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Item 646. Clinical and microbiological outcomes of omadacycline for pulmonary Mycobacterium abscessus complex(Oxford University Press, 2025-01-29) Al Musawa, Mohammed; Vemula, Raaga; Mammadova, Mehriban; Wadle, Carly; Muscarella, Anahit; Cimino, Christo; Zeuli, John; Howard, Catessa A.; Butt, Saira; Mejia-Chew, Carlos; Hamad, Yasir; Ong, Aaron; Cohen, Keira A.; Kaip, Emily A.; Tupayachi-Ortiz, Maria G.; Fiske, Christina T.; Judd, Chloe; Caniff, Kaylee E.; Rybak, Michael J.; Medicine, School of MedicineBackground: Mycobacterium abscessus complex (MABC) is a difficult-to-treat infection due to antibiotic resistance. Our study aimed to assess omadacycline’s (OMC) clinical and microbiological outcomes for the treatment of pulmonary MABC. Methods: A retrospective study was carried out across 12 US medical institutions from 1/2018-4/2023 to examine the clinical outcomes, and tolerability of OMC treatment for pulmonary MABC. Patients aged ≥ 18 years who were treated with OMC for ≥ 3 months were included. The primary outcome was clinical success at 3, 6, and 12 months. The secondary outcomes were sputum culture conversion rate, adverse effects, and clinical success by subspecies and macrolide susceptibility. Results: Thirty-five patients were included in this analysis. Most patients were female (74.3%) and Caucasian (74.3%), with a median (IQR) age of 61 years (51–70). Subspeciation was performed for 22 isolates with predominant M. abscessus subspecies (77.3%). Moreover, coinfection with other NTM species was present in 28.6% of cases where Mycobacterium avium complex was present in 8 cultures. Sixty-eight percent of the MABC isolates were confirmed to be macrolide resistance; half (12/24, 50.0%) were evident by the presence of functional erm gene, while the other half by antimicrobial susceptibility (Table 3). Of the remaining isolates, 14% were macrolide-susceptible, while no information was reported in 17%. The median (IQR) treatment duration of OMC was 8 months (3.9 – 15.7). The most commonly co-administered antibiotics were intravenous amikacin, imipenem/cilastatin, inhaled amikacin and clofazimine with the same percentage (42.9%) (Table 1). Overall, MABC clinical success was observed in 71.4%, 89.7%, and 90.9% in 3-, 6- and 12 months, respectively (Table 3). Adverse effects reported in 34.3%. The most common side effects were gastrointestinal intolerance (25.7%) and hepatoxicity (11.4%), which led to drug discontinuation in 22.9%. Conclusion: OMC treatment showed clinical success in > 70% of patients with pulmonary MABC including patients with macrolide resistant strains for more than 3 months. However, larger studies are needed to validate the outcomes beyond 12 months.Item 211. Defining Optimal Sampling Times for Cefepime Therapeutic Drug Monitoring in Clinical Practice(Oxford University Press, 2025-01-29) Rhodes, Nathaniel J.; Smith, Brandon; Shields, Ryan K.; Pan, Samantha; Weslander, Erin; Galvin, Shannon; Hughes, Jasmine; Hughes, Maria-Stephanie; Sime, Fekade B.; Roberts, Jason A.; Kiel, Patrick J.; Neely, Michael N.; Scheetz, Marc H.; Medicine, School of MedicineBackground: Clinicians performing beta-lactam therapeutic drug monitoring (TDM) lack evidence on when levels should ideally be drawn after a dose. Herein, we define the optimal timing (i.e., optimal sampling) for cefepime using real-world TDM data to validate our approach. Methods: De-identified data from two centers performing routine cefepime TDM were extracted by InsightRX and served as an external validation cohort. Plasma cefepime was quantified using validated LC-MS/MS assays for TDM and dosing was protocolized at each site. CRRT and ECMO patients were included but other dialysis patients were not. Bias (MPE) and precision (RMSE) of a non-parametric prior were assessed. Multiple-model optimal (MM-opt) sampling strategies were estimated for the first 24 hours of treatment. To mirror clinical practice, one- and two-sample designs were evaluated. Dose and covariate values informed optimal sampling times. Bayesian PK exposures were compared using all samples, trough-only sampling, or using a single optimally timed sample. AUCs were calculated from the posteriors. For fT >MIC analysis, the MIC was fixed at 8 mg/L. We used Pmetrics 2.1.1 for R. Results: 116 patients (42% female; median age, CRCL, and weight: 62 years, 76 mL/min, and 80 kg, respectively) contributed 235 levels. The PK model demonstrated acceptable bias and precision (-6% MPE, 30.9 RMSE) as a prior for estimating exposures from the TDM data (Fig1). For a one-sample approach, the most common MM-opt sampling times varied (Fig2) but were often a mid-point or trough. In the two-sample approach, sample one was often a mid-point and sample two was often a trough (Fig3). First 24-hr AUC and fT>MIC did not significantly differ using all available samples for analysis vs. limiting sampling to a single optimized time point vs. limiting sampling to a trough-only approach (P >0.05 for all comparisons; Fig4). Conclusion: Optimal cefepime sampling times depended on dosing regimen, and renal disposition. When limited to a single sample, optimal sampling times for cefepime TDM were often midpoint/trough levels, but when two samples were obtained the optimal sampling times were often a mid-point followed by a trough. Estimation of PK and PK/PD exposures was not significantly worse when using a validated Bayesian prior and a trough-only sampling approach.Item P-581. Racial/Ethnic Disparities of Renal Outcomes in People with HIV (PWH) on Tenofovir Alafenamide (TAF) Based Antiretroviral Treatment (ART) Regimens in the Real World(Oxford University Press, 2025-01-29) Gupta, Samir K.; Canada, Robert; Naik, Sarjita; Huang, Xiwen; Weinberg, Amy; Temme, Lauren; Tao, Li; Chiang, Betty; Chokkalingam, Anand; Slim, Jihad; Medicine, School of MedicineBackground: The risk of chronic kidney disease (CKD) is higher in PWH than HIV-negative persons. Black communities are not only disproportionately affected by HIV but also more at risk for kidney disease than other races. Despite Black PWH generally being underrepresented in clinical trials, the BRAAVE trial showed switching to bictegravir/emtricitabine/TAF demonstrated non-inferior efficacy and similar tolerability, including renal safety, compared to prior ART regimens in this group. With this analysis, we aim to assess whether these trial results translate to the real-world setting among Black PWH using a retrospective cohort analysis. Methods: The descriptive analysis was conducted using IQVIA ambulatory electronic medical record (EMR) database (November 2015 – July 2023). The study population included PWH (≥ 18 years) who were newly prescribed with ART regimens. Study endpoints evaluated the incidence of azotemia, Fanconi syndrome, renal tubular acidosis (RTA), renal toxicity, acute kidney injury (AKI), and CKD stages using diagnosis codes, stratified by racial group (Black and non-Black) and treatment with TAF-based regimens using prescription codes. Incidence rates were reported. The analysis was conducted using ATLAS Version 2.12.1. Results: Overall, 4,562 Black and 5,946 non-Black PWH were identified on TAF-containing regimen, with 7,933 and 10,198 person-years of follow-up, respectively (Table 1). Compared to non-Black PWH, Black PWH were more likely to be female, have diabetes and hypertension. Black PWH on TAF had a higher incidence of advanced CKD and similar incidence rates of azotemia, renal toxicity, AKI, and RTA compared to non-Black PWH on TAF (Table 2). When stratified by baseline hypertension, no significant differences in the incidence of renal disease were observed between Black and non-Black PWH. There were no cases of Fanconi syndrome in the study cohort. Conclusion: Despite the inherent limitations of real-world data, this analysis included a large cohort of Black PWH on TAF-containing ART and showed a low incidence of RTA and AKI, despite predisposition to increased rates of renal decline or safety outcomes in Black PWH starting ART.Item Sex and APOE ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease(Wiley, 2025) Peterson, Amalia; Sathe, Aditi; Zaras, Dimitrios; Yang, Yisu; Durant, Alaina; Deters, Kacie D.; Shashikumar, Niranjana; Pechman, Kimberly R.; Kim, Michael E.; Gao, Chenyu; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Gifford, Katherine A.; Wilson, Jo Ellen; Cambronero, Francis E.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Habes, Mohamad; Wang, Di; Zhang, Panpan; Schilling, Kurt; Alzheimer's Disease Neuroimaging Initiative (ADNI); BIOCARD Study Team; Alzheimer's Disease Sequencing Project (ADSP); Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Schneider, Julie; Barnes, Lisa L.; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Hohman, Timothy J.; Archer, Derek B.; Radiology and Imaging Sciences, School of MedicineIntroduction: The effects of sex and apolipoprotein E (APOE)-Alzheimer's disease (AD) risk factors-on white matter microstructure are not well characterized. Methods: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status. Results: Sex differences in FAFWcorr in projection tracts and APOE ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. Discussion: There are prominent differences in white matter microstructure by sex and APOE ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. Highlights: Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non-carriers.Item P-2109. Culture-Free Identification of Microbes in Seconds Directly from Clinical Samples using the MasSpec Pen Technology(Oxford University Press, 2025-01-29) Downey, Rachel; Kumar, Manoj; Kirkpatrick, Lindsey M.; Hauger, Sarmistha Bhaduri; Johnson, Coreen; Dunn, James; Jackobs, Faith; Keating, Michael; Eberlin, Livia; Pediatrics, School of MedicineBackground: Broad spectrum antibiotics are often used empirically in cases of suspected invasive infection requiring surgical intervention while awaiting results of conventional testing (cultures and molecular tests). Rapid and accurate diagnosis of the etiologic pathogens is critical to allow for selection of targeted antibiotics and improve outcomes for patients. We present current results of a large, multi-center clinical study using the MasSpec Pen (MSPen) technology to characterize the metabolic profiles of clinically relevant microbes in culture isolates and apply the technology to culture-independent identification of infectious agents directly in clinical samples. Methods: The MSPen allows direct sample analysis using a solvent droplet followed by immediate mass spectrometry analysis, with total acquisition time of ∼15 seconds (fig 1). In this study 785 samples (635 isolates and 150 clinical specimens) were analyzed using this technology to create distinct metabolic profiles to differentiate bacterial pathogens. 80% of data were used as a training set to develop such profiles; 20 percent of data were used as a test set to identify bacterial infection. Results: We identified over 400 bacterial metabolites and lipids in 10 different microbial species and compiled a unique metabolic profile for each that was used to directly identify specific microbes in cultures and clinical specimens. Among culture isolates, our statistical classifiers were able to achieve 99% accuracy for Gram-typing, and 99% accuracy among 10 bacteria in the test set (fig 2). Using species-specific metabolites and lipids, we were able to identify Pseudomonas aeruginosa directly from 3 infected specimens and Staphylococcus epidermidis directly from infected bone. Conclusion: Our results show the incredible promise that direct MSPen analysis has for rapid, culture-independent identification of bacteria from patient tissues. We are working to build classifiers to differentiate bacteria by specific m/z values to improve identification in tissue samples.Item Age-dependent phenotypes of cognitive impairment as sequelae of SARS-CoV-2 infection(Frontiers Media, 2025-01-07) Gonzalez Aleman, Gabriela; Vavougios, George D.; Tartaglia, Carmela; Uvais, Nalakath A.; Guekht, Alla; Hosseini, Akram A.; Lo Re, Vincenzina; Ferreccio, Catterina; D'Avossa, Giovanni; Zamponi, Hernan P.; Figueredo Aguiar, Mariana; Yecora, Agustin; Ul Haq Katshu, Mohammad Zia; Stavrou, Vasileios T.; Boutlas, Stylianos; Gourgoulianis, Konstantinos I.; Botero, Camila; González Insúa, Francisco; Perez-Lloret, Santiago; Zinchuk, Mikhail; Gersamija, Anna; Popova, Sofya; Bryzgalova, Yulia; Sviatskaya, Ekaterina; Russelli, Giovanna; Avorio, Federica; Wang, Sophia; Edison, Paul; Niimi, Yoshiki; Sohrabi, Hamid R.; Mukaetova Ladinska, Elizabeta B.; Neidre, Daria; de Erausquin, Gabriel A.; Psychiatry, School of MedicineCognitive changes associated with PASC may not be uniform across populations. We conducted individual-level pooled analyses and meta-analyses of cognitive assessments from eight prospective cohorts, comprising 2,105 patients and 1,432 controls from Argentina, Canada, Chile, Greece, India, Italy, Russia, and the UK. The meta-analysis found no differences by country of origin. The profile and severity of cognitive impairment varied by age, with mild attentional impairment observed in young and middle-aged adults, but memory, language, and executive function impairment in older adults. The risk of moderate to severe impairment doubled in older adults. Moderately severe or severe impairment was significantly associated with infection diagnoses (chi-square = 26.57, p ≤ 0.0001) and the severity of anosmia (chi-square = 31.81, p ≤ 0.0001). We found distinct age-related phenotypes of cognitive impairment in patients recovering from COVID-19. We identified the severity of acute illness and the presence of olfactory dysfunction as the primary predictors of dementia-like impairment in older adults.Item The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI)(Wiley, 2025) Mormino, Elizabeth C.; Biber, Sarah A.; Rahman-Filipiak, Annalise; Arfanakis, Konstantinos; Clark, Lindsay; Dage, Jeffrey L.; Detre, John A.; Dickerson, Bradford C.; Donohue, Michael C.; Kecskemeti, Steven; Hohman, Timothy J.; Jagust, William J.; Keene, Dirk C.; Kukull, Walter; Levendovszky, Swati R.; Rosen, Howie; Thompson, Paul M.; Villemagne, Victor L.; Wolk, David A.; Okonkwo, Ozioma C.; Rabinvovici, Gil D.; Rivera-Mindt, Monica; Foroud, Tatiana; Johnson, Sterling C.; Neurology, School of MedicineThe presence of multiple pathologies is the largest predictor of dementia. A major gap in the field is the in vivo detection of mixed pathologies and their antecedents. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address this gap. The ADRCs longitudinally follow ≈ 17,000 participants, ranging from cognitively unimpaired to dementia, arising from Alzheimer's disease (AD) and related dementias (ADRD; e.g., AD, Lewy body disorders, vascular). Motivated by the Alzheimer's Disease Neuroimaging Initiative's (ADNI) impact, the ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) was formed. Leveraging existing ADRC infrastructure, CLARiTI will integrate standardized imaging and plasma collection to characterize mixed pathologies and use community-engaged research methods to ensure that ≥ 25% of the sample is from underrepresented populations (e.g., ethnoculturally minoritized, low education). The resulting ADRD profiles, within a more diverse sample, will provide key resources for ADRCs and an unprecedented, more generalizable publicly available imaging-plasma dataset. HIGHLIGHTS: In vivo detection of mixed pathologies is critical for Alzheimer's disease and related dementias research. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address gaps related to mixed pathologies. The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will enhance this national program by adding standardized imaging and plasma collection to existing ADRC infrastructure. This effort will provide key resources for ADRCs and an unprecedented publicly available imaging-plasma-neuropath dataset.Item Development and Validation of a Routine Electronic Health Record-Based Delirium Prediction Model for Surgical Patients Without Dementia: Retrospective Case-Control Study(JMIR, 2025-01-09) Holler, Emma; Ludema, Christina; Ben Miled, Zina; Rosenberg, Molly; Kalbaugh, Corey; Boustani, Malaz; Mohanty, Sanjay; Surgery, School of MedicineBackground: Postoperative delirium (POD) is a common complication after major surgery and is associated with poor outcomes in older adults. Early identification of patients at high risk of POD can enable targeted prevention efforts. However, existing POD prediction models require inpatient data collected during the hospital stay, which delays predictions and limits scalability. Objective: This study aimed to develop and externally validate a machine learning-based prediction model for POD using routine electronic health record (EHR) data. Methods: We identified all surgical encounters from 2014 to 2021 for patients aged 50 years and older who underwent an operation requiring general anesthesia, with a length of stay of at least 1 day at 3 Indiana hospitals. Patients with preexisting dementia or mild cognitive impairment were excluded. POD was identified using Confusion Assessment Method records and delirium International Classification of Diseases (ICD) codes. Controls without delirium or nurse-documented confusion were matched to cases by age, sex, race, and year of admission. We trained logistic regression, random forest, extreme gradient boosting (XGB), and neural network models to predict POD using 143 features derived from routine EHR data available at the time of hospital admission. Separate models were developed for each hospital using surveillance periods of 3 months, 6 months, and 1 year before admission. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC). Each model was internally validated using holdout data and externally validated using data from the other 2 hospitals. Calibration was assessed using calibration curves. Results: The study cohort included 7167 delirium cases and 7167 matched controls. XGB outperformed all other classifiers. AUROCs were highest for XGB models trained on 12 months of preadmission data. The best-performing XGB model achieved a mean AUROC of 0.79 (SD 0.01) on the holdout set, which decreased to 0.69-0.74 (SD 0.02) when externally validated on data from other hospitals. Conclusions: Our routine EHR-based POD prediction models demonstrated good predictive ability using a limited set of preadmission and surgical variables, though their generalizability was limited. The proposed models could be used as a scalable, automated screening tool to identify patients at high risk of POD at the time of hospital admission.Item P-481. Characterization of People with HIV Who Are Virologically Suppressed with Treatment Experience Using a US Real-World Database(Oxford University Press, 2025-01-29) Gupta, Samir K.; Cappell, Katherine; Price, Kwanza; Bonafede, Mac; Gruber, Joshua; Mezzio, Dylan; Navadeh, Soodi; Sedgley, Robert; Segal-Maurer, Sorana; Medicine, School of MedicineBackground: People living with HIV who are virologically suppressed with treatment experience (PWH-VSTE) are often prescribed complex multi-tablet and/or multi-dose antiretroviral (ARV) regimens with increased risk of poor clinical outcomes due to adherence challenges, adverse events, and/or drug interactions. This population is not well characterized, with no universal definition. We conducted a retrospective, observational analysis of a large US database to characterize PWH-VSTE and better understand this subset of PWH. Methods: PWH with treatment experience (PWH-TE) with ≥ 2 ARV lines of therapy (LOT) were identified from the Veradigm Network electronic health record (EHR) database linked with claims during the study period, Jan 2015–Dec 2022. We defined VSTE as virologic suppression (HIV-1 RNA ≤ 200 copies/mL) during the LOT in which ≥ 1 of the following treatment criteria were met: (1) used ≥ 1 “complex” ARV regimen; (2) resistance to exactly 2 ARV classes out of nucleoside or non-nucleoside reverse transcriptase inhibitors (NRTI, NNRTI), integrase strand transfer inhibitor (INSTI), and protease inhibitor (PI); (3) prior exposure to exactly 2 ARV classes out of NNRTI, INSTI, and PI (Figure). For inclusion, PWH-VSTE were aged ≥ 18 years and had an HIV diagnosis, continuous claims enrollment, and EHR activity. We report the proportion of PWH-TE meeting VSTE-defining criteria, and their characteristics. Results: Of 308,088 PWH-TE, 13,192 (4%) met ≥ 1 VSTE-defining criterion (9957 met Criterion 1 and 8272 met Criterion 3); 6907 (52%) were eligible for analysis (Figure). PWH-VSTE were mostly male (71%), Black (41%), aged 50–59 years (36%), using Medicaid (55%), from the South (39%), and had a mean (SD) Charlson Comorbidity Index of 6.1 (2.6) (Table). Among those with data during the baseline period (6-month period prior to index date), 48.2% (990/2052) had a viral load of ≤ 200 copies/mL. Resistance testing was done for 13.3% of PWH-VSTE during the baseline period, but only 0.2% had results available. Conclusion: In this large, real-world database, PWH-VSTE comprised 4% of PWH-TE, were mostly male, and had a high level of comorbidities. Understanding the characteristics of PWH-VSTE will enable clinicians to better address the needs of this historically understudied population.Item Spirometry Versus Forced Oscillation to Assess Lung Function Outcome at 5 Years of Age(Wiley, 2025) Tepper, Robert S.; Milner, Kristin; Harris, Julia; Lee, Brianna; Cunningham, Michelle; Tiller, Christina; Shorey‐Kendrick, Lyndsey E.; Schilling, Diane; Brownsberger, Julie; MacDonald, Kelvin; Vu, Annette; Park, Byung S.; Spindel, Eliot R.; Morris, Cynthia D.; McEvoy, Cindy T.; Pediatrics, School of MedicineBackground: Spirometry is the gold standard for assessing airway function for clinical studies; however, obtaining high-quality data in young children remains challenging. Since the forced oscillation technique (FOT) requires less subject cooperations, there has been increasing interest in FOT, particularly in young children. We evaluated whether spirometry and FOT in young children provides comparable ability to detect a treatment effect. Methods: We recently reported in a randomized controlled trial that vitamin C compared to placebo treatment of mothers who smoked during pregnancy (MSDP) results in the offspring having significantly higher forced expiratory flows (FEFs) at 5-years of age, as well as significantly less wheeze at 4-6 years of age. In these same offspring, we also measured respiratory impedance using FOT at 8-Hz impedance at 3, 4, and 5 years of age. Results: Although spirometry demonstrated significantly increased FEFs in vitamin C compared to placebo-treatment group at 5 years of age (p < 0.001), we were not able to detect a similar treatment effect using FOT impedance. Conclusions: It may be challenging to obtain technically successful spirometry in preschool children; however, FEFs may provide a better outcome than single-frequency FOT impedance to assess improvements in airway function in these young subjects.