Abstract Chronic ultraviolet (UV) exposure drives the development of non-melanoma skin cancers (NMSCs), particularly cutaneous squamous cell carcinoma (cSCC), through persistent DNA damage and inflammation. However, how UV-induced epithelial damage is coupled to inflammatory signaling and tumor–stromal communication during skin carcinogenesis remains incompletely understood. Here, we identify CD70, a TNF superfamily member, as a UV- and DNA damage–inducible regulator that links epithelial stress responses to stromal activation and tumor-promoting signaling. Integrative analyses of transcriptomic (GTEx, GSE2503, GSE42677), proteomic (RPPA), and immunostaining datasets reveal robust upregulation of CD70 in sun-exposed skin, actinic keratoses, and cSCC lesions. Functionally, CD70 silencing suppresses cSCC proliferation and xenograft growth, whereas solar UV or DMBA exposure induces CD70 expression. CD70 depletion disrupts cytokine–receptor signaling and MAPK/NF-κB pathways and alters inflammatory gene expression in UV-irradiated keratinocytes. In dermal fibroblasts, CD70 enhances NF-κB activation and secretion of IL-6 and MCP3 in TGF-β–activated fibroblasts, thereby reinforcing paracrine inflammatory loops that support cSCC spheroid expansion and tumor progression. CD70 knockdown in fibroblasts abrogates these effects and reduces tumor proliferation and cytokine expression in vivo. Mechanistically, E2F1 directly binds and activates the CD70 promoter, linking the DNA damage response to CD70 upregulation. Collectively, our findings identify CD70 as a stress-inducible signaling hub that links DNA damage, inflammation, and tumor–stromal communication in skin carcinogenesis. Targeting CD70 may disrupt this feed-forward inflammatory circuit and provide a therapeutic strategy for UV-driven and inflammation-associated cSCC.

PURPOSE:Physical activity (PA) and sedentary behavior (SB) are associated with many diseases, including Alzheimer disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. This study aims to address this gap, with a specific focus on all-cause dementia. METHODS:We first assessed the conventional observational associations of three self-reported and three device-based PA/SB measures with circulating levels of 2911 plasma proteins measured in the UK Biobank ( nmax = 39,160) and assessed functional enrichment of identified proteins. We then used bidirectional Mendelian randomization to further evaluate the evidence for causal relationships of PA/SB with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia. RESULTS:Our findings revealed 41 proteins consistently associated with all PA measures and 1027 proteins associated with at least one PA measure. Both conventional observational and Mendelian randomization study designs converged on proteins that appear to increase as a result of PA, including integrins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, LPL, and ADGRG2; and on proteins that appear to decrease as a result of PA such as LEP, INHBC, CLMP, PTGDS, ADM, OGN, and PI3; and on proteins that are more responsive to high-intensity PA, such as CA14, CA6, CA4, KIT, and ANGPT2. Functional enrichment analyses revealed processes such as cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, GDF15, ITGAV, ITGAM, ITGA11, HPGDS, GFAP, ADM, AHNAK, and DPP4 were among 21 unique proteins found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis, and inflammation. CONCLUSIONS:Our results provide insights into how PA affects biological processes and protects against dementia, and provide avenues for future research into the health-promoting effects of PA.

Background: The EMS TBI Guidelines support carefully controlling ventilation in the EMS management of intubated TBI patients [preventing hyperventilation (to enhance cerebral blood flow) and over-ventilation (to provide lung-protective volumes). However, it is difficult to achieve guideline-compliant ventilation when manually ventilating intubated patients in the field. While mechanical ventilators (Mech) have been used for decades in air medical transport, little is known about the impact of their use in ground-based EMS systems. Methods: We analyzed the EPIC Study data (NIH-1R01NS071049; DOD-W81XWH-19-C-0058) to compare hospital mortality in intubated major TBI patients transported by ground-based EMS who received Manual vs. Mech. Context: The pre- and post-implementation cohorts of EPIC (intervention: aggressive prevention/treatment of hypoxia, hypotension, and hyperventilation). Chi-squared was used for unadjusted comparisons. Adjusted analysis used logistic regression, controlling for pre-determined confounders. Results: Included were 2083 intubated subjects [74.4% male; median age 36 years (IQR 22-54); Manual: n=1913; 1341 deaths (70.1% mortality); Mech: n=170; 51 deaths (30.0%; p<0.0001). The unadjusted OR for death in the Manual cohort vs Mech was 5.5 (95%CI: 3.9, 7.7) and the adjusted OR was 2.5 (1.3, 4.8; p=0.005). The Figure portrays the unadjusted and adjusted mortality comparisons in the pre- vs post-implementation periods. The association between ventilation method and mortality was marginally stronger in the post-implementation period (p=0.07). Conclusions: In this observational study of intubated, severe TBI patients cared for by ground-based EMS, prehospital Mech was associated with significantly lower mortality than Manual (both unadjusted and adjusted). Furthermore, in the setting of implementing the EMS TBI Guidelines, these associations were even stronger in the post-implementation period. This implies that, in the setting of ground EMS, the combination of mechanically-controlled ventilation and training that focuses on reducing hyper- and over-ventilation (by carefully managing End-Tidal CO2) may be associated with better outcome. We do not believe this finding has been previously reported. The magnitude of the associated improvement seen in this preliminary study clearly sets the stage for a large, multisystem clinical trial. These findings may also have implications for EMS resuscitative care in other critically ill patients.

The incidence of cutaneous squamous cell carcinoma (cSCC) is rising due to limited prevention strategies. Significant gaps persist in understanding the mechanisms of UV-induced DNA damage and immune modulation in skin cancer development. By analyzing expression data from sun-exposed and sun-protected skin in the Genotype-Tissue Expression (GTEx) database and the Gene Expression Omnibus (GEO), we identified CD70 as a key gene linking solar UV exposure, immune responses, and photocarcinogenesis. Reverse Phase Protein Microarray Analysis (RPPA) revealed a significant upregulation of CD70 in sun-damaged skin compared to sun-protected skin. CD70 expression was also markedly higher in actinic keratosis (AK) and cSCC compared to normal tissue. In this study, we investigated the mechanistic role of CD70 in solar simulated light (SSL,149 kJ/m2 UVA & 7.2 kJ/m2 UVB)-exposed keratinocytes and cSCC. CD70 expression was found to increase in keratinocytes following SSL irradiation in a dose- and time-dependent manner. Deletion of CD70 effectively suppressed cSCC cell growth in both 2D and 3D culture models. RNA sequencing (RNA-seq) analysis (shCon vs. shCD70) revealed that CD70 regulates gene expression changes induced by solar UV exposure through multiple oncogenic pathways. CD70-associated genes are strongly linked to AK and cSCC and involve critical signaling pathways, including MAPK, Rap1, and others. Additionally, CD70 deletion inhibits NFkappa B nuclear translocation, as demonstrated by luciferase assays and immunofluorescence analysis. In summary, these findings underscore the pivotal role of CD70 in SSL-induced skin damage and photocarcinogenesis. The CD70 inhibition may offer a novel targeted strategy for preventing and treating cSCC. Asad Khan, Qiushi Wang, Chengcheng Hu, Emannuel Petricoin, Rebecca Morris, Georg T. Wondrak, Ann M. Bode, Clara Curiel-Lewandrowski, Tianshun Zhang. Mechanistic role of CD70 in UV exposed keratinocytes and cutaneous squamous cell carcinoma (cSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3487.

The study used a qualitative approach to explore how perceived neighborhood disorder influences health-related decisions among people living with HIV. Recognizing the crucial role environmental factors play in health behaviors, this research seeks to bridge a gap in understanding how neighborhood dynamics affect individuals with HIV. A qualitative research design with interpretive qualitative analysis was used. The interview guide and analysis were guided by the Broken Windows Theory and Social Cognitive Theory, enabling an exploration of the intersection between environmental perceptions and healthcare behaviors. Data were collected through telephonic in-depth interviews with 18 participants from two HIV clinics from June 2022 to February 2023. Interviews were analyzed using the Dedoose software 9.0.17 and narratives were enriched using their survey data from a cross-sectional study with a validated scale to measure perceived neighborhood disorder. Our findings show that perceived neighborhood disorder influences HIV care-related decisions through a diminished sense of control pathway. Also, healthcare settings emerge as a mitigator of the influence of perceived neighborhood disorder on HIV care-related decisions by offering a sense of control. Perception of lower neighborhood disorder correlates with a strong sense of control and a preference for specialized care. As the perception of neighborhood disorder increases, there is a shift toward care settings that balance specialized services with a supportive care environment. A higher perception of neighborhood disorder leads to prioritized care settings that provide a sense of community support, and discretion, reflecting adaptations to a compromised sense of control. This research underscores the influence of neighborhood disorder on health-related decisions through the pathway of self-control, emphasizing the role that healthcare environments play as mitigators. For chronic disease management, such as with HIV, the development of healthcare settings that reinforce patient autonomy and control, alongside community efforts to diminish signs of disorder, and their underlying causes is crucial.

The immune checkpoint ligand PD-L1 has emerged as a molecular target for skin cancer therapy and might also hold promise for preventive intervention targeting solar ultraviolet light-induced skin damage. Here we have explored the role of PD-L1 in acute keratinocytic photodamage testing the effects of small molecule pharmacological inhibition. Epidermal PD-L1 upregulation in response to chronic photodamage was established using IHC and proteomic analyses of a human skin cohort, consistent with earlier observations that PD-L1 is upregulated in cSCC. Topical application of the small molecule PD-L1 inhibitor BMS-202 significantly attenuated UV-induced AP-1 transcriptional activity in SKH-1 bioluminescent reporter mouse skin, also confirmed in human HaCaT reporter keratinocytes. RT-qPCR analysis revealed that BMS-202 antagonized UV-induction of inflammatory gene expression. Likewise, UV-induced cleavage of procaspase-3, a hallmark of acute skin photodamage, was attenuated by topical BMS-202. NanoString nCounterTM transcriptomic analysis confirmed downregulation of cutaneous ‘innate immunity’- and ‘inflammation’-related responses together with upregulation of ‘immune response’ pathway gene expression. Further mechanistic analysis confirmed that BMS-202 antagonizes UV-induced PD-L1 expression both at the mRNA and protein levels in SKH-1 epidermis. These data suggest that topical pharmacological PD-L1 antagonism using BMS-202 shows promise for skin protection against photodamage.

Background: It is well established that prehospital hypoxia dramatically increases mortality in Traumatic Brain Injury (TBI). Thus, in EMS TBI research, case ascertainment and risk adjustment are highly dependent upon documentation of in-field O 2 saturation (SpO 2 ). Objective: To compare the rate of hypoxia identified by EMS personnel and documented in EMS patient care records (PCR) versus the actual rate of hypoxia recorded by continuous, non-invasive monitoring in TBI. Methods: A subset of major TBI cases (moderate/severe) from 5 EMS agencies reporting monitor data (Philips MRx™) in the EPIC EMS TBI Study (NIH 1R01NS071049) were evaluated (02/13-02/18). All monitor data available for post-hoc review were displayed and accessible to the providers during EMS care. We compared PCR documentation of hypoxia (SpO 2 <90%) to continuous monitor data in TBI patients (nasal canula O 2 , mask, basic or advanced airway). Statistic: exact McNemar’s test, α=0.05. Results: 120 cases were included [med. age 50; IQR (23.8, 68); 65% male. Monitors recorded 44 hypoxic cases (36.7%; 95%CI 28.1, 45.9%). Only 8 (6.7%; 2.9, 12.7%) were documented in the PCR (p<0.0001; Figure). Three machine-detected hypoxia cases had no PCR-documented SpO 2 at all. Conclusions: The difference in PCR-documented and monitor-identified hypoxia was dramatic. The monitor data revealed a five-fold greater incidence of hypoxia than that documented by EMS providers. This may be partially explained by the continuous nature of pulse oximetry in the face of ongoing care responsibilities and scene distractions. The field environment may cause providers to miss low readings as they fluctuate moment-by-moment. These findings have major clinical implications. While some of the discrepancy between PCR reporting and monitor data might simply be failure to document hypoxia, the much more concerning implication is that many cases might be unrecognized and untreated. Furthermore, these findings have important implications for case ascertainment, confounding, and risk-adjustment in EMS TBI research. Whenever possible, quality improvement and research projects should utilize continuous non-invasive monitor data to identify and evaluate hypoxic patients in the setting of TBI. These findings may also have implications for identifying hypoxia in EMS patients with other critical conditions.

AbstractObjectivesTraumatic brain injury (TBI) is an important public health problem resulting in significant death and disability. Emergency medical services (EMS) personnel often provide initial treatment for TBI, but only limited data describe the long‐term course and outcomes of this care. We sought to characterize changes in neurologic status among adults with TBI patients enrolled in the Resuscitation Outcomes Consortium Hypertonic Saline (ROC‐HS) trial.MethodsWe used data from the TBI cohort of the ROC‐HS trial. The trial included adults with TBI, with Glasgow Coma Scale (GCS) ≤8, and excluded those with shock (systolic blood pressure [SBP] ≤70 or SBP 71–90 with a heart rate [HR] ≥108). The primary outcome was Glasgow Outcome Scale–Extended (GOS‐E; 1 = dead, 8 = no disability) determined at (a) hospital discharge and (b) 6‐month follow‐up. We assessed changes in GOS‐E between hospital discharge and 6‐month follow‐up using descriptive statistics and Sankey graphs.ResultsAmong 1279 TBI included in the analysis, GOS‐E categories at hospital discharge were as follows: favorable (GOS‐E 5–8) 220 (17.2%), unfavorable (GOS‐E 2–4) 664 (51.9%), dead (GOS‐E 1) 321 (25.1%), and missing 74 (5.8%). GOS‐E categories at 6‐month follow‐up were as follows: favorable 459 (35.9%), unfavorable 279 (21.8%), dead 346 (27.1%), and missing 195 (15.2%). Among initial TBI survivors with complete GOS‐E, >96% followed one of three neurologic recovery patterns: (1) favorable to favorable (20.0%), (2) unfavorable to favorable (40.3%), and (3) unfavorable to unfavorable (36.0%). Few patients deteriorated from favorable to unfavorable neurologic status, and there were few additional deaths.ConclusionsAmong TBI receiving initial prehospital care in the ROC‐HS trial, changes in 6‐month neurologic status followed distinct patterns. Among TBI with unfavorable neurologic status at hospital discharge, almost half improved to favorable neurologic status at 6 months. Among those with favorable neurologic status at discharge, very few worsened or died at 6 months. These findings have important implications for TBI clinical care, research, and trial design.

INTRODUCTION:Identifying mild cognitive impairment (MCI) patients at risk for dementia could facilitate early interventions. Using electronic health records (EHRs), we developed a model to predict MCI to all-cause dementia (ACD) conversion at 5 years. METHODS:Cox proportional hazards model was used to identify predictors of ACD conversion from EHR data in veterans with MCI. Model performance (area under the receiver operating characteristic curve [AUC] and Brier score) was evaluated on a held-out data subset. RESULTS:Of 59,782 MCI patients, 15,420 (25.8%) converted to ACD. The model had good discriminative performance (AUC 0.73 [95% confidence interval (CI) 0.72-0.74]), and calibration (Brier score 0.18 [95% CI 0.17-0.18]). Age, stroke, cerebrovascular disease, myocardial infarction, hypertension, and diabetes were risk factors, while body mass index, alcohol abuse, and sleep apnea were protective factors. DISCUSSION:EHR-based prediction model had good performance in identifying 5-year MCI to ACD conversion and has potential to assist triaging of at-risk patients. Highlights:Of 59,782 veterans with mild cognitive impairment (MCI), 15,420 (25.8%) converted to all-cause dementia within 5 years.Electronic health record prediction models demonstrated good performance (area under the receiver operating characteristic curve 0.73; Brier 0.18).Age and vascular-related morbidities were predictors of dementia conversion.Synthetic data was comparable to real data in modeling MCI to dementia conversion. Key Points:An electronic health record-based model using demographic and co-morbidity data had good performance in identifying veterans who convert from mild cognitive impairment (MCI) to all-cause dementia (ACD) within 5 years.Increased age, stroke, cerebrovascular disease, myocardial infarction, hypertension, and diabetes were risk factors for 5-year conversion from MCI to ACD.High body mass index, alcohol abuse, and sleep apnea were protective factors for 5-year conversion from MCI to ACD.Models using synthetic data, analogs of real patient data that retain the distribution, density, and covariance between variables of real patient data but are not attributable to any specific patient, performed just as well as models using real patient data. This could have significant implications in facilitating widely distributed computing of health-care data with minimized patient privacy concern that could accelerate scientific discoveries.

Introduction and objectiveMaternal morbidity and mortality (MMM) is a public health concern in the USA, with Native American women experiencing higher rates than non-Hispanic White women. Research on risk factors for MMM among Native American women is limited. This systematic review comprehensively synthesizes and critically appraises the literature on risk factors for MMM experienced by Native American women.Methods and analysisA systematic search was conducted on 10 October 2022 in PubMed, Embase, CINAHL and Scopus for articles published since 2012. Selection criteria included observational studies set in the USA, involving Native American women in the perinatal period, and examining the relationship between risk factors and MMM outcomes. Three reviewers screened and extracted data from the included studies, with risk of bias assessed using the National Institutes of Health Quality Assessment Tools. Data were analysed descriptively.Results15 studies were included. All studies used administrative databases, with settings, including nationwide (seven studies), statewide (four studies) and Indian reservations (four studies). The majority of studies focused on hypertensive disorders of pregnancy (eight studies) and severe maternal morbidity (SMM) (four studies). 26 risk factors were identified. Key risk factors included Native American race (six studies), rural maternal residency (four studies), overweight/obese body mass index (two studies), maternal age (two studies), nulliparity (two studies) and pre-existing medical conditions (one study).ConclusionThis review identified risk factors associated with MMM among Native American women, including rural residency, overweight or obesity and advanced maternal age. However, the findings also reveal a scarcity of research specific to this population, limiting the ability to fully understand these risk factors and develop effective interventions. These results emphasise the need for further research and culturally relevant studies to inform public health and address disparities for Native American women, particularly those in rural areas.PROSPERO registration numberCRD42022363405.

Importance The Excellence in Prehospital Injury Care (EPIC) study demonstrated improved survival in patients with severe traumatic brain injury (TBI) following implementation of the prehospital treatment guidelines. The impact of implementing these guidelines in the subgroup of patients who received positive pressure ventilation (PPV) is unknown. Objective To evaluate the association of implementation of prehospital TBI evidence-based guidelines with survival among patients with prehospital PPV. Design, Setting, and Participants The EPIC study was a multisystem, intention-to-treat study using a before/after controlled design. Evidence-based guidelines were implemented by emergency medical service agencies across Arizona. This subanalysis was planned a priori and included participants who received prehospital PPV. Outcomes were compared between the preimplementation and postimplementation cohorts using logistic regression, stratified by predetermined TBI severity categories (moderate, severe, or critical). Data were collected from January 2007 to June 2017, and data were analyzed from January to February 2023. Exposure Implementation of the evidence-based guidelines for the prehospital care of patient with TBI. Main Outcomes and Measures The primary outcome was survival to hospital discharge, and the secondary outcome was survival to admission. Results Among the 21 852 participants in the main study, 5022 received prehospital PPV (preimplementation, 3531 participants; postimplementation, 1491 participants). Of 5022 included participants, 3720 (74.1%) were male, and the median (IQR) age was 36 (22-54) years. Across all severities combined, survival to admission improved (adjusted odds ratio [aOR], 1.59; 95% CI, 1.28-1.97), while survival to discharge did not (aOR, 0.94; 95% CI, 0.78-1.13). Within the cohort with severe TBI but not in the moderate or critical subgroups, survival to hospital admission increased (aOR, 6.44; 95% CI, 2.39-22.00), as did survival to discharge (aOR, 3.52; 95% CI, 1.96-6.34). Conclusions and Relevance Among patients with severe TBI who received active airway interventions in the field, guideline implementation was independently associated with improved survival to hospital admission and discharge. This was true whether they received basic airway interventions or advanced airways. These findings support the current guideline recommendations for aggressive prevention/correction of hypoxia and hyperventilation in patients with severe TBI, regardless of which airway type is used.

Serotonin 2A receptors (5-HT 2A Rs) mediate the effects of psychedelic drugs. 5-HT 2A R agonists, such as (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), that produce a psychedelic experience in humans induce a head-twitch response (HTR) behavior in rodents. However, it is unknown whether the activity of 5-HT 2A R expressing neurons is sufficient to produce the HTR in the absence of an agonist, or in which brain region 5-HT 2A Rs control the HTR. Here, we use an optogenetic approach to examine whether activation of 5-HT 2A R expressing neurons in the mouse prefrontal cortex (PFC) is sufficient to induce HTRs alone, or may augment the HTR produced by DOI, and if inhibition of these neurons prevents DOI-induced HTRs in mice. We crossed Htr2a -Cre mice to Cre-dependent optogenetic lines Ai32 (channelrhodopsin) and Ai39 (halorhodopsin) to selectively activate and inhibit (respectively) 5-HT 2A R-expressing neurons in the PFC of adult mice. We found that optogenetic stimulation of PFC 5-HT 2A R expressing neurons in the absence of an agonist does not increase HTRs in mice. In both male and female Ai32 mice that received vehicle, there was no difference in HTRs in mice that expressed Htr2a -Cre compared with control mice, indicating that optogenetic activation of 5-HT 2A R+ cells in the PFC was not sufficient to produce HTRs in the absence of an agonist. In female mice, activation of PFC 5-HT 2A R expressing neurons augmented the HTR produced by DOI. However, this result was not seen in male mice. In contrast, inhibition of 5-HT 2A R expressing neurons in the PFC prevented the increase in HTR produced by DOI in male, but not in female, mice. Together, these findings suggest that activation of 5-HT 2A Rs in the PFC is not sufficient to induce HTRs in the absence of a 5-HT 2A R agonist but is necessary for induction of HTRs by a 5-HT 2A R agonist in a sex-dependent manner.

Abstract The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers. Cancer Prev Res; 8(8); 720–8. ©2015 AACR.

Perspective on this Article from A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

Background: The EMS traumatic brain injury (TBI) guidelines recommend limiting intubation (ETI) to patients with profoundly-depressed level of consciousness (LOC) and who cannot protect their airway or adequately ventilate with basic maneuvers. Thus, many major TBIs are managed without ETI in the field. Monitoring ETCO2 via nasal sensors (NC-CO2) in non-ETI patients may provide valuable information about ventilatory status and trends. However, EMS NC-CO2 remains unstudied. Objective: To evaluate the association between LOC and NC-CO2 in non-intubated TBI. Methods: Cases from 7 EMS agencies reporting continuous monitor data (Philips MRx™) in the EPIC TBI Study (NIH 1R01NS071049) were evaluated (4/13-4/18). Comparisons in patient-level mean, median, lowest and highest NC-CO2 levels were made across GCS categories using clinically meaningful thresholds: <15, <12, <9, 3. Results: Included: 177 cases [median age: 52 (range: 9-94), 66% male]. Overall, while not statistically significant, NC-CO2 tended to be lower in patients with lower GCS (Table). In addition, minimum NC-CO2 was significantly lower (p=0.01) in patients with compromised LOC (Table). O2 management (Hi-flow/Lo-flow/No O2) was documented in 176 patients (99.4%). Among the 107 patients with all GCS = 15, 44 (41%) had Hi-flow administered compared to 47/69 (68%) with any GCS <15 (p=0.0008). Conclusion: The utility of prehospital capnography in non-intubated patients is unknown. In this study, NC-CO2 tended to be lower in TBI patients with lower GCS. Whether this reflects physiological/respiratory differences with changes in LOC, or variations in methods of managing oxygenation is unclear. These intriguing new findings require future study to determine if NC-CO2 is directly reflective of LOC-related ventilatory patterns. Furthermore, studies are needed to evaluate whether NC-CO2 monitoring has clinical utility as a non-invasive adjunct to care in spontaneously-breathing, non-ETI patients.