Titration of RAS alters senescent state and influences tumour initiation.

Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with premalignancy1,2. Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS dose-escalation models in vitro and in vivo, revealing a RAS dose-driven non-linear continuum of downstream phenotypes. In a hepatocyte OIS model in vivo, ectopic expression of NRAS(G12V) does not induce tumours, in part owing to OIS-driven immune clearance3. Single-cell RNA sequencing analyses reveal distinct hepatocyte clusters with typical OIS or progenitor-like features, corresponding to high and intermediate levels of NRAS(G12V), respectively. When titred down, NRAS(G12V)-expressing hepatocytes become immune resistant and develop tumours. Time-series monitoring at single-cell resolution identifies two distinct tumour types: early-onset aggressive undifferentiated and late-onset differentiated hepatocellular carcinoma. The molecular signature of each mouse tumour type is associated with different progenitor features and enriched in distinct human hepatocellular carcinoma subclasses. Our results define the oncogenic dosage-driven OIS spectrum, reconciling the senescence and tumour initiation phenotypes in early tumorigenesis.

CSU-ALS Certified Centers are Associated with Improved Failure to Rescue After Cardiac Arrest: A Propensity Score Match Analysis.

OBJECTIVE: The impact of Cardiac Surgical Unit - Advanced Life Support (CSU-ALS) training on failure to rescue after cardiac arrest (FTR-CA) is unknown. We hypothesized that institutional CSU-ALS certification would be associated with lower FTR-CA. METHODS: Patients undergoing Society of Thoracic Surgeons (STS) index operations from 2020-2023 from a regional collaborative were analyzed. Each institution was surveyed regarding its status as a CSU-ALS certified center. Patients stratified by CSU-ALS certification were 1:1 propensity score matched with subsequent multivariable model reviewing associations with failure to rescue after cardiac arrest. RESULTS: A total of 12209 patients were included in the study period across 15 institutions. Eight centers reported CSU-ALS certification. After propensity score matching, two patient cohorts were formed (n = 3557). Patients at CSU-ALS centers had higher rates of ICU readmission (3.9% vs 2.3%, p<0.01) and total OR time (340 min vs 323 min, p<0.01). Hospital readmission was less likely in the CSU-ALS centers (9.0% vs 10.1%, p <0.01). There was no difference in the rate of post-operative cardiac arrest (1.8% vs 2.2 %, p = 0.24) or operative mortality (2.5% vs 2.9%, p = 0.30). After risk-adjustment, CSU-ALS centers (OR 0.30 [CI 0.12 - 0.72], p <0.01) and higher-volume centers (OR 0.15 [CI 0.03 - 0.74], p = 0.02) had reduced odds of FTR after cardiac arrest. CONCLUSIONS: Centers with CSU-ALS certification are associated with a lower risk-adjusted likelihood of FTR after cardiac arrest. This highlights the importance of well-trained staff and treatment algorithms in the care of post-operative cardiac surgery patients.

Trigeminal neuralgia with enlarged suprameatal tubercle: A case report.

According to the International Classification of Orofacial Pain (ICOP), secondary trigeminal neuralgia can result from various conditions such as tumors in the cerebellopontine angle, arteriovenous malformation, and multiple sclerosis. This case report describes a 41-year-old woman with trigeminal neuralgia caused by narrowing of the cerebellopontine cistern due to an enlarged suprameatal tubercle. Carbamazepine treatment was initially effective, but became inadequate within a few months. Magnetic resonance imaging revealed compression of the trigeminal nerve by the superior cerebellar artery and an enlarged suprameatal tubercle. Microvascular decompression surgery was done to alleviate the neurovascular compression. Dentists should be aware of such anatomical factors contributing to trigeminal neuralgia, particularly in younger patients. Key words:Trigeminal neuralgia, enlarged suprameatal tubercle, microvascular decompression.

Therapeutic Efficacy of Mirogabalin in managing Trigeminal Neuralgia.

Trigeminal neuralgia presents significant challenges in management, often requiring alternative pharmacotherapy due to resistance or side effects to first-line medications like carbamazepine. This case series investigates the efficacy and safety of mirogabalin, a novel α2δ ligand, in six trigeminal neuralgia patients. Mirogabalin demonstrated varying degrees of pain reduction, with an average Numerical Rating Scale improvement rate of 43.1%. Side effects were generally mild, with drowsiness and dizziness being the most common. Despite limited efficacy in some cases, mirogabalin shows promise as a potential treatment option for trigeminal neuralgia, warranting further investigation. Key words:Trigeminal neuralgia, mirogabalin, α2δ lig.

Exposure Effects of Environmentally Relevant Concentrations of the Tricyclic Antidepressant Amitriptyline in Early Life Stage Zebrafish.

Antidepressants are one of the most globally prescribed classes of pharmaceuticals, and drug target conservation across phyla means that nontarget organisms may be at risk from the effects of exposure. Here, we address the knowledge gap for the effects of chronic exposure (28 days) to the tricyclic antidepressant amitriptyline (AMI) on fish, including for concentrations with environmental relevance, using zebrafish (Danio rerio) as our experimental model. AMI was found to bioconcentrate in zebrafish, was readily transformed to its major active metabolite nortriptyline, and induced a pharmacological effect (downregulation of the gene encoding the serotonin transporter; slc6a4a) at environmentally relevant concentrations (0.03 µg/L and above). Exposures to AMI at higher concentrations accelerated the hatch rate and reduced locomotor activity, the latter of which was abolished after a 14 day period of depuration. The lack of any response on the features of physiology and behavior we measured at concentrations found in the environment would indicate that AMI poses a relatively low level of risk to fish populations. The pseudopersistence and likely presence of multiple drugs acting via the same mechanism of action, however, together with a global trend for increased prescription rates, mean that this risk may be underestimated using current ecotoxicological assessment paradigms.

Adenosine 2A Receptor Agonism Improves Survival in Extracorporeal Cardiopulmonary Resuscitation.

INTRODUCTION: Despite resuscitation advances including extracorporeal cardiopulmonary resuscitation (ECPR), freedom from neurologic and myocardial insult after cardiac arrest remains unlikely. We hypothesized that adenosine 2A receptor (A2AR) agonism, which attenuates reperfusion injury, would improve outcomes in a porcine model of ECPR. METHODS: Adult swine underwent 20 min of circulatory arrest followed by defibrillation and 6 h of ECPR. Animals were randomized to receive saline vehicle or A2AR agonist (ATL1223 or Regadenoson) infusion during extracorporeal membrane oxygenation. Animals were weaned off extracorporeal membrane oxygenation and monitored for 24 h. Clinical and biochemical end points were compared. RESULTS: The administration of A2AR agonists increased survival (P = 0.01) after cardiac arrest compared to vehicle. Markers of neurologic damage including S100 calcium binding protein B and glial fibrillary acidic protein were significantly lower with A2AR agonist treatment. CONCLUSIONS: In a model of cardiac arrest treated with ECPR, A2AR agonism increased survival at 24 h and reduced neurologic damage suggesting A2AR activation may be a promising therapeutic target after cardiac arrest.

Mitral valve repair in a regional quality collaborative: Respect or resect?

Objective: Mitral valve repair is the gold standard for treatment of mitral regurgitation, but the optimal technique remains debated. By using a regional collaborative, we sought to determine the change in repair technique over time. Methods: We identified all patients undergoing isolated mitral valve repair from 2012 to 2022 for degenerative mitral disease. Those with endocarditis, transcatheter repair, or tricuspid intervention were excluded. Continuous variables were analyzed via Wilcoxon rank sum, and categorical variables were analyzed via chi-square testing. Results: We identified 1653 patients who underwent mitral valve repair, with 875 (59.2%) undergoing a no resection repair. Over the last decade, there was no significant trend in the proportion of repair techniques across the region (P = .96). Those undergoing no resection repairs were more likely to have undergone prior cardiac surgery (5.0% vs 2.2%, P = .002) or minimally invasive approaches (61.4% vs 24.7%, P < .001) with similar predicted risk of mortality (median 0.6% vs 0.6%, P = .75). Intraoperatively, no resection repairs were associated with longer bypass times (140 [117-167] minutes vs 122 [91-159] minutes, P < .001). Operative mortality was similar between both groups (1.1% vs 1.0%, P = .82), as were other postoperative outcomes. Anterior leaflet prolapse (odds ratio, 11.16 [6.34-19.65], P < .001) and minimally invasive approach (odds ratio, 6.40 [5.06-8.10], P < .001) were most predictive of no resection repair. Conclusions: Despite minor differences in operative times, statewide over the past decade there remains a diverse mix of both classic "resect" and newer "respect" strategies with comparable short-term outcomes and no major timewise trends. These data may suggest that both approaches are equivocal.

Pioglitazone does not enhance exogenous glucose oxidation or metabolic clearance rate during aerobic exercise in men under acute high-altitude exposure.

Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer before acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared with placebo (PLA) during aerobic exercise at HA. With the use of a randomized crossover design, native lowlanders (n = 7 males, means ± SD, age: 23 ± 6 yr, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80 min of steady-state (1.43 ± 0.16 V̇o2 L/min) treadmill exercise at HA (460 mmHg; [Formula: see text] 96.6 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes ([13C]glucose and 6,6-[2H2]glucose). Exogenous glucose oxidation was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation (PIO: 1.65 ± 0.22 g/min, PLA: 1.68 ± 0.32 g/min) or fat oxidation (PIO: 0.10 ± 0.0.08 g/min, PLA: 0.09 ± 0.07 g/min) was not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min), disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests that the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues.NEW & NOTEWORTHY Short-term (5 days) use of the oral insulin sensitizer pioglitazone does not alter circulating glucose or insulin responses to enhance exogenous glucose oxidation during steady-state aerobic exercise in young healthy men under simulated acute (8 h) high-altitude (460 mmHg) conditions. These results indicate that dysregulations in glucose metabolism in native lowlanders sojourning at high altitude may not be due to insulin resistance at peripheral tissue.

Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model.

OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel important in many physiological and pathophysiological processes, including pulmonary disease. Using a murine model, we previously demonstrated that TRPV4 mediates lung ischemia-reperfusion injury, the major cause of primary graft dysfunction after transplant. The current study tests the hypothesis that treatment with a TRPV4 inhibitor will attenuate lung ischemia-reperfusion injury in a clinically relevant porcine lung transplant model. METHODS: A porcine left-lung transplant model was used. Animals were randomized to 2 treatment groups (n = 5/group): vehicle or GSK2193874 (selective TRPV4 inhibitor). Donor lungs underwent 30 minutes of warm ischemia and 24 hours of cold preservation before left lung allotransplantation and 4 hours of reperfusion. Vehicle or GSK2193874 (1 mg/kg) was administered to the recipient as a systemic infusion after recipient lung explant. Lung function, injury, and inflammatory biomarkers were compared. RESULTS: After transplant, left lung oxygenation was significantly improved in the TRPV4 inhibitor group after 3 and 4 hours of reperfusion. Lung histology scores and edema were significantly improved, and neutrophil infiltration was significantly reduced in the TRPV4 inhibitor group. TRPV4 inhibitor-treated recipients had significantly reduced expression of interleukin-8, high mobility group box 1, P-selectin, and tight junction proteins (occludin, claudin-5, and zonula occludens-1) in bronchoalveolar lavage fluid as well as reduced angiopoietin-2 in plasma, all indicative of preservation of endothelial barrier function. CONCLUSIONS: Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant.

Circulating Monocytes Are Predictive and Responsive in Moderate-to-Severe Plaque Psoriasis Subjects Treated with Apremilast.

Monocytes play a critical role in the inflammation associated with psoriasis, and their abnormalities have been reported as biomarkers of cardiovascular event risk, a psoriasis comorbidity. Monocytic cells in chronic inflammatory disorders express elevated levels of cAMP phosphodiesterase. Restoring cAMP levels using the oral cAMP phosphodiesterase-4 inhibitor, apremilast, improves clinical outcomes for a subset of patients with psoriasis. We asked whether aberrant monocyte subsets or transcriptomic pathways can function as biomarkers of psoriasis endotypes that can predict enhanced clinical responses to cAMP phosphodiesterase inhibition. A 16-week open-label study of 22 patients with monocyte flow cytometric and transcriptomic analysis was performed. Subjects with elevated hyperadhesive monocyte doublets at baseline were more likely to be responders to apremilast (P < .0001); 82% of subjects with elevated hyperadhesive monocyte doublets achieved 50% reduction in PASI compared with 46% in those without elevated doublets. We observed a significant reduction in hyperadhesive monocyte-containing doublets and monocyte-platelet aggregates, suggesting an effect of apremilast on the adhesiveness of blood monocytes during chronic inflammation. Monocyte differentially expressed gene transcripts predictive of clinical response uncovered pharmacoendotypes with distinct patterns of nucleotide metabolism, energetics, and differentiation. Further study to understand the basis of drug responsiveness and to develop an apremilast psoriasis treatment algorithm using monocyte-refined gene expression is required to validate and become practical in clinical use, offering patients a test that personalizes their likelihood of clinical response.

Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination.

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.

Yield prediction in a peanut breeding program using remote sensing data and machine learning algorithms.

Peanut is a critical food crop worldwide, and the development of high-throughput phenotyping techniques is essential for enhancing the crop's genetic gain rate. Given the obvious challenges of directly estimating peanut yields through remote sensing, an approach that utilizes above-ground phenotypes to estimate underground yield is necessary. To that end, this study leveraged unmanned aerial vehicles (UAVs) for high-throughput phenotyping of surface traits in peanut. Using a diverse set of peanut germplasm planted in 2021 and 2022, UAV flight missions were repeatedly conducted to capture image data that were used to construct high-resolution multitemporal sigmoidal growth curves based on apparent characteristics, such as canopy cover and canopy height. Latent phenotypes extracted from these growth curves and their first derivatives informed the development of advanced machine learning models, specifically random forest and eXtreme Gradient Boosting (XGBoost), to estimate yield in the peanut plots. The random forest model exhibited exceptional predictive accuracy (R2 = 0.93), while XGBoost was also reasonably effective (R2 = 0.88). When using confusion matrices to evaluate the classification abilities of each model, the two models proved valuable in a breeding pipeline, particularly for filtering out underperforming genotypes. In addition, the random forest model excelled in identifying top-performing material while minimizing Type I and Type II errors. Overall, these findings underscore the potential of machine learning models, especially random forests and XGBoost, in predicting peanut yield and improving the efficiency of peanut breeding programs.

Glossopharyngeal neuralgia due to vertebrobasilar dolichoectasia: a case report.

Glossopharyngeal neuralgia due to vertebrobasilar dolichoectasia is a rare form of neuropathic pain, and presents diagnostic and therapeutic challenges. Clinical presentation: A 67-year-old man presented with severe burning pain in the left oral cavity, with no explanatory findings during dental and ear, nose, and throat evaluations. Temporomandibular joint examination revealed tenderness, and panoramic radiographs showed a noncontributory periapical radiolucency. Magnetic resonance imaging/magnetic resonance angiography revealed abnormally tortuous vertebral arteries compressing the glossopharyngeal nerves and the brainstem. Topical lidocaine reduced pain, confirming glossopharyngeal neuralgia. Carbamazepine was initially ineffective, but at 200 mg pain reduced from 90 to 20 on the visual analog scale. The patient requested and underwent microvascular decompression surgery, which eliminated his pain. Conclusion: When the vertebral artery compresses the glossopharyngeal nerve, the pain is more intense, attributed to its thicker vascular structure. Local anesthetic testing aids in identifying glossopharyngeal neuralgia. Dental practitioners must be skilled in diagnostics and possess anatomical knowledge for accurate evaluation and referral of throat and ear pain.

Spatial Mapping of Hematopoietic Clones in Human Bone Marrow.

Clonal hematopoiesis (CH) is the expansion of somatically mutated cells in the hematopoietic compartment of individuals without hematopoietic dysfunction. Large CH clones (i.e., >2% variant allele fraction) predispose to hematologic malignancy, but CH is detected at lower levels in nearly all middle-aged individuals. Prior work has extensively characterized CH in peripheral blood, but the spatial distribution of hematopoietic clones in human bone marrow is largely undescribed. To understand CH at this level, we developed a method for spatially aware somatic mutation profiling and characterized the bone marrow of a patient with polycythemia vera. We identified the complex clonal distribution of somatic mutations in the hematopoietic compartment, the restriction of somatic mutations to specific subpopulations of hematopoietic cells, and spatial constraints of these clones in the bone marrow. This proof of principle paves the way to answering fundamental questions regarding CH spatial organization and factors driving CH expansion and malignant transformation in the bone marrow. SIGNIFICANCE: CH occurs commonly in humans and can predispose to hematologic malignancy. Although well characterized in blood, it is poorly understood how clones are spatially distributed in the bone marrow. To answer this, we developed methods for spatially aware somatic mutation profiling to describe clonal heterogeneity in human bone marrow. See related commentary by Austin and Aifantis, p. 139.

Risk Minimization in Scale-Up of Biomass and Waste Carbon Upgrading Processes.

Improving the odds and pace of successful biomass and waste carbon utilization technology scale-up is crucial to decarbonizing key industries such as aviation and materials within timelines required to meet global climate goals. In this perspective, we review deficiencies commonly encountered during scale-up to show that many nascent technology developers place too much focus on simply demonstrating that technologies work in progressively larger units ("profit") without expending enough up-front research effort to identify and derisk roadblocks to commercialization (collecting "information") to inform the design of these units. We combine this conclusion with economic and timeline data collected from technology scale-up and piloting operations at the National Renewable Energy Laboratory (NREL) to motivate a more scientific, risk-minimized approach to biomass and waste carbon upgrading scale-up. Our proposed approach emphasizes maximizing information collection in the smallest, most agile, and least expensive experimental setups possible, emulating the mentality embraced by R&D across the petrochemical industry. Key points are supported by examples of successful and unsuccessful scale-up efforts undertaken at NREL and elsewhere. We close by showing that the U.S. national laboratory system is uniquely well equipped to serve as a hub to facilitate effective scale-up of promising biomass and waste carbon upgrading technologies.

Five-Year Sustained Impact of a Thoracic Enhanced Recovery After Surgery Program.

BACKGROUND: Our thoracic enhanced recovery program (ERP) decreased the use of postoperative morphine equivalents and hospital costs 1 year after implementation at our tertiary center. The sustainability and potential increasing benefit of this program were evaluated. METHODS: From 2015 to 2021, we prospectively analyzed the outcomes of patients who underwent elective pleural, pulmonary, or mediastinal operations at our institution. Patients were separated on the basis of the incision (video-assisted thoracoscopic surgery [VATS] or thoracotomy). The ERP protocol was initiated on May 1, 2016, and includes preoperative education, carbohydrate loading, opioid-sparing analgesia, conservative fluid management, protective ventilation, and early ambulation. Outcomes of patients before (2015, pre-VATS and pre-thoracotomy) and after (May 1, 2016, to December 31, 2021, ERP-VATS and ERP-thoracotomy) ERP implementation were compared. RESULTS: The cohort included 1079 patients (pre-ERP era, n = 224 [21%]; ERP era, n = 855 [79%]). There was a median reduction of 1.5 hospital days per patient for ERP-thoracotomy and 1 hospital day per patient for ERP-VATS. Median postoperative morphine equivalents decreased in both groups (125 vs 45 mg, in ERP-thoracotomy; 84 vs 23 mg, ERP-VATS; P < .001), as did total admission cost ($32,118 vs $23,775, ERP-thoracotomy; $17,367 vs $11,560, ERP-VATS; P < .001). Median total fluid balance during the hospital stay decreased significantly. Rates of postoperative atrial fibrillation and urinary retention decreased across both subgroups. CONCLUSIONS: ERP for thoracic surgery is sustainable and has been demonstrated to improve patient outcomes, to decrease opioid use, and to lower hospital costs. Therefore, it has the potential to become the standard of care.

Sixth cranial nerve palsy and trigeminal neuropathic pain due to a space-occupying lesion.

Various neuropathies of the cranil nerves can accompany trigeminal neuropathic pain attributed to space-occupying lesions. In this case report, the patient presented with persistent intraoral pain and numbness on the right side of the face. Cranial nerve examination revealed dysfunctional eye movements, diplopia, and mechanical hyposensitivity in the mandibular region. The patient was diagnosed with neuropathy due to intracranial lesions and referred to the Department of Neurosurgery and Otorhinolaryngology. The patient was suspected of having malignant lymphoma and is currently undergoing neurosurgical intervention. This article discusses the importance of the examination of the cranial nerve for patients with persistent pain in the trigeminal nerve distribution.

Outcomes of Injured Patients Before and After the Institution of a Third-Tier Activation at a Level 1 Trauma Center.

BACKGROUND: We hypothesized that the addition of a third-level trauma activation would improve outcomes by formalizing an evaluation process for patients in need of urgent evaluation who did not meet the criteria for full or partial trauma alert activation. METHODS: Admission records for all trauma patients admitted between 2000 and 2021 were obtained. The gamma alert trauma activation was implemented in 2011. A washout period of 6 months was used to account for adjustment to the new protocol. Propensity score matching was performed based on ISS scores, age, injury mechanism, and best-validated comorbidities to create a balanced patient distribution. Patients with missing data were excluded from this study. The association between era and outcomes was determined using logistic and linear regression analyses. RESULTS: The matched cohort was well balanced (SMD <.1, all balanced covariates) and included 18,572 patients. Patients in the gamma alert era had decreased ED dwell time, hospital length of stay, and intensive care unit (ICU) length of stay. Readmission rates and rates of upgrade to ICU status were reduced in the gamma alert era. This era was also associated with lower rates of renal failure, UTI, and pneumonia. There was no significant difference in mortality following implementation of the gamma alert. DISCUSSION: Implementation of the gamma alert was associated with an improvement in ED dwell times, fewer unplanned admissions to the ICU, decreased readmissions, and a reduction in other in-hospital events. We believe that this reflects improved triage of patients to the ICU and more effective care of trauma patients.