Faculty Bibliography

Use of magnetic resonance (MR) imaging in radiation therapy has increased substantially in recent years as more radiotherapy centers are having MR simulators installed, requesting more time on clinical diagnostic MR systems, or even treating with combination MR linear accelerator (MR-linac) systems. With this increased use, to ensure the most accurate integration of images into radiotherapy (RT), RT immobilization devices and accessories must be able to be used safely in the MR environment and produce minimal perturbations. The determination of the safety profile and considerations often falls to the medical physicist or other support staff members who at a minimum should be a Level 2 personnel as per the ACR. The purpose of this guidance document will be to help guide the user in making determinations on MR Safety labeling (i.e., MR Safe, Conditional, or Unsafe) including standard testing, and verification of image quality, when using RT immobilization devices and accessories in an MR environment.

BACKGROUND/UNASSIGNED:(MTBC) may influence transmission. We evaluated whether PneumoniaCheck (PMC), a commercial aerosol collection device, captures MTBC and the aeromicrobiome of people with TB. METHODS/UNASSIGNED:PMC was done in sputum culture-positive people (≥30 forced coughs each, n=16) pre-treatment and PMC air reservoir (bag, corresponding to upper airways) and filter (lower airways) washes underwent Xpert MTB/RIF Ultra (Ultra) and 16S rRNA gene sequencing (sequencing also done on sputum). In a subset (n=6), PMC microbiota (bag, filter) was compared to oral washes and bronchoalveolar lavage fluid (BALF). FINDINGS/UNASSIGNED:also depleted in filters vs. BALF). Compared to BALF, none of the aerosol-enriched taxa were enriched in oral washes or sputum. INTERPRETATION/UNASSIGNED:PMC captures aerosols with Ultra-detectable MTBC and MTBC is more detectable in aerosols than sputum by sequencing. The aeromicrobiome is distinct from sputum, oral washes and BALF and contains differentially-enriched lower respiratory tract microbes.

The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2-51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63-87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial.

During infectious disease outbreaks, estimates for the instantaneous reproduction number, R(t), are essential for understanding transmission dynamics. This study develops and analyzes new methodology to improve estimation of R(t) when observed case counts are subject to reporting patterns and available serial interval estimates are subject to uncertainty and non-representativeness. Specifically, we developed a Bayesian time-since-infection model with layers to adjust for reporting measurement error, integrate multiple candidate serial interval estimates, and estimate transmission with an autoregressive time-series model incorporating factors relevant to transmission. Additionally, we provide practical tools to identify reporting patterns and determine when to smooth case counts for more usable R(t) estimates. We evaluated model performance relative to widely adopted methodology by simulating outbreak data, finding improved R(t) estimation with the proposed methodology. We also used 2020 COVID-19 data to analyze transmission trends and predictors, identifying strong day-of-week and social distancing effects that subsequently reduced estimate volatility. In addition to new approaches for addressing serial interval uncertainty and incorporating transmission predictor information, this study provides an alternative approach for addressing case-reporting patterns without delaying detection or smoothing over relevant transmission signals. These tools and findings may be used or built upon for current and future outbreaks.

BACKGROUND/UNASSIGNED:Sweetened beverage taxes are associated with large decreases in sugar-sweetened beverage sales, but their effects on weight outcomes are unclear. We examined associations of the 2017 Philadelphia beverage tax with changes in adult weight outcomes. METHODS/UNASSIGNED:We obtained electronic health record data on adults 18-65 years old in Philadelphia (intervention) and other areas of Pennsylvania and New Jersey (control) from 2014 to 2019. Controlled interrupted time series models compared post-tax changes in trends of body mass index (BMI, primary outcome) and obesity prevalence (secondary outcome). A panel sample comprised 175,675 adults with at least one BMI measure in both the pre-tax (2014-2016) and post-tax (2017-2019) periods. A cross-sectional sample comprised 587,121 adults with at least one BMI measure from 2014 to 2019. FINDINGS/UNASSIGNED:(-1.04, -0.16) change at the end of the study period. Results for obesity prevalence were consistent with the BMI results. INTERPRETATION/UNASSIGNED:There was some limited evidence of a decrease in BMI and obesity prevalence in Philadelphia 3 years after beverage tax implementation. Replication of these results is needed. FUNDING/UNASSIGNED:National Institutes of Health.

BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation. METHODS:Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS. RESULTS:). CONCLUSIONS:In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.

The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures.

Higher brain functions depend on experience-dependent representations of relevant information that may be organized by attractor dynamics or by geometrical modifications of continuous "neural manifolds". To explore these scenarios we analyzed odor-evoked activity in telencephalic area pDp of juvenile and adult zebrafish, the homolog of piriform cortex. No obvious signatures of attractor dynamics were detected. Rather, olfactory discrimination training selectively enhanced the separation of neural manifolds representing task-relevant odors from other representations, consistent with predictions of autoassociative network models endowed with precise synaptic balance. Analytical approaches using the framework of manifold capacity revealed multiple geometrical modifications of representational manifolds that supported the classification of task-relevant sensory information. Manifold capacity predicted odor discrimination across individuals, indicating a close link between manifold geometry and behavior. Hence, pDp and possibly related recurrent networks store information in the geometry of representational manifolds, resulting in joint sensory and semantic maps that may support distributed learning processes.