Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1).

Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.

Benefits and challenges of combined pediatrics-anesthesiology residency programs: A qualitative study.

BACKGROUND: The combined pediatrics-anesthesiology residency program was created in 2011 for trainees interested in careers within both specialties. Prior studies have cited challenges of combined training, but none have systematically identified benefits. AIMS: Our objective was to describe the perceived educational and professional benefits and challenges of combined pediatrics-anesthesiology residency programs. METHODS: In this qualitative study using a phenomenological approach, all graduates of combined pediatrics-anesthesiology residency programs from 2016 to 2021, program directors, associate program directors, and faculty mentors were invited to participate in surveys and interviews. Study members conducted interviews using a semi-structured interview guide. Each transcript was coded inductively by two authors and themes were developed using thematic analysis through the lens of self-determination theory. RESULTS: 43 of 62 graduates and faculty responded to our survey (69% response rate), and 14 graduates and five faculty were interviewed. Survey and interview data represented seven programs, including five currently accredited combined programs. Themes emerged regarding benefits of training: it 1) fosters residents' clinical expertise in managing critically ill and medically complex children; 2) provides residents with exceptional knowledge and skills in communicating between medical and perioperative services; and 3) affords unique academic and career opportunities. Other themes emerged regarding the challenges of long duration of training and transitions between pediatrics and anesthesiology rotations. CONCLUSIONS: This is the first study to describe the perceived educational and professional benefits of combined pediatrics-anesthesiology residency programs. Combined training affords exceptional clinical competence and autonomy in the management of pediatric patients and the ability to skillfully navigate hospital systems, and leads to robust academic and career opportunities. However, the duration of training and challenging transitions may threaten residents' sense of relatedness to colleagues and peers, and their self-perceived competence and autonomy. These results can inform mentoring and recruitment of residents to combined pediatrics-anesthesiology programs and career opportunities for graduates.

Novel utilization of strand-specific reverse transcription polymerase chain reaction in perioperative clinical decision making for SARS-CoV-2 polymerase chain reaction positive patients.

In order to prevent in-hospital transmission and potential complications related to SARS-CoV-2 in the perioperative patient, most healthcare institutions require preoperative testing for SARS-CoV-2 prior to proceeding with elective surgery. The Centers for Disease Control and Prevention (CDC) recommends a time and symptom-based duration of isolation for the presumed infectious period. The guidance to avoid retesting of asymptomatic patients in the 90 days following a positive reverse transcription polymerase chain reaction (RT-PCR) test is because of the possibility of detection of non-infectious viral shedding. When to reschedule asymptomatic patients who test RT-PCR positive for SARS-CoV-2 preoperatively is of considerable debate, both from the perspective of ensuring a patient's full preoperative fitness, as well as reducing the risk of viral transmission within the hospital. We describe the novel perioperative use of a strand-specific assay to detect minus strand ribonucleic acid (RNA) in a clinical decision-making algorithm to determine optimal timing of elective surgery after a patient tests RT-PCR positive for SARS-CoV-2. This is the first description in the literature of an attempt to further stratify patients who repeatedly test positive for SARS-CoV-2 into infectious versus non-infectious for perioperative planning.

Increasing the Utilization of Moderate Sedation Services for Pediatric Imaging.

Performing motion-free imaging is frequently challenging in children. To bridge the gap between examinations performed in children who are awake and in those under general anesthesia, a moderate sedation program was implemented at our institution but was seldom used despite substantial eligibility. In conjunction with a 5-month quality improvement (QI) course, a multidisciplinary team was assembled and, by using an A3 approach, sought to address the most important key drivers of low utilization, namely the need for clear moderate sedation eligibility criteria, reliable protocol routing order, consistent moderate sedation screening performed by registered nurses (RNs), and enhanced visibility of moderate sedation services to ordering providers. Initial steps focused on developing better-defined criteria and protocoling standard work for technologists and RNs, with coaching and audits. Modality-specific forecasting was then implemented to reroute profiles of patients who were awaiting scheduling or already scheduled for an examination with general anesthesia to the moderate sedation queue to identify more eligible patients. These manual efforts were coupled with higher reliability but more protracted electronic health record changes, facilitating automated protocol routing on the basis of moderate sedation eligibility and order entry constraints. As a result, scheduled imaging examinations requiring moderate sedation increased from a mean of 1.2 examinations per week to a sustained 6.1 examinations per week (range, 4-8) over the 5-month period, exceeding the team SMART (specific, measurable, achievable, relevant, and time bound) goal to achieve an average of five examinations per week by the QI course end. By targeting the most high-impact yet modifiable process deficiencies through a multifaceted team approach and initially investing in manual efforts to gain cultural buy-in while awaiting higher-reliability interventions, the project achieved success and may serve as a more general model for workflow change when there is organizational resistance. ©RSNA, 2021.

Hospitalization Patterns for Inpatient Pediatric Surgery and Procedures in California: 2000-2016.

BACKGROUND: We report hospitalization patterns from 2000 to 2016 for young children (ages 0-5 years old) in California who underwent 1 of the 20 most common inpatient procedures that required general anesthesia and evaluate the estimated probability of treatment at a tertiary care children's hospital (CH) by year. METHODS: We hypothesized that children ≤5 years old increasingly undergo care at tertiary care CHs for common inpatient surgeries or other procedures that require general anesthesia. Data from the California Office of Statewide Health Planning and Development dataset were used to determine procedure, patient age, year of procedure, and hospital name. Hospitals were designated as either tertiary care CHs, children's units within general hospitals (CUGHs), or general hospitals (GHs) based on the California Children's Services Provider List. A tertiary care CH was defined using the California Children's Services definition as a referral hospital that provides comprehensive, multidisciplinary, regionalized pediatric care to children from birth up to 21 years of age with a full range of medical and surgical care for severely ill children. We report the unadjusted percentage of patients treated at each hospital type and, after controlling for patient covariates and comorbidities, the estimated probability of undergoing care at a tertiary care CH from 2000 to 2016. RESULTS: There were 172,318 treatment episodes from 2000 to 2016. The estimated probability of undergoing care at a tertiary care CH increased from 63.4% (95% confidence interval [CI], 62.4%-64.4%) in 2000 to 78.3% (95% CI, 77.3%-79.4%) in 2016. CONCLUSIONS: Children ≤5 years old undergoing common inpatient procedures that require general anesthesia increasingly receive care at tertiary care CHs in California.

Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors.

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.

Use of concurrent chemoradiation in advanced staged (T4) laryngeal cancer.

HYPOTHESIS: Patients with advanced laryngeal cancer sometimes desire organ preservation protocols even if it portends a worse outcome. BACKGROUND: To assess outcomes of patients with T4 laryngeal cancer treated with chemoradiation therapy. METHODS: Case series with chart review at a tertiary university hospital. Twenty-four patients with T4 laryngeal cancer all declined total laryngectomy with adjuvant radiation as the primary treatment modality and alternatively received concurrent chemoradiation therapy. The primary outcome was overall survival. Secondary outcomes were rates of tracheotomy dependence, gastric tube dependence, and need for salvage laryngectomy. RESULTS: All patients had T4 laryngeal disease, 71% had cartilage invasion and 59% had regional metastasis to the neck. Kaplan-Meier analysis determined 2-year and 5-year overall survival to be 64% and 59% respectively. The locoregional recurrence rate was 25%. The distant metastasis rate was 21%. The rate of salvage laryngectomy was 17%, which occurred at a mean of 56.5months after the original diagnosis. The rate of tracheotomy dependence was 33% while gastric tube dependence was 25%. CONCLUSION: Advanced T4 laryngeal cancer, particularly with cartilage invasion, remains a surgical disease best treated with total laryngectomy and adjuvant radiation. This data may help guide patients and practitioners considering concurrent chemoradiation therapy for definitive treatment of advanced laryngeal cancer.

Synthesis of Fmoc-Protected Arylphenylalanines (Bip Derivatives) via Nonaqueous Suzuki-Miyaura Cross-Coupling Reactions.

A one-step synthesis of Fmoc-protected aryl/heteroaryl-substituted phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) reaction of Fmoc-protected bromo- or iodophenylalanines is reported. This protocol allows for the direct formation of a variety of unnatural biaryl-containing amino acids in good to excellent yield, which can be readily used in subsequent Fmoc solid-phase peptide synthesis. The synthetic utility of this method is also demonstrated by the SMC reaction of bromophenylalanine-containing tripeptides.

Discovery of hydroxyl 1,2-diphenylethanamine analogs as potent cholesterol ester transfer protein inhibitors.

Hydroxyl 1,2-diphenylethanamine analogs were identified as potent inhibitors of cholesterol ester transfer protein (CETP), a therapeutic target to raise HDL cholesterol. In an effort to improve the pharmaceutical properties in the previously disclosed DiPhenylPyridineEthanamine (DPPE) series, polar groups were introduced to the N-linked quaternary center. Optimization of analogues for potency, in vitro liability profile and efficacy led to identification of lead compound 16 which demonstrated robust pharmacodynamic effects in human CETP/apo-B100 dual transgenic mice.

2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists.

Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 µM with 10 µM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.

Identification of 1-{2-[4-chloro-1'-(2,2-dimethylpropyl)-7-hydroxy-1,2-dihydrospiro[indole-3,4'-piperidine]-1-yl]phenyl}-3-{5-chloro-[1,3]thiazolo[5,4-b]pyridin-2-yl}urea, a potent, efficacious and orally bioavailable P2Y(1) antagonist as an antiplatelet agent.

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.

Impact of modern recreational conveyances on rates of pediatric craniofacial fractures.

Objective: Trauma remains the leading cause of death for children over a year old. Motorized recreational conveyances (RCs) adds another potential cause of pediatric trauma. This study aims to determine the impact of adding electric motors to RCs on the severity and frequency of pediatric injuries and craniofacial fractures. Methods: Pediatric trauma information was obtained from the National Electronic Injury Surveillance System (NEISS) database between 2012 and 2021. Demographics, injury cause, diagnoses, and incident narrative were collected. Bivariate and multivariate regression analyses were used to determine injury factors associated with serious injuries. Results: One million five hundred ninety-six thousand five hundred fifty-nine encounters were examined; 113,905 (7.1%) were related to pediatric RCs and 5354 (5.4%) of those involved RCs with electric motors. 14.3% of injuries were related to scooters, 18.6% to skateboards, 54.2% to bicycles, and 12.9% to other RCs. There were significant differences in age, sex, race, helmet use, serious injuries, and craniofacial fractures between RC modalities. RC users were more likely to develop facial fractures (OR 2.12; 95%CI 2.01, 2.23; p < .001) and be involved in serious injuries (OR 1.42; 95%CI 1.38, 1.46; p < .001). Compared to their self-propelled counterparts, motorized scooters (OR 2.24; 95%CI 1.86, 2.69; p < .001) but not motorized skateboards (OR 1.01; 95%CI 0.88, 1.17; p = 0.88) were more likely to cause serious injuries. Helmet use was associated with fewer serious injuries (OR 0.5; 95%CI 0.46, 0.54; p < .001), facial fractures (OR 0.48; 95%CI 0.41, 0.55; p < .001), and skull fractures (OR 0.13; 95%CI 0.09, 0.17; p < .001). Conclusions: The addition of electric motors to RCs significantly increases the risk of pediatric craniofacial fractures and serious injuries. Level of Evidence: 3.

The crosstalk between fibroblast growth factor 21 (FGF21) system and substance use.

Existing literature indicates that communication between the central nervous system and the peripheral nervous system is disrupted by substance use disorders (SUDs), including alcohol use disorder (AUD). Fibroblast growth factor 21 (FGF21), a liver-brain axis hormone governing energy homeostasis, has been shown to modulate alcohol intake/preference and other substances. To further elucidate the relationship between FGF21, alcohol use, and other substance use, we conducted a scoping review to explore the association between FGF21 and SUDs. Increases in FGF21 reduce alcohol consumption while suppressing FGF21 increases alcohol consumption, demonstrating an inverse relationship. Alcohol elevates FGF21 levels primarily via the liver, subsequently promoting neuronal signals to curb alcohol intake. FGF21 activation engages molecular pathways that defend against alcohol-induced fat accumulation, oxidative stress, and inflammation. Considering the bidirectional association between FGF21 and alcohol, further studies on the FGF21 system as a potential pharmacotherapy for AUD and alcohol-associated liver disease are warranted.

Discovery of diarylurea P2Y(1) antagonists with improved aqueous solubility.

Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.

A new model for interprofessional collaboration at a student-run free clinic.

The Case Western Reserve University Student-Run Free Clinic represents a unique model of interprofessional collaboration for medical and nursing students. This clinic operates on two Saturdays a month to provide acute medical services at the Free Medical Clinic of Greater Cleveland. We describe how this clinic promotes a sense of mutual investment and interdependence among students, who contribute to the clinic through leadership, planning and patient care. Students may also develop a broader perspective and deeper respect for their professional colleagues, which translates well to a future practice with team-based coordination of clinical services and an increasing emphasis on patient-centered care.

A human laboratory study on the link between alcohol administration and circulating fibroblast growth factor 21 (FGF21) in individuals with alcohol use disorder.

Growing evidence indicates that the crosstalk between the central nervous system and the periphery plays an important role in the pathophysiology of neuropsychiatric conditions, including addictive disorders. Fibroblast growth factor 21 (FGF21) is part of the liver-brain axis and regulates energy homeostasis, metabolism, and macronutrient intake. In addition, FGF21 signaling modulates alcohol intake and preference, and changes in FGF21 levels are observed following alcohol consumption. To further elucidate the relationship between alcohol use and FGF21, we assessed serum FGF21 concentrations in 16 non-treatment seeking individuals with alcohol use disorder (AUD) in a naturalistic outpatient setting, as well as a controlled laboratory experiment that included alcohol cue-reactivity, alcohol priming, and alcohol self-administration in a bar-like setting. FGF21 levels were stable during the outpatient phase when participants received placebo and had no significant lifestyle changes. During the bar-like laboratory experiment, a robust increase in serum FGF21 concentrations was found after the 2-hr alcohol self-administration session (F3, 49 = 23.39, p < 0.001). Percent change in FGF21 levels positively correlated with the amount of alcohol self-administered but did not reach statistical significance. No significant changes in FGF21 levels were found after exposure to alcohol cues or consuming the priming drink. Given the bidirectional link between FGF21 and alcohol, targeting the FGF21 system may be further examined as a potential pharmacotherapy for AUD.

Role of aldosterone and mineralocorticoid receptor (MR) in addiction: A scoping review.

Preclinical and human studies suggest a role of aldosterone and mineralocorticoid receptor (MR) in addiction. This scoping review aimed to summarize (1) the relationship between alcohol and other substance use disorders (ASUDs) and dysfunctions of the aldosterone and MR, and (2) how pharmacological manipulations of MR may affect ASUD-related outcomes. Our search in four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) indicated that most studies focused on the relationship between aldosterone, MR, and alcohol (n = 30), with the rest focused on opioids (n = 5), nicotine (n = 9), and other addictive substances (n = 9). Despite some inconsistencies, the overall results suggest peripheral and central dysregulations of aldosterone and MR in several species and that these dysregulations depended on the pattern of drug exposure and genetic factors. We conclude that MR antagonism may be a promising target in ASUD, yet future studies are warranted.

Sense of Belonging and Professional Identity Among Combined Pediatrics-Anesthesiology Residents.

OBJECTIVES: Combined pediatrics-anesthesiology programs uniquely prepare residents to care for critically ill children, but trainees in these combined programs face challenges as residents within 2 specialties. Social belonging predicts motivation and achievement and protects against burnout. The objective of our study was to evaluate sense of belonging and self-identified professional identity of current combined pediatrics-anesthesiology residents. METHODS: All current residents in combined pediatrics-anesthesiology programs were invited to participate in an anonymous survey assessing sense of belonging and professional identity. Open-ended responses were qualitatively analyzed using an inductive coding process and thematic analysis. Likert questions were analyzed using paired t-tests. RESULTS: Thirty-two of 36 residents completed the survey (89% response rate). A total of 92% of respondents had a lower sense of belonging in pediatrics than anesthesiology (3.32 vs 3.94) and more self-identified as anesthesiologists than pediatricians. Thematic analysis yielded 5 themes 1) the team-based nature of pediatrics results in strong initial bonds, but feelings of isolation as training pathways diverge; 2) the individual nature of anesthesiology results in less social interaction within daily work, but easier transitions in and out of anesthesiology; 3) divergent training timelines result in feeling left behind socially and academically; 4) residents identify different professional and personal characteristics of pediatricians and anesthesiologists that impact their sense of belonging; and 5) the structure of the combined program results in experiences unique to combined residents. CONCLUSIONS: Most residents in combined pediatrics-anesthesiology programs had a higher sense of belonging and self-identification in anesthesiology than pediatrics. Program structure and autonomy had significant impacts.

FGF21 regulates alcohol intake: New hopes on the rise for alcohol use disorder treatment?

FGF21 is a liver-derived hormone primarily involved in glucose/lipid metabolism. A recent study by Flippo and colleagues1 demonstrates that administration of FGF21 or an FGF21 analog suppresses alcohol consumption in rodents and non-human primates, likely through an amygdalo-striatal circuit.

Assessing Pediatric Life Support Skills Using Augmented Reality Medical Simulation With Eye Tracking: A Pilot Study.

Background: Augmented reality (AR) and eye tracking are promising adjuncts for medical simulation, but they have remained distinct tools. The recently developed Chariot Augmented Reality Medical (CHARM) Simulator combines AR medical simulation with eye tracking. We present a novel approach to applying eye tracking within an AR simulation to assess anesthesiologists during an AR pediatric life support simulation. The primary aim was to explore clinician performance in the simulation. Secondary outcomes explored eye tracking as a measure of shockable rhythm recognition and participant satisfaction. Methods: Anesthesiology residents, pediatric anesthesiology fellows, and attending pediatric anesthesiologists were recruited. Using CHARM, they participated in a pediatric crisis simulation. Performance was scored using the Anesthesia-centric Pediatric Advanced Life Support (A-PALS) scoring instrument, and eye tracking data were analyzed. The Simulation Design Scale measured participant satisfaction. Results: Nine each of residents, fellows, and attendings participated for a total of 27. We were able to successfully progress participants through the AR simulation as demonstrated by typical A-PALS performance scores. We observed no differences in performance across training levels. Eye tracking data successfully allowed comparisons of time to rhythm recognition across training levels, revealing no differences. Finally, simulation satisfaction was high across all participants. Conclusions: While the agreement between A-PALS score and gaze patterns is promising, further research is needed to fully demonstrate the use of AR eye tracking for medical training and assessment. Physicians of multiple training levels were satisfied with the technology.