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Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]). Intravenously administered NP-Ly6G(2-DG) to mice exhibited high specificity for circulating neutrophils. NP-Ly6G(2-DG)-treated neutrophils were unable to adapt to hypoglycemic conditions of the lung airspace environment as evident by the loss of demand-induced glycolysis, reductions in glycogen and ATP content, and an increased vulnerability to apoptosis. NP-Ly6G(2-DG) treatment inhibited pulmonary IRI following hilar occlusion and orthotopic lung transplantation. IRI protection was associated with less airspace neutrophil extracellular trap generation, reduced intragraft neutrophilia, and enhanced alveolar macrophage efferocytotic clearance of neutrophils. Collectively, our data show that pharmacologically targeting glycolysis in neutrophils inhibits their activation and survival leading to reduced pulmonary IRI.
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Glicólise , Transplante de Pulmão , Camundongos Endogâmicos C57BL , Nanopartículas , Neutrófilos , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Camundongos , Glicólise/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Nanopartículas/química , Masculino , Transplante de Pulmão/efeitos adversos , Desoxiglucose/farmacologia , Apoptose/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Pulmão/efeitos dos fármacosRESUMO
Epidermal growth factor receptor (EGFR) is a transmembrane protein commonly targeted by tyrosine kinase inhibitors (TKIs) as a front-line therapy for patients with many cancers including nonsmall cell lung cancer (NSCLC). Effective treatment requires efficient intracellular drug uptake and target binding. However, despite the recent success in the development of new TKI drugs, the mechanisms of uptake for many TKIs are still poorly understood due to the difficulty in imaging and measuring nonfluorescent drug molecules at a subcellular resolution. It has previously been shown that weakly basic TKI drugs are sequestered in lysosomes. Leveraging this property, we apply hyperspectral stimulated Raman scattering imaging to directly visualize and quantify two Food and Drug Administration-approved EGFR inhibitor drugs (lapatinib and afatinib) inside living cells and the changes in their cellular uptake upon the addition of organic cation transporter inhibitors. These single-cell quantitative measurements provide new insight into the role of membrane transporters in the uptake of TKI drugs in living cells.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Receptores ErbB/metabolismo , Resistencia a Medicamentos AntineoplásicosRESUMO
BACKGROUND: STARS (Students and Trainees Advocating for Resource Stewardship) is a medical student leadership program that promotes integration of resource stewardship (RS) into medical education in at least seven countries. Little is known about how participation affects student leaders. AIM: To understand how partaking in STARS impacted participants' knowledge, skills, and influenced career plans, and aspirations. SETTING AND PARTICIPANTS: We conducted qualitative semi-structured interviews with STARS participants (n = 27) from seven countries. PROGRAM DESCRIPTION: STARS was designed to facilitate grassroots efforts that embed RS principles into medical education. STARS programs globally share common features: participation from several medical schools, centralized organizing hubs and leadership summits, and support from faculty mentors. Students take lessons learnt from centralized programming to implement changes that advance RS initiatives at their schools. PROGRAM EVALUATION: Students finished STARS with better RS knowledge, enhanced change management skills (leadership, advocacy, collaboration), and a commitment to incorporate RS into future practice. Nearly all respondents hoped to pursue leadership activities in medicine, but most were unclear if they would focus efforts to advance RS. DISCUSSION: STARS participants gained knowledge as it relates to RS, change management skills, and catalyzed a commitment to incorporate high-value care into future practice. Medical education initiatives should be leveraged as a key strategic approach to build RS capacity.
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Refractive errors remain a global health concern, as a large proportion of the world's population is myopic. Current ablative approaches are costly, not without risks, and not all patients are candidates for these procedures. Electromechanical reshaping (EMR) has been explored as a viable cost-effective modality to directly shape tissues, including cartilage. In this study, stromal collagen structure and fibril orientation was examined before and after EMR with second-harmonic generation microscopy (SHG), a nonlinear multiphoton imaging method that has previously been used to study native corneal collagen with high spatial resolution. EMR, using a milled metal contact lens and potentiostat, was performed on the corneas of five extracted rabbit globes. SHG was performed using a confocal microscopy system and all images underwent collagen fibril orientation analysis. The collagen SHG signal in controls is uniform and is similarly seen in samples treated with pulsed potential, while continuous EMR specimens have reduced, nonhomogeneous signal. Collagen fibril orientation in native tissue demonstrates a broad distribution with suggestion of another peak evolving, while with EMR treated eyes a bimodal characteristic becomes readily evident. Pulsed EMR may be a means to correct refractive errors, as when comparing its SHG signal to negative control, preservation of collagen structures with little to no damage is observed. From collagen fiber orientation analysis, it can be inferred that simple DC application alters the structure of collagen. Future studies will involve histological assessment of these layers and multi-modal imaging analysis of dosimetry.
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Colágeno , Microscopia Confocal , Microscopia de Geração do Segundo Harmônico , Animais , Coelhos , Microscopia de Geração do Segundo Harmônico/métodos , Colágeno/metabolismo , Substância Própria/metabolismo , CórneaRESUMO
PURPOSE: The inclusion of quality improvement (QI) and patient safety (PS) into CanMEDS reflects an expectation that graduating physicians are competent in these areas upon training completion. To ensure that Canadian postgraduate specialty training achieves this, the translation of QI/PS competencies into training standards as part of the implementation of competency-based medical education requires special attention. METHODS: We conducted a cross-specialty, multi-method analysis to examine how QI/PS was incorporated into the EPA Guides across 11 postgraduate specialties in Canada. RESULTS: We identify cross-specialty variability in how QI/PS is incorporated, positioned, and emphasized in EPAs and milestones. QI/PS was primarily referenced alongside clinical activities rather than as a sole competency or discrete activity. Patterns were characterized in how QI/PS became incorporated into milestones through repetition and customization. QI/PS was also decoupled, conceptualized, and emphasized differently across specialties. CONCLUSIONS: Variability in the inclusion of QI/PS in EPAs and milestones has important implications considering the visibility and influence of EPA Guides in practice. As specialties revisit and revise EPA Guides, there is a need to balance the standardization of foundational QI/PS concepts to foster shared understanding while simultaneously ensuring context-sensitive applications across specialties. Beyond QI/PS, this study illuminates the challenges and opportunities that lie in bridging theoretical frameworks with practical implementation in medical education, prompting broader consideration of how intrinsic roles and emergent areas are effectively incorporated into competency-based medical education.
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The influences of shared orthography, semantics, and phonology on bilingual cognate processing have been investigated extensively. However, mixed results have been found regarding the effects of phonological similarity on L2 cognate processing. In addition, most existing studies examining the influence of phonological similarity on cognate processing have been conducted on alphabetic scripts, in which phonology and orthography are always associated. Hence, in this study, we recruited Cantonese-Japanese bilinguals who used two logographic scripts, traditional Chinese and Japanese Kanji, to examine the influence of phonological similarity on L2 cognate lexical decision. Importantly, these scripts allow the manipulation of phonological similarity using identical characters across both languages. In addition, we examined how word frequency and L2 proficiency modulate cognate processing. Results showed that although word frequency and L2 proficiency played important roles in cognate processing, there was minimal overall influence of phonological similarity on cognate lexical decision. The latter finding suggests that theoretical models of bilingual word recognition may need to be refined to enhance our understanding of cognate processing regarding the role of phonology among diverse bilingual populations.
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Background: Many open-access artificial intelligence (AI)-based websites that rate facial attractiveness are available, but none have been compared with human focus group outcomes. Objective: To compare human and AI-based websites scoring of facial attractiveness of adult female white faces. Methods: A 40-photograph database of AI-generated adult, white, female, expressionless, and frontal-view facial images were scored by otolaryngology residents and five AI-based facial rating websites: prettyscale.com, attractivenesstest.com, face-score.com/en, hotchat3000.com, and beautyscoretest.com. Sample t-test and bivariate correlation were performed for statistical analyses. Results: The focus group of 24 otolaryngology residents consisted of 62.5% males and 58.3% white participants. There was a strong positive correlation between average human score and average AI score for each photo (Pearson's correlation 0.84, p < 0.01). The average human raters' scores were significantly lower than the average AI scores (5.0 ± 1.8 vs. 6.9 ± 0.9, p < 0.01). Thirty images (75.0%) had statistically higher scores from the AI websites versus the focus group. On correlation analysis, all AI-based websites individually had scores that positively correlate with the human scores (all p < 0.05). Conclusion: AI-based websites and human focus-group scoring of facial attractiveness of adult white female faces were significantly correlated with the AI ratings biased toward higher values, encouraging their cautious utilization in future research.
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Inteligência Artificial , Beleza , Face , Grupos Focais , Humanos , Feminino , Masculino , Adulto , Face/anatomia & histologia , Fotografação , InternetRESUMO
In this case report, we present an unusual complication linked to a hydrogel explant in a 72-year-old male presenting to the emergency department with persistent left eye pain, redness, and discharge for one month. The patient had a history of retinal detachment in 1989, which was managed with scleral buckle surgery and gas injection. Initial examination revealed an extruding scleral buckle in the superior temporal region, along with signs of an infection. CT scans revealed a 1.9 × 1.2 × 3.8 cm abscess accompanied by preseptal cellulitis. This case report highlights the importance of how hydrogel scleral buckle explants may mimic the presentation and symptoms of an abscess as a long-term complication. Nevertheless, there have been several reports of long-term issues associated with the expansion of the hydrophilic hydrogel material. This case report further illustrates how complications linked to hydrogel explants can resemble abscess symptoms, underscoring the significance of accurate diagnosis and appropriate management.
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ABSTRACT: Systems-based practice (SBP) was first introduced as a core competency in graduate medical education (GME) in 2002 by the Accreditation Council for Graduate Medical Education as part of the Outcomes Project. While inclusion of SBP content in GME has become increasingly common, there have also been well-documented stumbling blocks, including perceptions that SBP has eroded the amount of curricular time available for more medically focused competencies, is not relevant for some practice contexts, and is not introduced early enough in training. As a result, SBP learning experiences often feel disconnected from medical trainees' practical reality. In this commentary, the authors provide guidance regarding potential changes that may facilitate the evolution of SBP toward an ideal future state where graduates bring a systems science mindset to all aspects of their work. Specific suggestions include the following: (1) expanding the SBP toolbox to reflect current-day health system needs, (2) evolve the teaching methodology, (3) broadening the scope of relevant SBP content areas, and (4) emphasizing SBP as an integrated responsibility for all health care team members. Levers to enact this transformation exist and must be used to influence change at the learner, faculty, program, and clinical learning environment levels.Physicians operate within an increasingly complex health care system that highlights the intersection of health care with complex social, environmental, and relational contexts. Consequently, the role of SBP in both physician work responsibilities and educational requirements continues to expand. To meet this growing demand, GME must adapt how it supports and trains the next generation of systems thinkers, ensuring they understand how levers in the health care system directly affect health outcomes for their patients, and integrate SBP into the foundation of GME curricula in an inclusive, holistic, and unrestrained way.
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Educação de Pós-Graduação em Medicina , Internato e Residência , Humanos , Educação de Pós-Graduação em Medicina/métodos , Currículo , Aprendizagem , Atenção à Saúde , Competência ClínicaRESUMO
Two classic experimental paradigms - masked repetition priming and the boundary paradigm - have played a pivotal role in understanding the process of visual word recognition. Traditionally, these paradigms have been employed by different communities of researchers, with their own long-standing research traditions. Nevertheless, a review of the literature suggests that the brain-electric correlates of word processing established with both paradigms may show interesting similarities, in particular with regard to the location, timing, and direction of N1 and N250 effects. However, as of yet, no direct comparison has been undertaken between the two paradigms. In the current study, we used combined eye-tracking/EEG to perform such a within-subject comparison using the same materials (single Chinese characters) as stimuli. To facilitate direct comparisons, we used a simplified version of the boundary paradigm - the single word boundary paradigm. Our results show the typical early repetition effects of N1 and N250 for both paradigms. However, repetition effects in N250 (i.e., a reduced negativity following identical-word primes/previews as compared to different-word primes/previews) were larger with the single word boundary paradigm than with masked priming. For N1 effects, repetition effects were similar across the two paradigms, showing a larger N1 after repetitions as compared to alternations. Therefore, the results indicate that at the neural level, a briefly presented and masked foveal prime produces qualitatively similar facilitatory effects on visual word recognition as a parafoveal preview before a single saccade, although such effects appear to be stronger in the latter case.
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Objectives: To evaluate trends in botulinum toxin (BTX) industry payments to physicians. Methods: Cross-sectional analysis of nonroyalty, BTX-specific payments made by Allergan (Botox), Ipsen (Dysport), and Merz (Xeomin) to physicians using the 2016-2020 Open Payments Database. Results: Between 2016 and 2020, >$27 million in payments was made for BTX-related activities to dermatologists, neurologists, ophthalmologists, otolaryngologists, and plastic surgeons, with payments ranging from $3.9 million in 2016 to $8.7 million in 2019. 21.7% was paid to dermatologists, 57.5% to neurologists, 5.9% to ophthalmologists, 5.7% to otolaryngologists, and 9.1% to plastic surgeons. Conclusions: Growing amounts are being paid to physicians for BTX-related activities-both medical and aesthetic. Despite the variety of indications for BTX within otolaryngology, otolaryngology payments were overshadowed by other specialties, which may reflect greater BTX utilization in those specialties.
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OBJECTIVE: Drug induced sleep endoscopy (DISE) is often performed for pediatric obstructive sleep apnea (OSA) when initial diagnostic studies do not provide adequate information for therapy. However, DISE scoring is subjective and with limitations. This proof-of-concept study demonstrates the use of a novel long-range optical coherence tomography (LR-OCT) system during DISE of two pediatric patients. METHODS: LR-OCT was used to visualize the airway of pediatric patients during DISE. At the conclusion of DISE, the OCT probe was guided in the airway under endoscopic visual guidance, and cross-sectional images were acquired at the four VOTE locations. Data processing involved image resizing and alignment, followed by rendering of three-dimensional (3D) volumetric models of the airways. RESULTS: Two patients were included in this study. Patient one had 18.4%, 20.9%, 72.3%, and 97.3% maximal obstruction at velum, oropharynx, tongue base, and epiglottis, while patient two had 40.2%, 41.4%, 8.0%, and 17.5% maximal obstruction at these regions, respectively. Three-dimensional reconstructions of patients' airways were also constructed from the OCT images. CONCLUSION: This proof-of-concept study demonstrates the successful evaluation of pediatric airway during DISE using LR-OCT, which accurately identified sites and degrees of obstruction with respective 3D airway reconstruction.
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Obstrução das Vias Respiratórias , Apneia Obstrutiva do Sono , Humanos , Criança , Tomografia de Coerência Óptica , Polissonografia , Endoscopia/métodos , Apneia Obstrutiva do Sono/diagnóstico , Sono , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/etiologiaRESUMO
Several studies have shown developmental changes in EEG oscillations during working memory tasks. Although the load-modulated theta and alpha activities in adults are well-documented, the findings are inconsistent if children possess the adult-like brain oscillations that are similarly modulated by memory load. The present study compares children's and adults' true theta and alpha EEG oscillations, separated from aperiodic components, in the maintenance stage of working memory. The EEG was recorded in 25 Chinese-speaking children (14 male, Mage = 9.4 yrs) and 31 adults (19 male, Mage = 20.8 yrs) in Hong Kong while they performed an n-back task that included four conditions differing in load (1- vs. 2-back) and stimulus type (Chinese character vs. visual pattern). The results show that aperiodic activities (i.e., broadband power and slope) during the maintenance stage in the n-back task were significantly higher in children than adults. The periodic theta and alpha oscillations also changed with age. More importantly, adults showed significant periodic theta increase with memory load, whereas such an effect was absent in children. Regardless of age, there was a significant alpha power decrease with load increase, and a significant theta power enhancement when maintaining visual patterns than Chinese characters. In adults, load-modulated alpha peak shift (towards higher frequency) was linked to higher behavioral efficiency in the n-back task. In children, higher load-modulated theta enhancement was linked to better behavioral efficiency. The findings suggest that the load-modulated theta power during working memory maintenance matures from childhood to adulthood.
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INTRODUCTION: The physical modification of cartilage grafts during rhinoplasty risks chondrocyte death at the margins where the tissue is cut. This study compares chondrocyte viability between diced, scaled, and pate samples in human models, and further computes percent chondrocyte viability as a function of sequential dicing size in a computational model. METHODS: Septal cartilage from 11 individuals was prepared as follows: diced (1 mm cubic), scaled (shaved to <1 mm thickness ~ translucent), pate (0.02 g of scraped cartilage surface), positive control (2 × 2 mm diced), and negative control (2 × 2 mm diced soaked in 70% EtOH). Viability analysis was performed using Live/Dead assay™ and confocal microscopy. Numerical simulation of cartilage dicing in 0.05 mm increments was performed using MATLAB assuming 250 chondrocytes/mm3 with each average chondrocyte size of 65 µm2. RESULTS: Chondrocyte viability was similar between 1 mm diced cartilage, scaled cartilage, and positive control samples (p > 0.05). Conversely, pate samples had significantly less viability compared to positive controls, diced samples, and scaled samples (all p < 0.01 after Bonferroni correction). Pate samples had similar chondrocyte viability compared to negative controls (p = 0.36). On computational modeling, cartilage viability decreased to 50% as the diced sample was cut from 1 mm edge length to 0.7-0.8 mm. Similarly, cartilage viability decreased to 26% at 0.55-0.65 mm, 11% at 0.4-0.5 mm, and <5% at <0.4 mm edge length. CONCLUSION: Modifying septal cartilage grafts into 1 mm diced or scaled samples maintains ideal chondrocyte viability whereas pate preparations result in significant chondrocyte death. According to computational analysis, chondrocyte viability sharply decreases as the cartilage is diced below 0.7-0.8 mm. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.
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ABSTRACT: Precision education (PE) leverages longitudinal data and analytics to tailor educational interventions to improve patient, learner, and system-level outcomes. At present, few programs in medical education can accomplish this goal as they must develop new data streams transformed by analytics to drive trainee learning and program improvement. Other professions, such as Major League Baseball (MLB), have already developed extremely sophisticated approaches to gathering large volumes of precise data points to inform assessment of individual performance.In this perspective, the authors argue that medical education-whose entry into precision assessment is fairly nascent-can look to MLB to learn the possibilities and pitfalls of precision assessment strategies. They describe 3 epochs of player assessment in MLB: observation, analytics (sabermetrics), and technology (Statcast). The longest tenured approach, observation, relies on scouting and expert opinion. Sabermetrics brought new approaches to analyzing existing data in a way that better predicted which players would help the team win. Statcast created precise, granular data about highly attributable elements of player performance while helping to account for nonplayer factors that confound assessment such as weather, ballpark dimensions, and the performance of other players. Medical education is progressing through similar epochs marked by workplace-based assessment, learning analytics, and novel measurement technologies. The authors explore how medical education can leverage intersectional concepts of MLB player and medical trainee assessment to inform present and future directions of PE.
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Beisebol , Educação Médica , Humanos , Escolaridade , Local de TrabalhoRESUMO
Background: A "boomerang" graft is an end-to-end caudal septal extension graft (SEG) that conforms to the geometry of the anterior septal angle, and avoids septal overlap, unlike a side-to-side SEG. Objective: To compare breathing improvements in rhinoplasty patients receiving boomerang SEGs and patients receiving side-to-side SEGs. Methods: Retrospective cohort analysis of patients undergoing rhinoplasty with either end-to-end boomerang SEG or a side-to-side SEG. Functional outcomes were assessed through the Nasal Obstruction Symptom Evaluation (NOSE) survey. Results: The boomerang SEG cohort had a mean age of 34 years and were 68% female compared with 38 years and 67% female in the side-to-side SEG cohort (p > 0.05). The cohorts did not differ in the proportion of the lateral crural tensioning, spreader graft placement, or history of rhinoplasty. The boomerang cohort demonstrated a 67% reduction in NOSE scores compared with a 70% reduction among the side-to-side SEG cohort (p = 0.14). Men undergoing boomerang graft placement reported significantly less postoperative functional improvement than men undergoing placement of a side-to-side SEG (62% vs. 77%, p = 0.01). Conclusion: Use of a boomerang graft is not likely to negatively affect rhinoplasty functional outcomes when compared with a side-to-side SEG.
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Obstrução Nasal , Septo Nasal , Rinoplastia , Humanos , Rinoplastia/métodos , Masculino , Feminino , Estudos Retrospectivos , Adulto , Septo Nasal/cirurgia , Obstrução Nasal/cirurgia , Resultado do Tratamento , Cartilagens Nasais/cirurgia , Cartilagens Nasais/transplante , Respiração , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Osteotomies are routinely incorporated in rhinoplasty, however, the influence of mass, velocity, kinetic energy (KE), and momentum (p) of the mallet on fracture patterns has not been studied. METHODS: An experimental sledge guillotine setup was designed simulating a mallet strike with adjustable height and mass and 2 mm-thick Sawbone blocks. KE and p were calculated using KE = ½ mass × velocity2 and p = mass × velocity formulas. Fracture lengths and angles were measured. RESULTS: Ten groups with varying mallet masses and drop heights were tested with 10 bones per group. Fracture length positively correlated with KE (R = 0.542, p < 0.001) and p (R = 0.508, p < 0.001). Fracture angle also positively correlated with KE (R = 0.367, p < 0.001) and p (R = 0.329, p < 0.001). In groups with similar KE, osteotomies with higher p (heavier mallet with slower velocity) had greater fracture lengths (29.31 ± 0.68 vs. 27.68 ± 2.12 mm, p = 0.013) but similar fracture angles (p = 0.189). In groups with similar p, osteotomies with higher KE (lighter hammer with faster velocity) had significantly greater fracture lengths (28.28 ± 1.28 vs. 20.45 ± 12.20 mm, p = 0.041) and greater divergent fracture angles (3.13 ± 1.97° vs. 1.40 ± 1.36°, p = 0.031). Regression modeling of the relationship between KE and fracture lengths and angles demonstrated that cubic followed by logarithmic regression models had the best fits. CONCLUSION: Osteotomy fracture patterns positively correlated with the mallet's KE more so than its p, suggesting that the mallet's velocity has an increased impact effect than its mass. Clinically, a heavier mallet with a lower velocity will likely generate a smaller fracture length and fracture angle, indicating a more controlled and ideal fracture. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.
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Postgraduate medical education is an essential societal enterprise that prepares highly skilled physicians for the health workforce. In recent years, PGME systems have been criticized worldwide for problems with variable graduate abilities, concerns about patient safety, and issues with teaching and assessment methods. In response, competency based medical education approaches, with an emphasis on graduate outcomes, have been proposed as the direction for 21st century health profession education. However, there are few published models of large-scale implementation of these approaches. We describe the rationale and design for a national, time-variable competency-based multi-specialty system for postgraduate medical education called Competence by Design. Fourteen innovations were bundled to create this new system, using the Van Melle Core Components of competency based medical education as the basis for the transformation. The successful execution of this transformational training system shows competency based medical education can be implemented at scale. The lessons learned in the early implementation of Competence by Design can inform competency based medical education innovation efforts across professions worldwide.