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Optimizing vancomycin dosing in neonates is a critical yet complex goal. Traditional trough concentration-based dosing strategies correlate poorly with therapeutic efficacy and often fail to account for the significant renal function variability and drug clearance in neonates. The 24-hour area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) ≥ 400 mg h/L has emerged as a superior pharmacodynamic target. Population pharmacokinetics (PopPK) models allow optimized dosing by incorporating neonatal-specific factors such as postmenstrual age (PMA), gestational age (GA), serum creatinine (SCr), and weight. To develop optimized vancomycin dosing regimens for neonates that achieve an 80% probability of target attainment (PTA) for an AUC24/MIC ≥ 400 mg h/L across diverse clinical cohorts and simulated neonatal populations. Real-world data from three international centers (Belgium, New Zealand, USA), including 610 individuals and 2399 vancomycin concentrations, were used to externally evaluate a previously published PopPK model (NONMEM®). Missing data, including body weight, were imputed using Amelia II version 1.7.3 for R, while Zelig for R integrated multiple imputed datasets. A virtual population of 10,000 neonates was independently generated using MATLAB to simulate clinical scenarios considering covariates such as PMA, GA, SCr, body weight, and imputed body length. Simulations showed that PMA and SCr were key covariates that significantly improved PTA, particularly in preterm neonates. Preterm neonates achieved PTAs of 80% with daily doses of 30 or 40 mg/kg/day, while term neonates required 15 mg/kg every 8 hours or 20 mg/kg every 12 hours. The simulations demonstrated that these optimized dosing strategies achieved an 80% PTA for AUC24/MIC ≥ 400 mg h/L in the virtual neonatal population. For neonates with PMA < 29 weeks and SCr > 0.6 mg/dL, including SCr as a covariate increased the likelihood of achieving the target from 65% to 87%. Incorporating developmental factors like PMA and SCr into vancomycin dosing strategies achieved robust and clinically relevant outcomes. The optimized regimens achieved an 80% PTA for the AUC24/MIC target for preterm and term neonates. These findings offer a scalable framework for improving neonatal vancomycin pharmacotherapy across diverse populations and clinical settings.

The Neural Engineering Data Consortium (NEDC) began annotating large amounts of EEG data in 2012 [1] [2] . The most current release of the Temple University EEG Corpus, TUEG v2.0.1, consists of 26,846 sessions from 14,987 patients. TUEG has become one of most significant open-source resources available in the community. Over 10,000 researchers have subscribed to this corpus. However, the TUEG data [3] consists of pruned EEGs [4] [5] . In clinical settings, technicians condense long term studies highlight any potential abnormalities, reducing the burden of reading long-term EEGs, and allowing a neurologist to focus on diagnosing the patient accurately and more efficiently. This results in data that has been split into a series of shorter files, destroying the continuous nature of the data. Gaps between files have been discarded (historically to save disk space and reduce review time), which prevents reconstruction of the original continuous recording. This makes it difficult to use this data to develop seizure prediction algorithms, accurately measure false alarm rate, or assess robustness to real-world artifacts like patient and electrode movement.

Abstract Success of immune checkpoint inhibitors (e.g., anti-PD1 antibodies) have revolutionized cancer immunotherapy by demonstrating that a patient’s own T-cells recognize and treat cancer. The efficacy of PD-1 blockade is driven by recruitment of new T-cells from blood rather than via activation of pre-existing tumor infiltrating lymphocytes (Yost K.E., et al. Nat. Med. 2019). However, anti-PD1 therapy is most effective in ~5% of malignancies i.e., cancers with high mutational burden. Hence, the challenge of addressing most lower mutational burden cancers (the ~95%) needs an alternate treatment strategy. We address this challenge by using RNA to prime and expand peripheral T-cells to cancer-specific mutations ex-vivo. Using our proprietary, patented, and robust manufacturing method, we can generate T-cell populations reactive to as low as 8 and as high as 40 cancer-specific mutant proteins. In-vitro, these T-cells have cancer mutation-specific cytotoxicity and do not kill the normal cells. Further, the T-cells express homing receptors enabling them to infiltrate tumors and express high levels of TNFα and IFNγ, which are associated with effective tumor cytotoxicity and pro-inflammatory modification of tumor microenvironment (TME). Additional characterization shows these cells to be predominantly CD4+ and CD8+ T-cells bearing central and effector memory phenotypic with negligible regulatory or exhausted T-cells. We believe our T-cells can be used for cellular therapy in conjunction with, or as an alternative to, immune checkpoint inhibitors to treat lower mutational burden cancers present in most patients. Citation Format: Alfred E. Slanetz, Sriram Srivatsa, Farzona Muzaffar, Walter Barry, David Ryan, Salim Metri, Michael Slanetz. RNA primed SMAR-T cells against multiple driver mutations, all HLA's designed for first line therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5251.

The motor unit size index (MUSIX) may provide insight into reinnervation patterns in diseases such as amyotrophic lateral sclerosis (ALS). However, it is not known whether MUSIX detects clinically relevant changes in reinnervation, or if all muscles manifest changes in MUSIX in response to reinnervation after motor unit loss. Fifty-seven patients with ALS were assessed at 3-month intervals for 12 months in four centers. Muscles examined were abductor pollicis brevis, abductor digiti minimi, biceps brachii, and tibialis anterior. Results were split into two groups: muscles with increases in MUSIX and those without increases. Longitudinal changes in MUSIX, motor unit number index (MUNIX), compound muscle action potential amplitude, and Medical Research Council strength score were investigated. One hundred thirty-three muscles were examined. Fifty-nine percent of the muscles exhibited an increase in MUSIX during the study. Muscles with MUSIX increases lost more motor units (58% decline in MUNIX at 12 months, P< .001) than muscles that did not increase MUSIX (34.6% decline in MUNIX at 12 months, P< .001). However, longitudinal changes in muscle strength were similar. When motor unit loss was similar, the absence of a MUSIX increase was associated with a significantly greater loss of muscle strength (P= .002). MUSIX increases are associated with greater motor unit loss but relative preservation of muscle strength. Thus, MUSIX appears to be measuring a clinically relevant response that can provide a quantitative outcome measure of reinnervation in clinical trials. Furthermore, MUSIX suggests that reinnervation may play a major role in determining the progression of weakness.

The virtual cathode (VC) is a site near the anode where the nerve can be stimulated. Costimulation of neighboring nerves via the VC can affect recording and interpretation of responses. Hence, it is important to teach trainees the concept of the VC. The VC has been demonstrated previously with subtle changes in response latency, amplitude, and shape. Herein we describe an experiment that simply demonstrates a VC with its effects recognizable by gross changes in waveforms. Compound muscle action potentials of the abductor pollicis brevis were recorded using various placements of the cathode and anode at different stimulus intensity levels. Studies were performed in nine healthy subjects. Three patterns were observed that demonstrated no stimulation, partial stimulation, and complete nerve stimulation by the VC. Partial stimulation yielded responses with long duration and low amplitude. Response patterns also depended on stimulus strength and proximity of the nerve from the skin surface. This experiment demonstrates that nerve stimulation can occur near the anode when high-intensity stimulus is used. It also illustrates collision of action potentials. This exercise can help trainees understand potential pitfalls in nerve conduction studies, especially at very proximal stimulation sites or when high stimulus intensity is used.

Estimation of Reference Intervals for Transcranial Magnetic Stimulation : Derived Parameters Via the Hoffman Indirect Method Reply