methods This was a sequential mixed methods study from 2020 to 2021 of stakeholders at three academic medical centers with varying degrees of BL TDM implementation - Mayo Clinic (BL TDM not implemented), University of Florida Health Shands (partially implemented), and Royal Brisbane and Women’s Hospital (fully implemented). Stakeholders completed a survey to characterize their knowledge, perceptions, and experience with BL TDM. A diverse group of 30 respondents were then purposively sampled for semi-structured interviews. Results from the two strands were integrated, themes were identified, and findings were situated within implementation science frameworks. Results Among the 138 survey respondents (22% response rate), the majority were physicians (38%) and pharmacists (33%). 71% practiced in critical care and 21% in infectious diseases. The majority of respondents felt BL TDM was relevant to their practice and improved medication effectiveness and safety (Figure 1). Two implementation themes were identified: individual internalization and organizational features. Individuals needed to internalize, make sense of, and agree to BL TDM implementation which was positively influenced by repeated exposure to evidence and expertise. The process of internalization seemed more complex with BL TDM than with other antibiotics (i.e., vancomycin). Organizational considerations relevant to BL TDM implementation included adequate physical and informational infrastructure, access to trained personnel, supportive governance/leadership, and robust process and workflow development. Conclusion We found broad enthusiasm about the relevance and potential benefits of BL TDM among stakeholders. Prior literature suggested the primary barrier to implementation was assay availability, but we identified many more individual and organizational attributes which impacted the scale and spread of BL TDM. Disclosures Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Allecra: Grant/Research Support|Merck: Advisor/Consultant|Nevakar: Advisor/Consultant|Nevakar: Grant/Research Support|Premier Healthcare Solutions: Honoraria|Spero: Advisor/Consultant|SuperTrans Medical: Advisor/Consultant|SuperTrans Medical: Grant/Research Support|Takeda: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant.