Characterization of non-coding variants associated with transcription factor binding through ATAC-seq-defined footprint QTLs in liver.

Non-coding variants discovered by genome-wide association studies (GWAS) are enriched in regulatory elements harboring transcription factor (TF) binding motifs, strongly suggesting a connection between disease association and the disruption of cis-regulatory sequences. Occupancy of a TF inside a region of open chromatin can be detected in ATAC-seq where bound TFs block the transposase Tn5, leaving a pattern of relatively depleted Tn5 insertions known as a "footprint". Here, we sought to identify variants associated with TF-binding, or "footprint quantitative trait loci" (fpQTLs) in ATAC-seq data generated from 170 human liver samples. We used computational tools to scan the ATAC-seq reads to quantify TF binding likelihood as "footprint scores" at variants derived from whole genome sequencing generated in the same samples. We tested for association between genotype and footprint score and observed 693 fpQTLs associated with footprint-inferred TF binding (FDR < 5%). Given that Tn5 insertion sites are measured with base-pair resolution, we show that fpQTLs can aid GWAS and QTL fine-mapping by precisely pinpointing TF activity within broad trait-associated loci where the underlying causal variant is unknown. Liver fpQTLs were strongly enriched across ChIP-seq peaks, liver expression QTLs (eQTLs), and liver-related GWAS loci, and their inferred effect on TF binding was concordant with their effect on underlying sequence motifs in 80% of cases. We conclude that fpQTLs can reveal causal GWAS variants, define the role of TF binding site disruption in disease and provide functional insights into non-coding variants, ultimately informing novel treatments for common diseases.

Combat Medic-Performed Auscultation Versus Thoracic Ultrasound Image Interpretation for Pneumothorax Detection: Look or Listen?

Background Pneumothorax (PTX) is a potentially life-threatening condition encountered by U.S. Army combat medics on the battlefield. PTX, when left untreated, can progress to tension PTX, a leading cause of preventable death on the battlefield which can be difficult to diagnose based on physical exam alone due to variable physical exam findings. Prior literature shows medics can accurately use point-of-care ultrasound (POCUS) to diagnose PTX in cadaver and porcine models; however, no studies have directly compared the diagnostic accuracy of ultrasound (US) and physical exams performed by this population. We sought to compare medic diagnostic accuracy of a simulated PTX using these two diagnostic modalities. Methodology We conducted a prospective, observational study in which medics from the Flight Paramedic Program at Joint Base San Antonio-Sam Houston, TX received a standardized 30-minute training on physical exam and US diagnosis of PTX, followed by a 20-minute hands-on US familiarization session. Participants were then randomly selected into cohorts to evaluate 12 high-fidelity manikin lung fields and 12 thoracic US video clips for the presence of PTX in a simulated combat environment. Cohorts evaluated the same manikins and thoracic US video clips but in opposing sequences. Our primary outcome compared the sensitivity and specificity of PTX identification via thoracic US image interpretation and physical exam. Results In total, 21 medics evaluated 252 hemithoraces and interpreted 252 thoracic US images. We found a statistically significant difference favoring medics' sensitivity with US image interpretation over physical exam to detect PTX (85.7% vs. 72.4%, p = 0.004). There was no statistically significant difference in specificity between these modalities (81.9% vs. 69.4%, p = 0.139). Conclusions After brief training, medics demonstrated greater sensitivity to detect PTX using thoracic US image interpretation compared to physical exam in a simulated combat environment. Further studies involving medics' ultrasound image acquisition capability in human patients in austere combat environments are warranted.

Modeling health risks using neural network ensembles.

This study aims to demonstrate that demographics combined with biometrics can be used to predict obesity related chronic disease risk and produce a health risk score that outperforms body mass index (BMI)-the most commonly used biomarker for obesity. We propose training an ensemble of small neural networks to fuse demographics and biometrics inputs. The categorical outputs of the networks are then turned into a multi-dimensional risk map, which associates diverse inputs with stratified, output health risk. Our ensemble model is optimized and validated on disjoint subsets of nationally representative data (N~100,000) from the National Health and Nutrition Examination Survey (NHANES). To broaden applicability of the proposed method, we consider only non-invasive inputs that can be easily measured through modern devices. Our results show that: (a) neural networks can predict individual conditions (e.g., diabetes, hypertension) or the union of multiple (e.g., nine) health conditions; (b) Softmax model outputs can be used to stratify individual- or any-condition risk; (c) ensembles of neural networks improve generalizability; (d) multiple-input models outperform BMI (e.g., 75.1% area under the receiver operator curve for eight-input, any-condition models compared to 64.2% for BMI); (e) small neural networks are as effective as larger ones for the inference tasks considered; the proposed models are small enough that they can be expressed as human-readable equations, and they can be adapted to clinical settings to identify high-risk, undiagnosed populations.

Shape Memory Polymer Bioglass Composite Scaffolds Designed to Heal Complex Bone Defects.

An off-the-shelf scaffold with requisite properties could enable the viable treatment of irregular craniomaxillofacial bone defects. Notably, the scaffold should be conformally fitting, innately bioactive, and bioresorbable. In prior work, we developed a series of shape memory polymer (SMP) scaffolds based on cross-linked poly(ε-caprolactone) (PCL). These were capable of "self-fitting" into complex bone defects when exposed to temperatures above the melt transition of the constituent PCL, either linear-PCL-diacrylate (linear-PCL-DA, Tm ∼55 °C) or star-PCL-tetraacrylate (star-PCL-TA, Tm ∼45 °C) for the potential to improve tissue safety. To achieve favorably increased degradation rates versus PCL-only scaffolds, semi-interpenetrating networks (semi-IPNs) were formed by including linear- or star-poly(l-lactic acid) (PLLA). A potential limitation of these self-fitting scaffolds is the lack of bioactivity, which is essential to osteoinductivity and osseointegration. Herein, analogous composite scaffolds were formed with 45S5 bioglass (BG) to impart bioactivity. The solvent-cast particulate leaching fabrication method was adapted to introduce BG to the fused salt template, resulting in composites with BG concentrated on the pore wall surfaces rather than within pore struts. Composite scaffolds with good pore wall integrity were produced with 2.5, 5, and 10 wt % BG. All composite scaffolds exhibited non-brittle behavior and did not fracture with 85% strain. For semi-IPN composite scaffolds, PLLA crystallinity was lost, and mechanical properties were not appreciably altered versus the non-BG controls. Sufficient retention of PCL crystallinity led to excellent shape memory behavior. The inclusion of 5 and 10 wt % BG led to hydroxyapatite mineralization after 1 day of exposure to simulated body fluid, as well as increased rates of in vitro degradation.

Effect of exogenous lipids contamination on blood gas analysis.

Objectives: The purpose of this study was to investigate the effects of contamination of venous blood with a lipid-containing solution on parameters measured by a modern blood gas analyzer. Methods: We collected venous blood from 17 healthcare workers (46 ± 11 years; 53 % women) into three blood gas syringes containing 0 , 5 and 10 % lipid-containing solution. Blood gas analysis was performed within 15 min from sample collection on GEM Premier 5000, while triglycerides and serum indices were assays on Roche COBAS C702. Results: Triglycerides concentration increased from 1.0 ± 0.3 mmol/L in the uncontaminated blood gas syringe, to 39.4 ± 7.8 and 65.3 ± 14.4 mmol/L (both p<0.001) in syringes with 5 and 10 % final lipid contamination. The lipemic and hemolysis indices increased accordingly. Statistically significant variation was noted for all analytes except hematocrit and COHb in the syringe with 5 % lipids, while only COHb did not vary in the syringe with 10 % lipids. Significant increases were observed from 5 % lipid contamination for pO2, SO2 and lactate, while the values of pH, pCO2, sodium, potassium, chloride, ionized calcium, glucose, hematocrit (10 % contamination), hemoglobin and MetHB decreased. All these changes except lactate and CoHb exceeded their relative performance specifications. Conclusions: Artifactual hyperlipidemia caused by contamination with exogenous lipids can have a clinically significant impact on blood gas analysis. Manufacturers of blood gas analyzers must be persuaded to develop new instruments equipped with serum indices.

The Readiness Imperative: Leveraging Large Animal Resident Research to Enhance Expeditionary Surgical Skills.

INTRODUCTION: The Defense Health Agency aims to ensure that military surgical residents have the expeditionary general surgical skills necessary to deploy to a combat environment and maintains the Clinical Investigation Programs (CIPs) that foster research during graduate medical education. This project evaluates the potential to achieve both aims simultaneously through a large animal Combat Casualty Care Research Program (CCCRP). MATERIALS AND METHODS: Large animal experimental protocols within a single CIP's CCCRP were collected from July 1, 2017, to June 30, 2022. Operations performed were tabulated and categorized by Emergency General Surgery procedure equivalent. In addition, procedures performed by a single resident from July 1, 2020, to June 30, 2022, were separately indexed for a more granular analysis. RESULTS: The results are presented with total 5-year numbers listed first, followed by single resident 2-year numbers in parentheses. The residents at the CIP carried out 8676 (1,609) tabulated procedures. Major surgical procedures included 573 (154) laparotomies, 364 (129) thoracotomies, 279 (125) splenectomies, 219 (108) craniotomies, 206 (81) hepatorrhaphies, 363 (62) nephrectomies, 383 (48) bowel resections, 215 (48) spine exposures with laminectomies, and 173 (9) sternotomies. Additional procedures included 1028 (127) central venous lines, 878 (127) arterial lines, 90 (67) tube thoracostomies, 199 (37) carotid artery exposures, 394 (29) suprapubic urostomies, and placement of 278 (10) aortic occlusion catheters. At this time, the residents had 17 (10) presentations at national meetings, 8 (7) research awards, and published 20 peer-reviewed manuscripts. Additionally, the residents involved in the CCCRP gained valuable experience in critical care, including management of 110 traumatic brain injuries, 121 Intercranial Pressure catheters, 316 cases of hemorrhagic shock, and 211 massive transfusion protocols, among a variety of other vital critical care skills. CONCLUSIONS: This large animal CCCRP represents a unique training model that not only achieves its primary goal of fostering graduate medical education research but also bolsters Emergency General Surgery readiness for military surgical residents.

Ultrasound Imaging of Various Ingested Foreign Bodies in an Ex Vivo Intestinal Model.

OBJECTIVE: Foreign body ingestion is an increasingly prevalent issue for children who are in the preverbal to early verbal stages of life. Foreign bodies lodged in the gastrointestinal tract can cause issues such as obstruction, perforation, and fistulae. Radiographic imaging can often locate most foreign bodies; however, radiolucent objects may be missed. Ultrasound is an alternative imaging modality that can be used to locate and track foreign objects as they pass through the bowel. The objective of this study was to characterize the sonographic appearance of various ingested foreign bodies of varying characteristics in an ex vivo gastrointestinal tract segment. METHODS: A GE Logiq 9 ultrasound machine with a linear transducer at a frequency of 15 MHz was used to examine various ingested foreign bodies placed in a segment of pig intestinal tract. RESULTS: Imaged objects varied in visual appearance from echogenicity, texture, size, and shape; acoustic shadows and reverberation artifacts cast were particularly distinguishing characteristics. CONCLUSIONS: Ultrasound evaluation to assess foreign body ingestion in the pediatric population may provide a useful alternative or supportive imaging modality in confirming the location and real-time tracking of the ingested item. This may be especially useful for objects of varying radiodensities that cannot always be reliably seen in traditional radiographs.

Therapist perspectives on telehealth-based virtual reality exposure therapy.

Virtual reality (VR) can enhance mental health care. In particular, the effectiveness of VR-based exposure therapy (VRET) has been well-demonstrated for treatment of anxiety disorders. However, most applications of VRET remain localized to clinic spaces. We aimed to explore mental health therapists' perceptions of telehealth-based VRET (tele-VRET) by conducting semi-structured, qualitative interviews with 18 telemental health therapists between October and December 2022. Interview topics included telehealth experiences, exposure therapy over telehealth, previous experiences with VR, and perspectives on tele-VRET. Therapists described how telehealth reduced barriers (88.9%, 16/18), enhanced therapy (61.1%, 11/18), and improved access to clients (38.9%, 7/18), but entailed problems with technology (61.1%, 11/18), uncontrolled settings (55.6%, 10/18), and communication difficulties (50%, 9/18). Therapists adapted exposure therapy to telehealth by using online resources (66.7%, 12/18), preparing client expectations (55.6%, 10/18), and adjusting workflows (27.8%, 5/18). Most therapists had used VR before (72.2%, 13/18) and had positive impressions of VR (55.6%, 10/18), but none had used VR clinically. In response to tele-VRET, therapists requested interactive session activities (77.8%, 14/18) and customizable interventions components (55.6%, 10/18). Concerns about tele-VRET included risks with certain clients (77.8%, 14/18), costs (50%, 9/18), side effects and privacy (22.2%, 4/18), and inappropriateness for specific forms of exposure therapy (16.7%, 3/18). These results reveal how combining telehealth and VRET may expand therapeutic options for mental healthcare providers and can help inform collaborative development of immersive health technologies.

Clinical and genomic features of classical and basal transcriptional subtypes in pancreatic cancer.

PURPOSE: Transcriptional profiling of pancreatic cancers (PC) has defined two main transcriptional subtypes, classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX (FFX) and gemcitabine nab-Paclitaxel (GnP) by transcriptional subtype. EXPERIMENTAL DESIGN: We examined 8,743 patients with RNA sequencing from PCs performed at Caris Life Sciences (Phoenix, AZ). Classical and basal subtypes were identified using PurIST algorithm on RNA-sequencing and two cohorts were analyzed: (1) Biomarker cohort included patients with complete molecular profiling data (n = 7,250); (2) Outcomes cohort included patients with metastatic disease with available survival outcomes (n=5,335). RESULTS: In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC), and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy site. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcomes cohort, SB subtype was associated with shorter overall survival time, regardless of whether they received FFX or GnP as first line chemotherapy. Mutant KRAS allele type was prognostic of outcomes, however this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors. CONCLUSIONS: SB subtype is a strong independent predictor of worse outcomes, irrespective of upfront chemotherapy regimen. Clinical trials should investigate PC transcriptional subtypes as a biomarker.

Non-Steroidal Anti-Inflammatory Drugs Do Not Affect the Bone Metabolic Response to Exercise.

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAID) are associated with increased stress fracture risk, potentially due to inhibiting the adaptive bone formation responses to exercise. This study investigated if a single, maximal dose of three different NSAIDs alters bone formation biomarker response to strenuous exercise. METHODS: In a randomized, counter-balanced order, 12 participants (10 male, 2 female), performed four bouts of plyometric jumps, each separated by at least one week. Two hours before exercise, participants consumed either placebo (PLA) or NSAID: Ibuprofen (IBU, 800 mg), celecoxib (CEL, 200 mg), flurbiprofen (FLU, 100 mg). Blood was collected before (PRE), and at 0, 15, 60, 120, and 240 minutes post-exercise. Parathyroid hormone (PTH), ionized calcium (iCa), procollagen type 1 N-terminal propeptide (P1NP), bone alkaline phosphatase (BAP), osteocalcin (OCN), C-terminal telopeptide of type 1 collagen (CTX), tartrate resistant acid phosphatase (TRAP5b), and sclerostin (SCL) were measured. Prostaglandin E2 metabolite (PGE2M) and creatinine (Cr) were measured in urine. Data were analyzed using repeated measures ANOVA and area under the curve analysis (AUC). Data are mean ± SD. RESULTS: There was an exercise effect for P1NP, BAP, OCN, CTX, TRAP5b, SCL, OPG, PTH, and iCa (all p < 0.05), but no NSAID treatment effect for any biomarker (all p > 0.05). AUC analyses were not different for any biomarker (p > 0.05). PGE2M was higher during the PLA trial (322 ± 153 pg/mg Cr, p < 0.05) compared to IBU (135 ± 83 pg/mg), CEL (202 ± 107 pg/mg), and FLU (159 ± 74 pg/mg). CONCLUSIONS: Plyometric exercise induced changes in bone metabolism, but the responses were unaltered by consuming NSAIDs two hours before exercise.

Mental health providers are inexperienced but interested in telehealth-based virtual reality therapy: survey study.

Virtual reality (VR) is an emerging technology that can enhance experiences and outcomes in mental healthcare. However, mental health therapists have been slow to adopt VR into practice. Implementation of telehealth-based VR therapy (tele-VR) could catalyze adoption and innovation in mental healthcare. To explore therapists' perspectives on tele-VR, we conducted a cross-sectional survey of practicing mental health providers in the United States in June-July 2023. We analyzed 176 completed surveys from therapists, of whom 51.14% had no prior experience with VR, only 6.25% had used VR clinically, and 56.82% had neutral impressions of VR for therapy. Despite therapists' general inexperience with VR, therapists indicated a wide variety of tele-VR simulations (e.g., social situations, flying, heights) and features (e.g., personalized spaces, homework, interactivity) would be moderately to extremely useful for their practices. Therapists also requested additional VR simulations and features for their telehealth clients such as behavioral skills training, exposure therapy, gender identity therapy, and psychological assessments in VR. Therapists rated Health Insurance Portability and Accountability Act compliance, the ability to try VR before buying, affordability for therapists, accessibility for clients, and insurance coverage as the five most influential implementation factors for tele-VR. Overall, therapists were generally inexperienced and neutral about VR for telehealth therapy, but were interested in tele-VR for specific applications. These findings provide actionable directions for future research and collaborative development of therapeutic VR content and features.

Value of Imaging Measurements in Micrognathia-Related Fetal Airway Obstruction Within a Fetal Center.

OBJECTIVE: Fetal imaging often identifies signs of upper airway obstruction due to micrognathia that may require airway intervention at delivery. This study investigated the role of quantitative fetal imaging measurements in predicting the need for otolaryngology consultation and intervention within a multidisciplinary Fetal Center. METHODS: Data were retrospectively collected from expectant mothers attending a multidisciplinary Fetal Center from January 2017 to October 2023. Cases of fetal micrognathia associated with potential upper airway obstruction were analyzed, focusing on prenatal ultrasound and magnetic resonance imaging (MRI) findings, genetic testing results, and interventions at birth. RESULTS: Among 25 pregnancies identified, diverse prenatal diagnoses were observed. Post hoc quantitative fetal ultrasound/MRI measurements included inferior facial angle, anteroposterior diameter, biparietal distance, and Jaw Index. Otolaryngology teams were present at delivery for a subset of cases, with various interventions performed, including tracheostomy and intubation. Lower gestational age at birth, rather than more severe quantitative measurements, was associated with the need for intervention. Intubation failure due to airway difficulty was also predicted by lower gestational age. CONCLUSION: While certain quantitative fetal imaging measurements are often used for clinical decision-making regarding airway management at birth, they did not clearly predict the need for airway intervention in our sample. Gestational age is an important consideration in decision-making for fetal teams and should be considered in preterm fetuses to plan for airway difficulties. The findings highlight the complexity of fetal micrognathia management and highlight the need for further research to refine predictive models and optimize clinical decision-making in this challenging clinical scenario. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 2024.

Evaluating Disparities in End-Stage Kidney Disease Survival Among American Indian/Alaska Native Persons with Diabetes.

BACKGROUND: American Indian/Alaska Natives (AI/ANs) disproportionately suffer from diabetes compared to non-Hispanic whites (NHW). In 2013, 69% of end-stage kidney disease (ESKD) in AI/ANs was caused by diabetes (ESKD-D) but accounts for only 44% of ESKD diagnoses in the overall USA population. Moreover, the diagnosis of diabetes and ESKD-D may be significantly related to social determinants of health. The purpose of this study was to conduct a survival analysis of AI/ANs and NHWs diagnosed with ESKD-D nationally and by Indian Health Service region and correlate the survival analysis to the Area Deprivation Index® (ADI®). METHODS: This manuscript reports a retrospective cohort analysis of 2021 United States Renal Data System data. Eligible patient records were AI/AN and NHWs with diabetes as the primary cause of ESKD and started dialysis on January 1, 2014, or later. RESULTS: A total of 81,862 patient records were included in this analysis, of which 1798 (2.2%) were AI/AN. AI/ANs survive longer, with an 18.4% decrease in risk of death compared to NHW. However, AI/ANs are diagnosed with ESKD-D and start dialysis earlier than NHWs. ADI® variables became significant as ADI® ratings increased, meaning persons with greater social disadvantage had worse survival outcomes. CONCLUSIONS: The findings reveal that AI/ANs have better survival outcomes than NWH, explained in part by initiating dialysis earlier than NHW. Additional research is needed to explore factors (e.g., social determinants; cultural; physiologic) that contribute to earlier diagnosis of ESKD-D in AI/ANs and the impact of prolonged dialysis on quality of life of those with ESKD-D.

Sarcopenia Predicts the Development of Early Adjacent Segment Disease After Transforaminal Lumbar Interbody Fusion.

BACKGROUND AND OBJECTIVES: Predicting the development of adjacent segment disease (ASD) after lumbar spine fusion would help guide preoperative and postoperative therapies to prevent reoperation. We sought to evaluate whether sarcopenia predicts the development of early ASD after transforaminal lumbar interbody fusion (TLIF). METHODS: Retrospective data were collected from 109 patients who underwent TLIF from 2013 to 2023. Patients older than 18 years who underwent elective posterior midline approach TLIF were included. Patients with prior lumbar instrumented fusions, cases of trauma, central nervous system infection, cancer, or long-construct thoracolumbar deformity corrections and those who lacked sufficient follow-up were excluded. The primary outcome was radiographic ASD development within 3 years of surgery. Psoas volumetric measurements were recorded from the most recent preoperative MRI. Odds ratios were calculated with logistic regression analyses. RESULTS: In 109 patients undergoing elective TLIF, 22 (20.2%) developed ASD within 3 years. Gender, body mass index, and extent of surgery were not associated with ASD development. Multivariate analysis showed left/right psoas cross-sectional area, and psoas:vertebral body ratio (P:VBR) predicted early ASD (P < .0001). Sarcopenia was further categorized as having bilateral P:VBR ≥1 SD below gender mean (T-score -1). Of 18 sarcopenic patients, 15 developed early ASD (83.33%) vs 7 of 91 nonsarcopenic patients (7.69%; P < .0001). Postoperative mismatch between pelvic incidence and lumbar lordosis was predictive of ASD on univariate (P = .0480) but not multivariate analysis. Pelvic tilt and lumbar lordosis postoperatively were not associated with early ASD. CONCLUSION: Sarcopenia, measured by decreased psoas area and P:VBR, predicts ASD formation within 3 years of surgery. Morphometric analysis of psoas size is a simple tool to identify patients at risk of developing ASD. This information can potentially guide preoperative and postoperative therapies, affect surgical decision making, and effectively counsel patients on risks of reoperation.

A Phase 1 Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer.

Ovarian cancers and microsatellite stable (MSS) colorectal cancers (CRC) are insensitive to anti-PD1 immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggests a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase 1 dose-escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS CRC. Trebananib was administered intravenously weekly for 12 weeks with 200 mg intravenous pembrolizumab every 3 weeks. The toxicity profile of this combination was manageable, and the protocol-defined highest dose level (trebananib 30 mg/kg weekly plus pembrolizumab 200 mg every 3 weeks) was declared the maximum tolerated dose. The objective response rate for all patients was 7.3% (90% confidence interval: 2.5-15.9%). Three patients with MSS CRC had durable responses for ≥3 years. One responding patient's CRC harbored a POLE mutation. The other two responding patients had left-sided CRCs with no baseline liver metastases, and genomic analysis revealed that they both had KRAS wild-type, ERBB2 amplified tumors. After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.

People make mistakes: Obtaining accurate ground truth from continuous annotations of subjective constructs.

Accurately representing changes in mental states over time is crucial for understanding their complex dynamics. However, there is little methodological research on the validity and reliability of human-produced continuous-time annotation of these states. We present a psychometric perspective on valid and reliable construct assessment, examine the robustness of interval-scale (e.g., values between zero and one) continuous-time annotation, and identify three major threats to validity and reliability in current approaches. We then propose a novel ground truth generation pipeline that combines emerging techniques for improving validity and robustness. We demonstrate its effectiveness in a case study involving crowd-sourced annotation of perceived violence in movies, where our pipeline achieves a .95 Spearman correlation in summarized ratings compared to a .15 baseline. These results suggest that highly accurate ground truth signals can be produced from continuous annotations using additional comparative annotation (e.g., a versus b) to correct structured errors, highlighting the need for a paradigm shift in robust construct measurement over time.

EASIX and m-EASIX Predict CRS and ICANS in Pediatric and AYA Patients post CD19-CAR T cell Therapy.

Cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) are complications of CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy. The Endothelial Activation and Stress Index (EASIX) and modified EASIX (m-EASIX) scores have been retrospectively proven to be predictive of CRS and ICANS in adult CAR T cell recipients. However, these scores have not been evaluated in pediatric cohorts. We retrospectively report on 76 pediatric, adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) treated with CD19-CAR T cells at St. Jude Children's Research Hospital or John's Hopkins Hospital. Data included patient-, disease-, and treatment characteristics. EASIX and m-EASIX scores were calculated at days -5 pre, 0 and +3 post CAR T cell infusion. CRS and ICANS occurred in 47 and 17 patients, respectively. At all evaluated time points, compared to those with no/mild CRS/ICANS, median EASIX scores were higher for patients who developed severe CRS and any-grade ICANS, and median m-EASIX scores were higher in patients who developed severe CRS and severe ICANS. Receiver Operating Characteristic (ROC) curve analysis showed that both scores were strong predictors of CRS, especially severe CRS, at all time points. Any grade and severe ICANS were best predicted by both scores at day +3. m-EASIX uniformly outperformed EASIX, except for predicting any grade ICANS. Our results validate the potential utility for EASIX and m-EASIX scores for predicting CAR T-cell related complications for pediatric and AYA patients.