The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation.

Immune checkpoint inhibitors represent some of the most important cancer treatments developed in the last 20 y. However, existing immunotherapy approaches benefit only a minority of patients. Here, we provide evidence that the aryl hydrocarbon receptor (AhR) is a central player in the regulation of multiple immune checkpoints in oral squamous cell carcinoma (OSCC). Orthotopic transplant of mouse OSCC cells from which the AhR has been deleted (MOC1AhR-KO) results, within 1 wk, in the growth of small tumors that are then completely rejected within 2 wk, concomitant with an increase in activated T cells in tumor-draining lymph nodes (tdLNs) and T cell signaling within the tumor. By 2 wk, AhR+ control cells (MOC1Cas9), but not MOC1AhR-KO cells up-regulate exhaustion pathways in the tumor-infiltrating T cells and expression of checkpoint molecules on CD4+ T cells (PD-1, CTLA4, Lag3, and CD39) and macrophages, dendritic cells, and Ly6G+ myeloid cells (PD-L1 and CD39) in tdLNs. Notably, MOC1AhR-KO cell transplant renders mice 100% immune to later challenge with wild-type tumors. Analysis of altered signaling pathways within MOC1AhR-KO cells shows that the AhR controls baseline and IFNγ-induced Ido and PD-L1 expression, the latter of which occurs through direct transcriptional control. These observations 1) confirm the importance of malignant cell AhR in suppression of tumor immunity, 2) demonstrate the involvement of the AhR in IFNγ control of PD-L1 and IDO expression in the cancer context, and 3) suggest that the AhR is a viable target for modulation of multiple immune checkpoints.

The Ah Receptor from Toxicity to Therapeutics: Report from the 5th AHR Meeting at Penn State University, USA, June 2022.

The aryl hydrocarbon receptor (AHR) is a sensor of low-molecular-weight molecule signals that originate from environmental exposures, the microbiome, and host metabolism. Building upon initial studies examining anthropogenic chemical exposures, the list of AHR ligands of microbial, diet, and host metabolism origin continues to grow and has provided important clues as to the function of this enigmatic receptor. The AHR has now been shown to be directly involved in numerous biochemical pathways that influence host homeostasis, chronic disease development, and responses to toxic insults. As this field of study has continued to grow, it has become apparent that the AHR is an important novel target for cancer, metabolic diseases, skin conditions, and autoimmune disease. This meeting attempted to cover the scope of basic and applied research being performed to address possible applications of our basic knowledge of this receptor on therapeutic outcomes.

Serial Neurologic Assessment in Pediatrics (SNAP): A New Tool for Bedside Neurologic Assessment of Critically Ill Children.

OBJECTIVES: We developed a tool, Serial Neurologic Assessment in Pediatrics, to screen for neurologic changes in patients, including those who are intubated, are sedated, and/or have developmental disabilities. Our aims were to: 1) determine protocol adherence when performing Serial Neurologic Assessment in Pediatrics, 2) determine the interrater reliability between nurses, and 3) assess the feasibility and acceptability of using Serial Neurologic Assessment in Pediatrics compared with the Glasgow Coma Scale. DESIGN: Mixed-methods, observational cohort. SETTING: Pediatric and neonatal ICUs. SUBJECTS: Critical care nurses and patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serial Neurologic Assessment in Pediatrics assesses Mental Status, Cranial Nerves, Communication, and Motor Function, with scales for children less than 6 months, greater than or equal to 6 months to less than 2 years, and greater than or equal to 2 years old. We assessed protocol adherence with standardized observations. We assessed the interrater reliability of independent Serial Neurologic Assessment in Pediatrics assessments between pairs of trained nurses by percent- and bias- adjusted kappa and percent agreement. Semistructured interviews with nurses evaluated acceptability and feasibility after nurses used Serial Neurologic Assessment in Pediatrics concurrently with Glasgow Coma Scale during routine care. Ninety-eight percent of nurses (43/44) had 100% protocol adherence on the standardized checklist. Forty-three nurses performed 387 paired Serial Neurologic Assessment in Pediatrics assessments (149 < 6 mo; 91 ≥ 6 mo to < 2 yr, and 147 ≥ 2 yr) on 299 patients. Interrater reliability was substantial to near-perfect across all components for each age-based Serial Neurologic Assessment in Pediatrics scale. Percent agreement was independent of developmental disabilities for all Serial Neurologic Assessment in Pediatrics components except Mental Status and lower extremity Motor Function for patients deemed "Able to Participate" with the assessment. Nurses reported that they felt Serial Neurologic Assessment in Pediatrics, compared with Glasgow Coma Scale, was easier to use and clearer in describing the neurologic status of patients who were intubated, were sedated, and/or had developmental disabilities. About 92% of nurses preferred to use Serial Neurologic Assessment in Pediatrics over Glasgow Coma Scale. CONCLUSIONS: When used by critical care nurses, Serial Neurologic Assessment in Pediatrics has excellent protocol adherence, substantial to near-perfect interrater reliability, and is feasible to implement. Further work will determine the sensitivity and specificity for detecting clinically meaningful neurologic decline.

Providing Early Attending Physician Expertise via Telemedicine to Improve Rapid Response Team Evaluations.

OBJECTIVES: To evaluate the effect of providing early attending physician involvement via telemedicine to improve the decision process of rapid response teams. DESIGN: Quasi-experimental; three pairs of control/intervention months: June/July; August/October; November/December. SETTING: Single-center, urban, quaternary academic children's hospital with three-member rapid response team: critical care fellow or nurse practitioner, nurse, respiratory therapist. Baseline practice: rapid response team leader reviewed each evaluation with an ICU attending physician within 2 hours after return to ICU. SUBJECTS: 1) Patients evaluated by rapid response team, 2) rapid response team members. INTERVENTIONS: Implementation of a smartphone-based telemedicine platform to facilitate early co-assessment and disposition planning between the rapid response team at the patient's bedside and the attending in the ICU. MEASUREMENTS AND MAIN RESULTS: As a marker of efficiency, the primary provider outcome was time the rapid response team spent per patient encounter outside the ICU prior to disposition determination. The primary patient outcome was percentage of patients requiring intubation or vasopressors within 60 minutes of ICU transfer. There were three pairs of intervention/removal months. In the first 2 pairs, the intervention was associated with the rapid response team spending less time on rapid response team calls (June/July: point estimate -5.24 min per call; p < 0.01; August/October: point estimate -3.34 min per call; p < 0.01). During the first of the three pairs, patients were significantly less likely to require intubation or vasopressors within 60 minutes of ICU transfer (adjusted odds ratio, 0.66; 95 CI, 0.51-0.84; p < 0.01). CONCLUSIONS: Early in the study, more rapid ICU attending involvement via telemedicine was associated with rapid response team providers spending less time outside the ICU, and among patients transferred to the ICU, a significant decrease in likelihood of patients requiring vasopressors or intubation within the first 60 minutes of transfer. These findings provide evidence that early ICU attending involvement via telemedicine can improve efficiency of rapid response team evaluations.

How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression.

For decades, the aryl hydrocarbon receptor (AHR) was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a "normal" physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus is placed on the association between AHR activity and poor cancer outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival.

Apneic Oxygenation As a Quality Improvement Intervention in an Academic PICU.

OBJECTIVES: To evaluate if the use of apneic oxygenation during tracheal intubation in children is feasible and would decrease the occurrence of oxygen desaturation. DESIGN: Prospective pre/post observational study. SETTING: A large single-center noncardiac PICU in North America. PATIENTS: All patients less than 18 years old who underwent primary tracheal intubation from August 1, 2014, to September 30, 2018. INTERVENTIONS: Implementation of apneic oxygenation for all primary tracheal intubation as quality improvement. MEASUREMENTS AND MAIN RESULTS: Total of 1,373 tracheal intubations (661 preimplementation and 712 postimplementation) took place during study period. Within 2 months, apneic oxygenation use reached to predefined adherence threshold (> 80% of primary tracheal intubations) after implementation and sustained at greater than 70% level throughout the postimplementation. Between the preimplementation and postimplementation, no significant differences were observed in patient demographics, difficult airway features, or providers. Respiratory and procedural indications were more common during preintervention. Video laryngoscopy devices were used more often during the postimplementation (pre 5% vs post 75%; p < 0.001). Moderate oxygen desaturation less than 80% were observed in fewer tracheal intubations after apneic oxygenation implementation (pre 15.4% vs post 11.8%; p = 0.049); severe oxygen desaturation less than 70% was also observed in fewer tracheal intubations after implementation (pre 10.4% vs post 7.2%; p = 0.032). Hemodynamic tracheal intubation associated events (i.e., cardiac arrests, hypotension, dysrhythmia) were unchanged (pre 3.2% vs post 2.0%; p = 0.155). Multivariable analyses showed apneic oxygenation implementation was significantly associated with a decrease in moderate desaturation less than 80% (adjusted odds ratio, 0.55; 95% CI, 0.34-0.88) and with severe desaturation less than 70% (adjusted odds ratio, 0.54; 95% CI, 0.31-0.96) while adjusting for tracheal intubation indications and device. CONCLUSIONS: Implementation of apneic oxygenation in PICU was feasible, and was associated with significant reduction in moderate and severe oxygen desaturation. Use of apneic oxygenation should be considered when intubating critically ill children.

Inter-Rater Reliability Between Critical Care Nurses Performing a Pediatric Modification to the Glasgow Coma Scale.

OBJECTIVES: Estimate the inter-rater reliability of critical care nurses performing a pediatric modification of the Glasgow Coma Scale in a contemporary PICU. DESIGN: Prospective observation study. SETTING: Large academic PICU. PATIENTS/SUBJECTS: All 274 nurses with permanent assignments in the PICU were eligible to participate. A subset of 18 nurses were selected as study registered nurses. All PICU patients were eligible to participate. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PICU nurses were educated and demonstrated proficiency on a pediatric modification of the Glasgow Coma Scale we created to make it more applicable to a diverse PICU population that included patients who are sedated, mechanically ventilated, and/or have developmental disabilities. Each study registered nurse observed a sample of nurses perform the Glasgow Coma Scale, and they independently scored the Glasgow Coma Scale. Patients were categorized as having developmental disabilities if their preillness Pediatric Cerebral Performance Category score was greater than or equal to 3. Fleiss' Kappa (κ), intraclass correlation coefficient, and percent agreement assessed inter-rater reliability for each Glasgow Coma Scale component (eye, verbal, motor) and age-specific scale (≥ 2 and < 2-yr-old). The overall percent agreement between study registered nurses and nurses was 89% for the eye, 91% for the verbal, and 79% for the motor responses. Inter-rater reliability ranged from good (intraclass correlation coefficient = 0.75) to excellent (intraclass correlation coefficient = 0.96) for testable patients. Agreement on the motor response was significantly lower for children with developmental disabilities (< 2 yr: 59% vs 95%; p = 0.0012 and ≥ 2 yr: 55% vs 91%; p = 0.0012). Agreement was significantly worse for intermediate range Glasgow Coma Scale motor responses compared with responses at the extremes (e.g., motor responses 2, 3, 4 vs 1, 5, 6; p < 0.05). CONCLUSIONS: A pediatric modification of the Glasgow Coma Scale performed by trained PICU nurses has excellent inter-rater reliability, although reliability was reduced in patients with developmental disabilities and for intermediate range Glasgow Coma Scale responses. Further research is needed to determine the effectiveness of this Glasgow Coma Scale modification to detect clinical deterioration.

Survey of Bedside Clinical Neurologic Assessments in U.S. PICUs.

OBJECTIVE: To understand how routine bedside clinical neurologic assessments are performed in U.S. PICUs. DESIGN: Electronic survey. SETTING: Academic PICUs throughout the United States. SUBJECTS: Faculty representatives from PICUs throughout the United States. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We surveyed how routine bedside neurologic assessments are reported to be performed in U.S. PICUs and the attitudes of respondents on the utility of these assessments. The survey contained questions regarding 1) components of neurologic assessments; 2) frequency of neurologic assessments; 3) documentation and communication of changes in neurologic assessment; and 4) optimization of neurologic assessments. Surveys were received from 64 of 67 institutions (96%). Glasgow Coma Scale and pupillary reflex were the most commonly reported assessments (80% and 92% of institutions, respectively). For patients with acute brain injury, 95% of institutions performed neurologic assessments hourly although assessment frequency was more variable for patients at low risk of developing brain injury and those at high risk for brain injury, but without overt injury. In 73% of institutions, any change detected on routine neuroassessment was communicated to providers, whereas in 27%, communication depended on the severity or degree of neurologic decline. Seventy percent of respondents thought that their current practice for assessing and monitoring neurologic status was suboptimal. Only 57% felt that the Glasgow Coma Scale was a valuable tool for the serial assessment of neurologic function in the ICU. Ninety-two percent felt that a standardized approach to assessing and documenting preillness neurologic function would be valuable. CONCLUSIONS: Routine neurologic assessments are reported to be conducted in nearly all academic PICUs in the United States with fellowship training programs although the content, frequency, and triggers for communication vary between institutions. Most physicians felt that the current paradigms for neurologic assessments are suboptimal. These data suggest that optimizing and standardizing routine bedside nursing neurologic assessments may be warranted.

Bedside clinical neurologic assessment utilisation in paediatric cardiac intensive care units.

IntroductionNeurodevelopmental disabilities in children with CHD can result from neurologic injury sustained in the cardiac ICU when children are at high risk of acute neurologic injury. Physicians typically order and specify frequency for serial bedside nursing clinical neurologic assessments to evaluate patients' neurologic status.Materials and methodsWe surveyed cardiac ICU physicians to understand how these assessments are performed, and the attitudes of physicians on the utility of these assessments. The survey contained questions regarding assessment elements, assessment frequency, communication of neurologic status changes, and optimisation of assessments. RESULTS: Surveys were received from 50 institutions, with a response rate of 86%. Routine clinical neurologic assessments were reported to be performed in 94% of institutions and standardised in 56%. Pupillary reflex was the most commonly reported assessment. In all, 77% of institutions used a coma scale, with Glasgow Coma Scale being most common. For patients with acute brain injury, 82% of institutions reported performing assessments hourly, whereas assessment frequency was more variable for low-risk and high-risk patients without overt brain injury. In all, 84% of respondents thought their current practice for assessing and monitoring neurologic status was suboptimal. Only 41% felt that the Glasgow Coma Scale was a valuable tool for assessing neurologic function in the cardiac ICU, and 91% felt that a standardised approach to assessing pre-illness neurologic function would be valuable. CONCLUSIONS: Routine nursing neurologic assessments are conducted in most surveyed paediatric cardiac ICUs, although assessment characteristics vary greatly between institutions. Most clinicians rated current neurologic assessment practices as suboptimal.

Using LEAN to improve a segment of emergency department flow.

Emergency department (ED) overcrowding is an organizational concern. This article describes how Toyota LEAN methods were used as a performance improvement framework to address ED overcrowding. This initiative also impacted "bolus of patients" or "batching" concerns, which occur when inpatient units receive an influx of patients from EDs and other areas at the same time. In addition to decreased incidence of overcrowding, the organization realized increased interprofessional collaboration.

Enhancing Evidence-Based Practice Integration Into Clinical Practice: Using Policy as a Tool for Culture Change in a Large Urban Academic Medical Center.

PURPOSE: This article describes how a large urban medical center was able to enhance the integration of evidence-based practice in the clinical environment by reconfiguring its approach to policy and procedures documentation. PROJECT DESCRIPTION: Leaders at a large urban medical center observed that numerous nursing practice documents lacked a base of evidence. No standard process existed for building staff awareness of the evidence-based underlying practice, and there was uneven knowledge of evidence-based practice in the milieu. To address the problem, a team of Clinical Nurse Specialists developed a novel policy establishing procedures for document review, formal structures for policy assignment, and rigorous standards for the development and sharing of evidence tables. OUTCOME: The proportion of nursing guidance documents connected to evidence tables increased from 45% to 77% in the first year and a half following implementation. The change has enabled streamlining and consolidation of nursing practice guidance documents and has led to significant increases in engagement with clinical inquiry at the bedside. CONCLUSION: A policy specifically requiring evidence to be incorporated into nursing practice guidance documents can help enhance the understanding and uptake of evidence-based practice in a complex clinical environment. Clinical Nurse Specialists played a vital role in facilitating this organizational culture change.

The merry-go-round of patient rounding: assure your patients get the brass ring.

Staff members on a medical-surgical unit in a large community teaching hospital adapted the hourly rounding concept to their specific patient population. Lessons learned and strategies to assure continuous success with the rounding process are addressed.

Preventing Catheter-Associated Urinary Tract Infections in the Pediatric Intensive Care Unit.

BACKGROUND: Catheter-associated urinary tract infections are common health care-associated infections and have been associated with increased mortality, morbidity, length of stay, and cost. Prevention strategies are grouped into bundles focused on reducing unnecessary catheter use and promptly removing urinary catheters. Before intervention in the study institution, no urinary catheters were unnecessarily used and compliance with the catheter-associated urinary tract infection bundle was 84%. OBJECTIVE: To increase bundle compliance by using targeted rounds specifically focused on eliminating dependent loops in drainage tubing and ensuring appropriate catheter use to reduce the incidence of catheter-associated urinary tract infections. METHODS: A multidisciplinary team was formed to identify misperceptions, highlight best practices, and eliminate barriers to success over 1 year in a single pediatric intensive care unit. The team completed a quality improvement project of daily targeted rounding for patients with an indwelling urinary catheter. The goals were to assess appropriateness of catheterization, increase bundle compliance, and decrease catheter-associated urinary tract infection risk. Targeted rounds were conducted in addition to the medical team rounds. RESULTS: Bundle compliance supported by targeted rounding increased from 84% to 93% and helped reduce the overall catheter-associated urinary tract infection rate from 2.7 infections per 1000 catheter-days at baseline to 0. This change was sustained for 1 year. CONCLUSION: Targeted rounding for pediatric patients with an indwelling urinary catheter is an effective and sustainable strategy to reduce catheter-associated urinary tract infections. The ease of implementation for this intervention lends itself to generalizability to other patient populations.

Routine Neurological Assessments by Nurses in the Pediatric Intensive Care Unit.

BACKGROUND: Brain injury with changes in clinical neurological signs and symptoms can develop while children are undergoing treatment in the intensive care unit. Critical care nurses routinely screen for neurological decline by using serial bedside neurological assessments. However, assessment components, frequency, and communication thresholds are not standardized. OBJECTIVES: To standardize neurological assessment procedures used by nurses, improve compliance with physicians' ordering and nurses' documentation of neurological assessments, and explore the frequency with which changes from preillness neurological status and previous assessments can be detected by using the assessment tool developed. METHODS: A quality improvement intervention was implemented during a 1-year period in a 55-bed pediatric intensive care unit with 274 nurses. Procedures for neurological assessment by nurses were standardized, a system for physicians to order neurological assessments by nurses at a frequency based on the patient's risk for brain injury was developed and implemented, and a system to compare patients' current neurological status with their preillness neurological status was developed and implemented. RESULTS: Process metrics that focused on compliance of ordering and documenting the standardized neurological assessments indicated improvement and sustained compliance greater than 80%. Exploratory analyses indicated that 29% of patients had an episode of neurological decline and that these episodes were more common in patients with developmental disabilities than in patients without such disabilities. CONCLUSIONS: Compliance with physicians' ordering and nurses' documentation of standardized neurological assessments significantly increased and had excellent sustainability. Further work is needed to determine the sensitivity of standardized nurses' neurological assessment tools for clinically meaningful neurological decline.

Effects of aging on the biomechanics of Coquerel's sifaka (Propithecus coquereli): Evidence of robustness to senescence.

It is well-known that as humans age they experience significant changes in gait including reduction in velocity and ground reaction forces and changes in leg mechanics. Progressive changes in gait can lead to disability and frailty, defined as an inability to carry out activities of daily living. This topic is relevant to basic understanding of the aging process and for clinical intervention. As such, studies of frailty can benefit from nonhuman animal models, yet little is known about gait frailty in nonhuman primates. This study examines a nonhuman primate model to evaluate its relevance to understanding human aging processes. To test the null hypothesis that age-related changes in joint function and gait do occur in primate models in a similar fashion to humans, a detailed gait analysis, including velocity, footfall timings, and vertical ground reaction forces, on bipedal locomotion was performed in Coquerel's sifaka (Propithecus coquereli), ranging in age from 5 years to 24 years. None of the spatiotemporal or kinetic gait variables measured was significantly correlated with age alone. There was a slight but significant reduction in locomotor velocity when animals were grouped into "young" and "old" categories. These data show that aging P. coquereli experience only subtle age-related changes, that were not nearly as extensive as reported in humans. This lack of change suggests that unlike humans, lemurs maintain gait competency at high levels, possibly because these animals maintain reproductive capacity close to their age of death and that frailty may be selected against, since gait disability would result in injury and death that would preclude independent living. Although nonhuman primates should experience age-related senescence, their locomotor performance should remain robust throughout their lifetimes, which raises questions about the use of primate models of gait disability, an area that deserves further investigation.