CNS Antitumor Activity of Amivantamab With Osimertinib in Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer With Acquired Mesenchymal-Epithelial Transition Amplification Resistance Mechanism: A Case Report.

NSCLC w/EGFRex19del & MET amp: durable intracranial + systemic response to amivantamab/osimertinib.

Quantifying the activity profile of ASO and siRNA conjugates in glioblastoma xenograft tumors in vivo.

Glioblastoma multiforme is a universally lethal brain tumor that largely resists current surgical and drug interventions. Despite important advancements in understanding GBM biology, the invasiveness and heterogeneity of these tumors has made it challenging to develop effective therapies. Therapeutic oligonucleotides-antisense oligonucleotides and small-interfering RNAs-are chemically modified nucleic acids that can silence gene expression in the brain. However, activity of these oligonucleotides in brain tumors remains inadequately characterized. In this study, we developed a quantitative method to differentiate oligonucleotide-induced gene silencing in orthotopic GBM xenografts from gene silencing in normal brain tissue, and used this method to test the differential silencing activity of a chemically diverse panel of oligonucleotides. We show that oligonucleotides chemically optimized for pharmacological activity in normal brain tissue do not show consistent activity in GBM xenografts. We then survey multiple advanced oligonucleotide chemistries for their activity in GBM xenografts. Attaching lipid conjugates to oligonucleotides improves silencing in GBM cells across several different lipid classes. Highly hydrophobic lipid conjugates cholesterol and docosanoic acid enhance silencing but at the cost of higher neurotoxicity. Moderately hydrophobic, unsaturated fatty acid and amphiphilic lipid conjugates still improve activity without compromising safety. These oligonucleotide conjugates show promise for treating glioblastoma.

Profiling injuries sustained following implementation of a progressive load carriage program in United States marine corps recruit training.

BACKGROUND: Load carriage tasks during United States Marine Corps (USMC) recruit training can cause injury. Load carriage conditioning, if optimized, can reduce injury risk. OBJECTIVE: To compare injuries sustained by USMC recruits following participation in either the Original Load Carriage (OLC) program or a Modified Load Carriage (MLC) program. METHODS: Retrospective musculoskeletal injury data were drawn from the USMC San Diego Sports Medicine injury database for recruits completing the OLC (n = 2,363) and MLC (n = 681) programs. Data were expressed as descriptive statistics and a population estimate of the OLC:MLC relative risk ratio (RR) was calculated. RESULTS: The proportion of injuries sustained in the MLC cohort (n = 268; 39% : OLC cohort, n = 1,372 : 58%) was lower, as was the RR (0.68, 95% CI 0.61- 0.75). The leading nature of injury for both cohorts was sprains and strains (OLC n = 396, 29%; MLC n = 66; 25%). Stress reactions were proportionally higher in MLC (n = 17, 6%; OLC n = 4, 0.3%), while stress fractures were proportionately lower (MLC n = 9, 3%; OLC n = 114, 8%). Overuse injuries were lower in MLC (- 7%). The knee, lower leg, ankle, and foot were the top four bodily sites of injuries and the Small Unit Leadership Evaluation (SULE), Crucible, overuse-nonspecific, running, and conditioning hikes were within the top five most common events causing injury. The prevalence rates of moderate severity injury were similar (MLC = 23%; OLC = 24%), although MLC presented both a higher proportion and prevalence of severe injuries (MLC = 6%; OLC = 3%, respectively). CONCLUSION: A periodized load carriage program concurrently increased exposure to load carriage hikes while reducing injuries both during the load carriage hikes and overall.

Quantification of daily workload, energy expenditure, and sleep of US Marine recruits throughout a 10-week boot camp.

BACKGROUND: During periods of high-volume vigorous exercise, United States Marine Corps recruits often experience musculoskeletal injuries. While the program of instruction (POI) for basic training is a defined training volume, the total workload of boot camp, including movements around the base, is unknown. OBJECTIVE: The present study aimed to quantify the daily total workload, energy expenditure, and sleep during basic recruit training at Marine Corps Recruit Depot (MCRD) San Diego. METHODS: Eighty-four male recruits from MCRD San Diego wore wrist wearable physiological monitors to capture their complete workload (mileage from steps), energy expenditure, and sleep throughout the 10-week boot camp. RESULTS: Marine recruits traveled an average of 11.5±3.4 miles per day (M±SD), expended 4105±823 kcal per day, and slept an average of 5 : 48±1 : 06 hours and minutes per night. While the POI designates a total of 46.3 miles of running and hiking, the actual daily average miles yielded approximately 657.6±107.2 miles over the 10-week boot camp. CONCLUSION: Recruit training requires high physical demand and time under tension due to the cumulative volume of movements around base in addition to the POI planned physical training.

Domain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scope.

Nme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we engineer Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors. We first use domain insertion to position the deaminase domain nearer the displaced DNA strand in the target-bound complex. These domain-inlaid Nme2Cas9 variants exhibit shifted editing windows and increased activity in comparison to the N-terminally fused Nme2-ABE. We next expand the editing scope by swapping the Nme2Cas9 PAM-interacting domain with that of SmuCas9, which we had previously defined as recognizing a single-cytidine PAM. We then use these enhancements to introduce therapeutically relevant edits in a variety of cell types. Finally, we validate domain-inlaid Nme2-ABEs for single-AAV delivery in vivo.

Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial.

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.

The International Association for the Study of Lung Cancer Early Lung Imaging Confederation Open-Source Deep Learning and Quantitative Measurement Initiative.

INTRODUCTION: With global adoption of computed tomography (CT) lung cancer screening, there is increasing interest to use artificial intelligence (AI) deep learning methods to improve the clinical management process. To enable AI research using an open-source, cloud-based, globally distributed, screening CT imaging data set and computational environment that are compliant with the most stringent international privacy regulations that also protect the intellectual properties of researchers, the International Association for the Study of Lung Cancer sponsored development of the Early Lung Imaging Confederation (ELIC) resource in 2018. The objective of this report is to describe the updated capabilities of ELIC and illustrate how this resource can be used for clinically relevant AI research. METHODS: In this second phase of the initiative, metadata and screening CT scans from two time points were collected from 100 screening participants in seven countries. An automated deep learning AI lung segmentation algorithm, automated quantitative emphysema metrics, and a quantitative lung nodule volume measurement algorithm were run on these scans. RESULTS: A total of 1394 CTs were collected from 697 participants. The LAV950 quantitative emphysema metric was found to be potentially useful in distinguishing lung cancer from benign cases using a combined slice thickness more than or equal to 2.5 mm. Lung nodule volume change measurements had better sensitivity and specificity for classifying malignant from benign lung nodules when applied to solid lung nodules from high-quality CT scans. CONCLUSIONS: These initial experiments revealed that ELIC can support deep learning AI and quantitative imaging analyses on diverse and globally distributed cloud-based data sets.

Self-delivering, chemically modified CRISPR RNAs for AAV co-delivery and genome editing in vivo.

Guide RNAs offer programmability for CRISPR-Cas9 genome editing but also add challenges for delivery. Chemical modification, which has been key to the success of oligonucleotide therapeutics, can enhance the stability, distribution, cellular uptake, and safety of nucleic acids. Previously, we engineered heavily and fully modified SpyCas9 crRNA and tracrRNA, which showed enhanced stability and retained activity when delivered to cultured cells in the form of the ribonucleoprotein complex. In this study, we report that a short, fully stabilized oligonucleotide (a 'protecting oligo'), which can be displaced by tracrRNA annealing, can significantly enhance the potency and stability of a heavily modified crRNA. Furthermore, protecting oligos allow various bioconjugates to be appended, thereby improving cellular uptake and biodistribution of crRNA in vivo. Finally, we achieved in vivo genome editing in adult mouse liver and central nervous system via co-delivery of unformulated, chemically modified crRNAs with protecting oligos and AAV vectors that express tracrRNA and either SpyCas9 or a base editor derivative. Our proof-of-concept establishment of AAV/crRNA co-delivery offers a route towards transient editing activity, target multiplexing, guide redosing, and vector inactivation.

Validation of Polar Grit X Pro for Estimating Energy Expenditure during Military Field Training: A Pilot Study.

Wearables are lightweight, portable technology devices that are traditionally used to monitor physical activity and workload as well as basic physiological parameters such as heart rate. However recent advances in monitors have enabled better algorithms for estimation of caloric expenditure from heart rate for use in weight loss as well as sport performance. can be used for estimating energy expenditure and nutritional demand. Recently, the military has adopted the use of personal wearables for utilization in field studies for ecological validity of training. With popularity of use, the need for validation of these devices for caloric estimates is needed to assist in work-rest cycles. Thus the purpose of this effort was to evaluate the Polar Grit X for energy expenditure (EE) for use in military training exercises. Polar Grit X Pro watches were worn by active-duty elite male operators (N = 16; age: 31.7 ± 5.0 years, height: 180.1 ± 6.2 cm, weight: 91.7 ± 9.4 kg). Metrics were measured against indirect calorimetry of a metabolic cart and heart rate via a Polar heart rate monitor chest strap while exercising on a treadmill. Participants each performed five 10-minute bouts of running at a self-selected speed and incline to maintain a heart rate within one of five heart rate zones, as ordered and defined by Polar. Polar Grit X Pro watch had a good to excellent interrater reliability to indirect calorimetry at estimating energy expenditure (ICC = 0.8, 95% CI = 0.61-0.89, F (74,17.3) = 11.76, p < 0.0001) and a fair to good interrater reliability in estimating macronutrient partitioning (ICC = 0.49, 95% CI = 0.3-0.65, F (74,74.54) = 2.98, p < 0.0001). There is a strong relationship between energy expenditure as estimated from the Polar Grit X Pro and measured through indirect calorimetry. The Polar Grit X Pro watch is a suitable tool for estimating energy expenditure in free-living participants in a field setting and at a range of exercise intensities.

A Fluorescent Reporter Mouse for In Vivo Assessment of Genome Editing with Diverse Cas Nucleases and Prime Editors.

CRISPR-based genome-editing technologies, including nuclease editing, base editing, and prime editing, have recently revolutionized the development of therapeutics targeting disease-causing mutations. To advance the assessment and development of genome editing tools, a robust mouse model is valuable, particularly for evaluating in vivo activity and delivery strategies. In this study, we successfully generated a knock-in mouse line carrying the Traffic Light Reporter design known as TLR-multi-Cas variant 1 (TLR-MCV1). We comprehensively validated the functionality of this mouse model for both in vitro and in vivo nuclease and prime editing. The TLR-MCV1 reporter mouse represents a versatile and powerful tool for expediting the development of editing technologies and their therapeutic applications.

Addressing the dNTP bottleneck restricting prime editing activity.

Prime editing efficiency is modest in cells that are quiescent or slowly proliferating where intracellular dNTP levels are tightly regulated. MMLV-reverse transcriptase - the prime editor polymerase subunit - requires high intracellular dNTPs levels for efficient polymerization. We report that prime editing efficiency in primary cells and in vivo is increased by mutations that enhance the enzymatic properties of MMLV-reverse transcriptase and can be further complemented by targeting SAMHD1 for degradation.

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons. RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001). CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

International Association for the Study of Lung Cancer Study of Reproducibility in Assessment of Pathologic Response in Resected Lung Cancers After Neoadjuvant Therapy.

INTRODUCTION: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria. METHODS: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion. RESULTS: Unanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76-0.92) and 0.86 (95% CI: 0.79-0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96-1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89-0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma. CONCLUSIONS: Our study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy.

Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial.

Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial.

Cytotoxic CD4 development requires CD4 effectors to concurrently recognize local antigen and encounter type I IFN-induced IL-15.

Cytotoxic CD4 T cell effectors (ThCTLs) kill virus-infected major histocompatibility complex (MHC) class II+ cells, contributing to viral clearance. We identify key factors by which influenza A virus infection drives non-cytotoxic CD4 effectors to differentiate into lung tissue-resident ThCTL effectors. We find that CD4 effectors must again recognize cognate antigen on antigen-presenting cells (APCs) within the lungs. Both dendritic cells and B cells are sufficient as APCs, but CD28 co-stimulation is not needed. Optimal generation of ThCTLs requires signals induced by the ongoing infection independent of antigen presentation. Infection-elicited type I interferon (IFN) induces interleukin-15 (IL-15), which, in turn, supports CD4 effector differentiation into ThCTLs. We suggest that these multiple spatial, temporal, and cellular requirements prevent excessive lung ThCTL responses when virus is already cleared but ensure their development when infection persists. This supports a model where continuing infection drives the development of multiple, more differentiated subsets of CD4 effectors by distinct pathways.

Altered Sympathoadrenal Activity Following Cold-Water Diving.

INTRODUCTION: Little data exist on the effect of extremely cold-water diving on thermo-metabolic hormone secretion. Moreover, the impact of repetitive dives on the stress response is unknown. The purpose of this study was to determine the effects of two daily bouts of cold-water diving on the hormonal and metabolic profile of elite military personnel and to measure the stress response. METHODS: Healthy, male, Norwegian Special Forces operators (n = 5) volunteered for this study. Physiological and hormone data were analyzed prior to and following twice-daily Arctic dives (3.3°C). RESULTS: Core temperature was maintained (p > .05), whereas skin temperature was significantly reduced over the course of each dive (p < .01). Pairwise comparisons revealed adrenocorticotropic hormone (ACTH) and cortisol concentration significantly decreased across both dives and days (p < .001). Adrenaline and noradrenaline significantly increased across both time and day (p < .001). Leptin, testosterone, and IGF-1 significantly decreased over time but recovered between days. CONCLUSION: The main findings of this effort are that there is a rapid sympathetic-adreno-medullary (SAM/SNS) response to cold-water diving and a suppression of the hypothalamic-pituitary-adrenal (HPA) axis and hormones related to repair and recovery. While the sample size was too small to determine the role of SAM/SNS, HPA, and thyroid hormone effect on thermoregulation, it addresses a gap in our understanding of physiological adaptions that occurs in extreme environments.

Efficacy of closed cell wet-suit at various depths and gas mixtures for thermoprotection during military training dives.

Purpose: To evaluate a closed-cell wet-suit for thermal protective capability during extreme cold water exposure at various depths. Methods: Thirteen (n = 13) elite military divers who were tasked with cold-water training, participated in this study. To mimic various depths, the Ocean Simulation Facility (OSF) at the Navy Experimental Diving Unit (NEDU) was pressurized to simulate dive depths of 30, 50, and 75fsw. Water temperature remained at 1.8-2.0°C for all dives. Four divers dove each day and used the MK16 underwater breathing apparatus with gas mixes of either N202 (79:21) or HeO2 (88:12). Mean skin temperature (TSK) (Ramanathan, 1964), core temperature (Tc), hand and foot readings were obtained every 30 min for 30 and 50fsw and every 15 min during the 75fsw dive. Results: TC was significantly reduced across all dives (p = 0.004); however, was preserved above the threshold for hypothermia (post dive Tc = 36.5 ± 0.4). There was no effect of gas mix on TC. TSK significantly decreased (p < 0.001) across all dives independent of depth and gas. Hand and foot temperatures resulted in the termination of three of the dives. There were no significant main effects for depth or gas, but there were significant main effects for time on hand temperature (p < 0.001) and foot temperature (p < 0.001). Conclusion: Core temperature is maintained above threshold for hypothermia. Variatioins in TC and TSK are a function of dive duration independent of depth or gas for a closed-cell wet-suit in cold water at various depths. However, both hand and foot temperatures reached values at which dexterity is compromised.

Not according to plan: Cognitive failures in marksmanship due to effects of expertise, unknown environments, and the likelihood of shooting unintended targets.

Shooting errors have multi-faceted causes with contributing factors that include sensorimotor activity and cognitive failures. Empirical investigations often assess mental errors through threat identification, yet other cognitive failures could contribute to poor outcomes. The current study explored several possible sources of cognitive failures unrelated to threat identification with live fire exercises. Experiment 1 examined a national shooting competition to compare marksmanship accuracy, expertise, and planning in the likelihood of hitting no-shoot or unintended targets. Experts demonstrated an inverse speed/accuracy trade-off and fired upon fewer no-shoot targets than lesser skilled shooters, yet overall, greater opportunity to plan produced more no-shoot errors, thereby demonstrating an increase in cognitive errors. Experiment 2 replicated and extended this finding under conditions accounting for target type, location, and number. These findings further dissociate the roles of marksmanship and cognition in shooting errors while suggesting that marksmanship evaluations should be re-designed to better incorporate cognitive variables.

Emotional Distress, Anxiety, and General Health Status in Patients With Newly Identified Small Pulmonary Nodules: Results From the Watch the Spot Trial.

BACKGROUND: Anxiety and emotional distress have not been studied in large, diverse samples of patients with pulmonary nodules. RESEARCH QUESTION: How common are anxiety and distress in patients with newly identified pulmonary nodules, and what factors are associated with these outcomes? STUDY DESIGN AND METHODS: This study surveyed participants in the Watch the Spot Trial, a large, pragmatic clinical trial of more vs less intensive strategies for radiographic surveillance of patients with small pulmonary nodules. The survey included validated instruments to measure patient-centered outcomes such as nodule-related emotional distress (Impact of Event Scale-Revised) and anxiety (Six-Item State Anxiety Inventory) 6 to 8 weeks following nodule identification. Mixed-effects models were used to compare outcomes between study arms following adjustment for potential confounders and clustering within enrollment site, while also examining a limited number of prespecified explanatory factors, including nodule size, mode of detection, type of ordering clinician, and lack of timely notification prior to contact by the study team. RESULTS: The trial enrolled 34,699 patients; 2,049 individuals completed the baseline survey (5.9%). Respondents and nonrespondents had similar demographic and nodule characteristics, although more respondents were non-Hispanic and White. Impact of Event Scale-Revised scores indicated mild, moderate, or severe distress in 32.2%, 9.4%, and 7.2% of respondents, respectively, with no difference in scores between study arms. Following adjustment, greater emotional distress was associated with larger nodule size and lack of timely notification by a clinician; distress was also associated with younger age, female sex, ever smoking, Black race, and Hispanic ethnicity. Anxiety was associated with lack of timely notification, ever smoking, and female sex. INTERPRETATION: Almost one-half of respondents experienced emotional distress 6 to 8 weeks following pulmonary nodule identification. Strategies are needed to mitigate the burden of distress, especially in younger, female, ever smoking, and minoritized patients, and those with larger nodules. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02623712; URL: www. CLINICALTRIALS: gov.