Faculty Bibliography

β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily^1-3. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt β-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and β-arrestin-dependent physiological functions while sparing G protein-receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin-receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.

Three-dimensional (3D) printing has emerged as a useful adjunct in spine surgery, particularly for preoperative planning, surgical rehearsal, education, patient communication, navigation template development, and selected patient-specific applications. This scoping review maps the available literature on the use of 3D printing in preoperative planning and related applications for spine surgery. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines using PubMed, Google Scholar, Embase, SCOPUS, and Web of Science. Databases were searched from inception through September 2025. Seventy-one unique articles were included: 12 comparative studies; 20 non-comparative clinical, technical, simulation, or education-focused studies; and 39 additional case reports or technical notes. The retrospective studies were further stratified into 20 non-comparative retrospective studies and 12 comparative retrospective studies evaluating 3D printing-assisted approaches against control or comparator approaches. Across the included literature, 3D printing was most commonly used for anatomical visualization, surgical rehearsal, screw trajectory planning, navigation template or drill guide development, patient education, trainee education, intraoperative reference, and selected custom implant or prosthetic applications. Several comparative studies reported favorable study-level findings associated with 3D printing, including reported improvements in screw placement accuracy or acceptable placement, operative duration, blood loss, fluoroscopy exposure, and complications; however, these outcomes were reported inconsistently and were not pooled quantitatively. Reported limitations included upfront production costs, prolonged preparation time, imaging and segmentation requirements, limited soft-tissue or biomechanical realism, and the need for specialized software, equipment, and personnel. Overall, 3D printing appears to be a promising adjunct for selected spine surgery applications, but current evidence remains largely retrospective, heterogeneous, and descriptive. Prospective, multicenter, controlled studies with standardized outcome measures, cost-effectiveness analyses, and longer follow-up are needed before 3D printing can be recommended as a standard component of preoperative planning in spine surgery.

OBJECTIVE:Maxillomandibular advancement (MMA) is the most effective surgical treatment for obstructive sleep apnea (OSA) after tracheotomy. However, the influence of patient characteristics such as age and gender on MMA outcomes remains understudied. This meta-analysis evaluates MMA outcomes stratified by age and gender. DATA SOURCES/METHODS:A comprehensive literature search of CINAHL, Cochrane Library, PubMed, and Scopus was performed from inception through 2026. Studies reporting age- or gender-specific outcomes of MMA for adults with OSA were included. REVIEW METHODS/METHODS:Extracted data included cephalometric measurements, apnea-hypopnea index (AHI), Epworth Sleepiness Scale (ESS), SpO2 nadir (LSAT), surgical success, and cure rates. Meta-analysis was performed. RESULTS: = 1.17 [95% CI 0.51-2.69]). Increasing age was associated with decreased surgical success and cure, although only the decline in odds of cure reached statistical significance (OR = 0.97 annually, p = 0.029). CONCLUSION/CONCLUSIONS:Maxillomandibular advancement yields significant improvements in OSA outcomes regardless of age or gender. While outcomes are generally consistent across groups, clinicians should counsel older adults on the reduced likelihood of surgical cure. LEVEL OF EVIDENCE/METHODS:N/A.

We are delighted to share with you our fifteenth Journal Club and highlight some of the most interesting papers published recently [...].

This study evaluated the effects of glass infiltration and hydrothermal aging on the microstructural and optical properties of minimally processed recycled 3Y-TZP. Unprocessed 3Y-TZP remnants were milled into powder, compacted into discs, and sintered. Specimens were divided into six groups according to glass infiltration and hydrothermal aging (immediate, 50 h, and 100 h at 134 °C/2.2 bar). Particle size was measured by laser diffraction. Density and optical properties (contrast ratio and translucency) were longitudinally evaluated on the same specimens using Archimedes' principle and reflectance measurements (n = 10), whereas crystalline phases (Raman spectroscopy, n = 3), surface and cross-sectional morphology (n = 3), and elemental composition (n = 3) were analyzed on independent specimens allocated to each experimental condition. Color stability and translucency variation were compared with perceptibility (PT = 0.81; TPT = 0.62) and acceptability (AT = 1.77; TAT = 2.62) thresholds (n = 10). Density data were analyzed using one-way repeated-measures ANOVA, while optical properties were analyzed using two-way repeated-measures ANOVA, followed by Tukey's post hoc test. Mean particle size of recycled powder was 1.61 μm. Relative densities for immediate, 50 h, and 100 h groups were 99.68%, 99.24%, and 99.04%. Raman spectra revealed predominance of tetragonal-cubic phases in immediate non-infiltrated group, while monoclinic phase prevailed in others. SEM showed homogeneous surfaces. EDS confirmed zirconium, yttrium, and hafnium in non-infiltrated groups, and silicon, aluminum, sodium, potassium, and calcium in infiltrated. Non-infiltrated groups showed lower contrast ratio and greater translucency than infiltrated, independent of aging. Aging minimally affected optical properties, except infiltrated specimens, where translucency was higher immediately than after 50-100 h. All groups exhibited color and translucency variation below perceptibility and acceptability thresholds. Prolonged hydrothermal degradation influenced the microstructural and optical features of recycled 3Y-TZP, while glass infiltration further modified these characteristics, reducing translucency while increasing opacity and color stability.

BACKGROUND:In situ simulation (ISS) has seen broad use in academic emergency medicine (EM). Studies with limited clinical data suggest a dual paradigm model to assess the efficacy of these educational activities based on their impact on both ongoing and future quality of care. We conducted a retrospective cohort study to assess the impact of government-mandated mass casualty incident (MCI) ISS drills on ongoing department operations and quality clinical care. METHODS:We conducted a retrospective study of patients presenting to an adult tertiary academic emergency department during scheduled and unscheduled ISS MCI drills. We assessed the impact of ISS on operational and triage metrics by comparing scheduled and unscheduled drills. RESULTS:Being treated during an ongoing MCI ISS, in both the scheduled and unscheduled simulation formats, was associated with a higher average door to triage times (20.6 min in the MCI ISS cohort vs 15.8 min in the control cohort; p<0.005) and lower Canadian Triage and Acuity Scale (CTAS) scores (CTAS 1 and 2: 0.8% and 14.5% in the MCI ISS cohort vs 1.6% and 17.1% in the control cohort, p<0.025). Secondary analysis, evaluating differences between case and control cohorts in distinct scheduled and unscheduled ISS subgroups, showed that unscheduled but not scheduled ISS were associated with higher average door to triage times (29.0 min in the unscheduled MCI ISS case cohort vs 21.2 min in the unscheduled MCI ISS control cohort; p<0.001) and lower CTAS acuity scores (CTAS 1 and 2: 0.0% and 17.9% in the unscheduled MCI ISS cohort vs 2.8% and 27.9% in the unscheduled MCI ISS control cohort; p<0.001). CONCLUSION/CONCLUSIONS:In this study, there was a significant association between increased door to triage time and lower acuity triage score designation for patients treated during an ongoing MCI ISS education drill. Secondary analysis demonstrated that these findings were only observed during unscheduled simulations, suggesting that the effects may be modifiable.

Children with Down syndrome (DS) frequently develop transient abnormal myelopoiesis that can evolve to the myeloid leukemia of DS (ML-DS). TAM spontaneously resolves in most cases but progresses to ML-DS with additional mutations, most commonly in the cohesin complex. However, the mechanisms by which these alterations promote leukemia are unknown. We leveraged the RAD21-mutant CMY cell line and RAD21-corrected CMY isogenic clones, as well as patient data, to investigate the effect of cohesin mutations during leukemia progression. RNA-sequencing revealed that HLA-class II genes were significantly down-regulated with cohesin mutations. Furthermore, HLA-DR was found to be lower in ML-DS relative to TAM, and these decreased levels were associated with increased risk of leukemia progression. Multi-omic analyses revealed that haploinsufficiency of RAD21 altered chromatin accessibility and impaired the occupancy of GATA1s and CIITA, the master regulator of HLA-class II gene expression. Chromatin binding of CIITA was increased with RAD21 correction, providing a mechanism by which restoration of cohesin improves HLA-class II expression. Finally, decreased levels of RAD21 or STAG2 expression in other subtypes of AML also exhibited reduced expression of HLA-class II genes. Thus, cohesin may contribute to leukemia by altering HLA-class II gene expression.

BACKGROUND:Falls among older adults are associated with increased morbidity, mortality, and healthcare costs; therefore, it is critical to assess modifiable risk factors. This study aimed to determine if low protein intake among older women was associated with injuries among fallers. METHODS:The Women's Health Initiative ancillary studies, Live Long Study (LLS), Food Intake (FI), and Objective Physical Activity and Cardiovascular Health in Older Women study (OPACH) were combined for analyses (n = 6,580; n = 1,285 fallers). Protein intake was assessed by food frequency questionnaires at LLS/FI/OPACH baseline. Participants completed fall calendars for 13 months and self-reported injuries in interviews. Logistic regression determined odds ratios (OR) and 95% confidence intervals (CI) for risk of injurious falls and falls with fracture. Diabetes medication use had a significant interaction between protein density and fall with any injury; thus, models were stratified. RESULTS:Of the participants who fell, 841 (65.4%) fell without injury, 444 (34.6%) fell with injury, and 70 (7.7%) fell with fracture. Lower protein density (<15% calories from protein) increased risk of fracture from falling (OR: 1.73; 95% CI: 1.02-2.92) compared to those with higher protein density (≥15% calories from protein). Among participants with diabetes medication use and lower protein density, the OR for any injury from falling was 5.54 (95% CI: 1.79-17.19) compared to those with higher protein density though based on a small subgroup. CONCLUSION/CONCLUSIONS:Lower protein density increased risk of injurious falls. Dietary and medication screening may facilitate selection and tailoring for behavioral falls prevention to reduce injurious falls and fractures.

Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.