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1.
Adv Healthc Mater ; : e2402167, 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39402780

RESUMEN

Mechanotransduction is the process whereby cells convert mechanical signals into electrochemical responses, where mechanosensitive proteins mediate this interaction. To characterize these critical proteins, numerous techniques have been developed that apply forces and measure the subsequent cellular responses. While these approaches have given insight into specific aspects of many such proteins, subsequent validation and cross-comparison between techniques remain difficult given significant variations in reported activation thresholds and responses for the same protein across different studies. Accurately determining mechanosensitivity responses for various proteins, however, is essential for understanding mechanotransduction and potential physiological implications, including therapeutics. This critical review provides an assessment of current and emerging approaches used for mechanosensitive ion channel and G-Coupled Receptors (GPCRs) stimulation and measurement, with a specific focus on the ability to quantitatively measure mechanosensitive responses.

2.
Nature ; 634(8036): 1096-1102, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39478212

RESUMEN

Additive manufacturing is an expanding multidisciplinary field encompassing applications including medical devices1, aerospace components2, microfabrication strategies3,4 and artificial organs5. Among additive manufacturing approaches, light-based printing technologies, including two-photon polymerization6, projection micro stereolithography7,8 and volumetric printing9-14, have garnered significant attention due to their speed, resolution or potential applications for biofabrication. Here we introduce dynamic interface printing, a new 3D printing approach that leverages an acoustically modulated, constrained air-liquid boundary to rapidly generate centimetre-scale 3D structures within tens of seconds. Unlike volumetric approaches, this process eliminates the need for intricate feedback systems, specialized chemistry or complex optics while maintaining rapid printing speeds. We demonstrate the versatility of this technique across a broad array of materials and intricate geometries, including those that would be impossible to print with conventional layer-by-layer methods. In doing so, we demonstrate the rapid fabrication of complex structures in situ, overprinting, structural parallelization and biofabrication utility. Moreover, we show that the formation of surface waves at the air-liquid boundary enables enhanced mass transport, improves material flexibility and permits 3D particle patterning. We, therefore, anticipate that this approach will be invaluable for applications where high-resolution, scalable throughput and biocompatible printing is required.


Asunto(s)
Impresión Tridimensional , Aire , Acústica , Bioimpresión/métodos , Ingeniería de Tejidos/métodos , Factores de Tiempo
3.
J Surg Educ ; 81(12): 103296, 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39418938

RESUMEN

OBJECTIVE: The integration of robotic surgical training in a time-scarce residency program is a challenge for surgical educators. Simulation-based training is a tool that allows residents to acquire the necessary robotic skills without compromising patient safety. This study aimed to assess the learning curve of a robotic inanimate intestinal anastomosis drill. DESIGN: Two trained graders performed a video-based assessment of each attempt of a side-to-side intestinal anastomosis drill using the Objective Structured Assessment of Technical Skill (OSATS) scale. Residents who achieved a passing score of 28 were included in the study. We assessed the number of attempts required to achieve a passing score and evaluated technical performance on different OSATS domains. Data were analyzed using independent t-test, 1-way ANOVA, and binary logistic regression. SETTING: The University of Texas Southwestern PARTICIPANTS: 33 residents across 4 academic years RESULTS: Thirty-three residents performed 139 attempts with a mean of 4.2 ± 2 attempts per resident. On average, 3.3 attempts were required to achieve a passing score. Average OSATS score increased from 21.7 to 27.2 between the 1st and the 4th attempt, respectively (p < 0.001). Of the OSATS subcategories, time and motion showed the greatest score improvement of 1.5 on a 5-point Likert scale, 95% CI [0.82, 2.18] (p < 0.001). Despite varying baseline OSATS scores between residents on initial assessment, there was no significant difference in the final attempt score. On the initial attempt, a lower score and failure to finish were associated with greater odds of requiring 5 or more attempts to pass the drill. CONCLUSION: All OSATS metrics improved on an intestinal anastomosis drill after simulation training. A maximum of 6 attempts were required to achieve a passing score. Initial performance strongly predicts the number of attempts required to achieve a passing score. This feasible and effective drill provides trainees with robotic intestinal anastomosis training.

4.
Surg Endosc ; 38(10): 5967-5973, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39075312

RESUMEN

BACKGROUND: Simulation and video-based assessment (VBA) offer residents the opportunity to develop operative skills while ensuring patient safety. This study aims to determine whether simulation training can predict residents' operative performance, focusing on the gastrojejunal (GJ) anastomosis during robotic pancreatoduodenectomy. METHODS: Twenty-seven general surgery residents completed simulated robotic GJ drills and subsequently performed GJs in the operating room (OR). Both simulated and intraoperative performances were video recorded and retrospectively assessed by two blinded graders using the Objective Structural Assessment of Technical Skills (OSATS) scale, time to completion, and occurrence of errors. Intraoperative GJ OSATS scores were compared in cases with and without Clinically Relevant Delayed Gastric Emptying (CRDGE). Statistical analysis was performed using Spearman's rho, Chi-square, and Kruskal-Wallis tests. RESULTS: For simulated GJs, the median OSATS score was 29 (IQR 27-33), time to completion was 30 min (IQR 27-35), and 11 cases had at least one error. Intraoperative GJs had a median OSATS of 30 (IQR 27-31), time to completion of 41 min (IQR 36-51), and errors occurred in nine cases. The OSATS score on the simulated GJs demonstrated a significant positive correlation to the OSATS score on the operative GJs (r = 0.74; p < 0.001) and less time to completion (r = - 0.68; p < 0.001). A shorter simulated GJ completion time significantly correlated with a higher intraoperative OSATS score (r = - 0.52; p < 0.01). Residents with at least one error in the simulated GJs had lower OSATS scores and higher times intraoperatively. Those cases with CRDGE had significantly lower intraoperative OSATS scores than those without CRDGE. CONCLUSION: Performance on a simulated robotic GJ environment is a robust predictor of OR GJ performance, demonstrating predictive validity. VBA of residents' operative GJ performance is associated with the presentation of CRDGE. Simulation-based training may be crucial to optimizing surgical outcomes before operating on patients.


Asunto(s)
Competencia Clínica , Derivación Gástrica , Internado y Residencia , Pancreaticoduodenectomía , Procedimientos Quirúrgicos Robotizados , Entrenamiento Simulado , Humanos , Derivación Gástrica/educación , Derivación Gástrica/métodos , Procedimientos Quirúrgicos Robotizados/educación , Procedimientos Quirúrgicos Robotizados/métodos , Entrenamiento Simulado/métodos , Pancreaticoduodenectomía/educación , Pancreaticoduodenectomía/métodos , Estudios Retrospectivos , Quirófanos , Cirugía General/educación , Masculino , Femenino
5.
Angew Chem Int Ed Engl ; 63(42): e202408423, 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-38946592

RESUMEN

The hydrostannylation of white phosphorus (P4) allows this crucial industrial precursor to be easily transformed into useful P1 products via direct, 'one pot' (or even catalytic) procedures. However, a thorough mechanistic understanding of this transformation has remained elusive, hindering attempts to use this rare example of successful, direct P4 functionalization as a model for further reaction development. Here, we provide a deep and generalizable mechanistic picture for P4 hydrostannylation by combining DFT calculations with in situ 31P NMR reaction monitoring and kinetic trapping of previously unobservable reaction intermediates using bulky tin hydrides. The results offer important insights into both how this reaction proceeds and why it is successful and provide implicit guidelines for future research in the field of P4 activation.

6.
Ann Surg ; 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38989569

RESUMEN

OBJECTIVE: The purpose of this study was to determine quality improvement outcomes following the pilot implementation of an in-situ simulation designed to enhance surgical safety checklist performance. BACKGROUND: OR Black Box (ORBB) technology allows near real-time assessment for surgical safety checklist performance. Before our study, timeout quality was 73.3%, compliance was 99.9%, and engagement was 89.7% (n=1993 cases); Debrief Quality was 76.0%, compliance was 66.9%, and engagement was 66.7% (n=1842 cases). METHODS: This IRB-approved study used prospective convergent multi-methods. During 2 months, a 15-minute in-situ simulation, incorporating rapid cycle deliberate practice, was implemented for OR teams. ORBB analytics generated Timeout and Debrief scores for actual operations performed by surgeons who participated in simulation (Sim-group) versus those who did not (No-sim group) over 6 months, including 2 months pre-intervention, during-intervention, and post-intervention. Inductive content analysis was performed based on simulation discussions to determine team member perspectives. RESULTS: Thirty simulations with 163 interprofessional participants were conducted. ORBB data from 1570 cases were analyzed. Scores were significantly better for the Sim-group compared with the No-sim group for debrief quality (84% vs. 79% P<0.001, during-intervention), compliance (73% vs. 66%, P<0.001, post-intervention), and engagement (80% vs. 73%, P=0.012, during-intervention). There were no between-group differences for Timeout scores. Thematic analysis identified 2 primary categories: "culture of safety" and "policy." CONCLUSIONS: This simulation-based QI intervention created a psychologically safe training environment for OR teams. The novel use of ORBB technology facilitated outcome analysis and showed significantly better Debrief scores for simulation-trained surgeons compared with nontrained surgeons.

7.
Angew Chem Int Ed Engl ; 63(28): e202405780, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38693673

RESUMEN

Precious metal complexes remain ubiquitous in photoredox catalysis (PRC) despite concerted efforts to find more earth-abundant catalysts and replacements based on 3d metals in particular. Most otherwise plausible 3d metal complexes are assumed to be unsuitable due to short-lived excited states, which has led researchers to prioritize the pursuit of longer excited-state lifetimes through careful molecular design. However, we report herein that the C-H arylation of pyrroles and related substrates (which are benchmark reactions for assessing the efficacy of photoredox catalysts) can be achieved using a simple and readily accessible octahedral bis(diiminopyridine) cobalt complex, [1-Co](PF6)2. Notably, [1-Co]2+ efficiently functionalizes both chloro- and bromoarene substrates despite the short excited-state lifetime of the key photoexcited intermediate *[1-Co]2+ (8 ps). We present herein the scope of this C-H arylation protocol and provide mechanistic insights derived from detailed spectroscopic and computational studies. These indicate that, despite its transient existence, reduction of *[1-Co]2+ is facilitated via pre-assembly with the NEt3 reductant, highlighting an alternative strategy for the future development of 3d metal-catalyzed PRC.

8.
ACS Pharmacol Transl Sci ; 7(5): 1252-1261, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38751631

RESUMEN

Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease first reported over a century ago, but its management still poses an unmet challenge. A therapeutic agent found to stabilize the condition is a short cyclic peptide, vasopressin analogue, terlipressin (TP). While TP is commonly prescribed for HRS patients in most parts of the world, it was only recently approved for use in the United States. TP exhibits short circulation half-lives and adverse side effects associated with the dose required. Herein, we present a 1,18-octadecanedioic acid (ODDA) conjugate of the cyclic peptide (ODDA-TP), which enables noncovalent binding to serum albumin via native fatty acid binding modes. ODDA-TP is demonstrated to outperform TP alone in studies including in vitro cellular receptor activation, stability in plasma, pharmacokinetics, and performance in vivo in rats. Specifically, ODDA-TP had an elimination half-life 20 times that of TP alone while exhibiting a superior safety profile.

9.
J Am Acad Orthop Surg ; 32(16): 728-737, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38759226

RESUMEN

Periprosthetic joint infection (PJI) after total ankle arthroplasty (TAA) is a dreaded complication that may lead to catastrophic outcomes. Risk factors include a history of surgery on the operated ankle, low preoperative function scores, diabetes, extended surgical time, and postoperative wound-healing problems. Clinical presentation varies and may include increasing ankle pain and swelling, high temperature, local erythema, wound drainage, and dehiscence. The initial diagnostic evaluation should include plain radiographs, erythrocyte sedimentation rate, C-reactive protein levels, and leukocyte count. In suspected cases with elevated erythrocyte sedimentation rate and C-reactive protein, aspiration of the ankle joint for synovial fluid analysis, Gram staining, and culture should be performed. Antibiotic therapy should be based on the pathogen identified, and the surgical strategy should be determined based on the time lines of PJI. Early PJI can be treated with irrigation and débridement with polyethylene exchange. The surgical treatment of choice for late PJI is two-stage revision arthroplasty, which includes removal of the implant, insertion of an antibiotic spacer, and reimplantation of a TAA. In certain chronic PJI cases, permanent articulating antibiotic spacers can be left in place or an ankle arthrodesis can be performed. Below-knee amputation is considered as the final option after limb-sparing procedures have failed.


Asunto(s)
Antibacterianos , Artroplastia de Reemplazo de Tobillo , Desbridamiento , Infecciones Relacionadas con Prótesis , Humanos , Infecciones Relacionadas con Prótesis/diagnóstico , Infecciones Relacionadas con Prótesis/etiología , Infecciones Relacionadas con Prótesis/terapia , Artroplastia de Reemplazo de Tobillo/efectos adversos , Antibacterianos/uso terapéutico , Reoperación , Factores de Riesgo , Irrigación Terapéutica , Articulación del Tobillo/cirugía
10.
Biochem Pharmacol ; 224: 116239, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38679208

RESUMEN

Human insulin-like peptide 5 (INSL5) is a gut hormone produced by colonic L-cells, and its biological functions are mediated by Relaxin Family Peptide Receptor 4 (RXFP4). Our preliminary data indicated that RXFP4 agonists are potential drug leads for the treatment of constipation. More recently, we designed and developed a novel RXFP4 antagonist, A13-nR that was shown to block agonist-induced activity in cells and animal models. We showed that A13-nR was able to block agonist-induced increases in colon motility in mice of both genders that express the receptor, RXFP4. Our data also showed that colorectal propulsion induced by intracolonic administration of short-chain fatty acids was antagonized by A13-nR. Therefore, A13-nR is an important research tool and potential drug lead for the treatment of colon motility disorders, such as bacterial diarrhea. However, A13-nR acted as a partial agonist at high concentrations in vitro and demonstrated modest antagonist potency (∼35 nM). Consequently, the primary objective of this study is to pinpoint novel modifications to A13-nR that eliminate partial agonist effects while preserving or augmenting antagonist potency. In this work, we detail the creation of a series of A13-nR-modified analogues, among which analogues 3, 4, and 6 demonstrated significantly improved RXFP4 affinity (∼3 nM) with reduced partial agonist activity, enhanced antagonist potency (∼10 nM) and maximum agonist inhibition (∼80 %) when compared with A13-nR. These compounds have potential as candidates for further preclinical evaluations, marking a significant stride toward innovative therapeutics for colon motility disorders.


Asunto(s)
Insulina , Receptores Acoplados a Proteínas G , Receptores de Péptidos , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Animales , Humanos , Ratones , Masculino , Receptores de Péptidos/metabolismo , Receptores de Péptidos/antagonistas & inhibidores , Receptores de Péptidos/agonistas , Insulina/metabolismo , Femenino , Motilidad Gastrointestinal/efectos de los fármacos , Células HEK293 , Ratones Endogámicos C57BL , Proteínas
11.
Foot Ankle Surg ; 30(6): 488-492, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38594104

RESUMEN

BACKGROUND: This study seeks to evaluate the relationship between American Society of Anesthesiologist (ASA) score and postoperative outcomes following TAA. METHODS: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database was queried from 2007 to 2020 to identify 2210 TAA patients. Patients were stratified into low (n = 1328; healthy/mild systemic disease) or high (n = 881; severe/life-threatening systemic disease) ASA score cohorts. RESULTS: There was no statistically significant difference in complications, readmission, or reoperation rate based on ASA score. Increased ASA score was significantly associated with longer length of stay (low = 1.69 days, high = 1.98 days; p < .001) and higher rate of adverse discharge (low = 95.3 %, high = 87.4 %; p < .001). CONCLUSION: Higher ASA scores (3 and 4) were statically significantly associated with increased length of stay and non-home discharge disposition. These findings are valuable for physicians and patients to consider prior to TAA given the increased utilization of resources and cost associated with higher ASA scores. LEVEL OF EVIDENCE: Level III, Retrospective cohort study.


Asunto(s)
Artroplastia de Reemplazo de Tobillo , Tiempo de Internación , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Tiempo de Internación/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Readmisión del Paciente/estadística & datos numéricos , Resultado del Tratamiento , Reoperación/estadística & datos numéricos
12.
Foot Ankle Spec ; : 19386400241247256, 2024 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-38676630

RESUMEN

INTRODUCTION: Previous studies have demonstrated a positive correlation between case volume and outcomes in foot and ankle surgery. This study elucidates surgical case volume benchmarks for Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopaedic foot and ankle fellowship training in the United States. METHODS: The ACGME provided case logs for orthopaedic residents and foot and ankle fellows (2018-2021). Variabilities in reported fellowship case volumes were defined as the fold-difference between 90th and 10th percentiles. Reported case volumes were compared between training cohorts with parametric tests. RESULTS: Case logs from 65 orthopaedic foot and ankle fellows and 3146 orthopaedic residents were included. Fellows reported 1.3- to 1.5-fold more foot and ankle cases during fellowship training than during residency training (P < .001). On average, orthopaedic foot and ankle fellows reported 405.4 cases and most were arthrodesis (17%), forefoot reconstruction (17%), mid/hindfoot reconstruction (13%), tendon repair/transfer (12%), and trauma ankle hindfoot (11%). Case categories with the highest variabilities were amputation (14.8-fold difference), infection/tumor (11.6-fold difference), arthroscopy (9.2-fold difference), and calcaneus (8.7-fold difference). DISCUSSION: Case volume benchmarks can assist trainees and faculty during orthopaedic foot and ankle training. More research is needed to determine case minimum requirements needed for autonomous practice in foot and ankle surgery. LEVEL OF EVIDENCE: Level III.

13.
Foot Ankle Spec ; : 19386400241233844, 2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38424705

RESUMEN

INTRODUCTION: This study analyzes the incidence rate and median workdays missed due to foot and ankle injuries across age groups, sexes, and industries. METHODS: Workplace injury data from 2003 to 2019 were obtained using the Nonfatal Cases Involving Day Away from Work: Selected Characteristics database provided by the Bureau of Labor Statistics (BLS). The data were grouped by injury location (ie, foot, ankle), injury type (ie, fracture, sprain), and industry, and reported with injury incidence rates and median workdays missed. RESULTS: The incidence rate of foot and ankle injuries significantly decreased from 2003 to 2019 (P < .001). With increasing age, the incidence rate of foot and ankle injuries decreased (P < .001) and median workdays missed increased (P < .001). Men had significantly higher rates of foot and ankle injuries (P < .001). Agriculture, forestry, fishing, and hunting (foot=10.23%, ankle=10.41%); construction (foot=8.14%, ankle=8.68%); and transportation and warehousing (foot=11.06%, ankle=13.80%) industries had the highest injury incidence rates. Transportation and warehousing (foot=16.8 days, ankle=16.3 days), mining (foot=44.9 days, ankle=17.1 days), and utilities (foot=26.7 days, ankle=24.4 days) industries had the highest median workdays missed. CONCLUSION: Increased incidence and severity of workplace foot and ankle injuries are associated with male sex and heavy labor industries. Age was positively associated with severity and negatively associated with incidence of workplace ankle injuries. LEVELS OF EVIDENCE: Level III, Retrospective cohort study.

14.
Biochem Pharmacol ; 222: 116092, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38408679

RESUMEN

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.


Asunto(s)
Clioquinol , Ratas , Humanos , Animales , Chlorocebus aethiops , Clioquinol/farmacología , Oxiquinolina , Receptores Adrenérgicos alfa 1/metabolismo , Ionóforos , Zinc
15.
Surg Endosc ; 38(4): 2219-2230, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38383688

RESUMEN

BACKGROUND: Laparoscopic hiatal hernia repair (LHHR) is a complex operation requiring advanced surgical training. Surgical simulation offers a potential solution for learning complex operations without the need for high surgical volume. Our goal is to develop a virtual reality (VR) simulator for LHHR; however, data supporting task-specific metrics for this procedure are lacking. The purpose of this study was to develop and assess validity and reliability evidence of task-specific metrics for the fundoplication phase of LHHR. METHODS: In phase I, structured interviews with expert foregut surgeons were conducted to develop task-specific metrics (TSM). In phase II, participants with varying levels of surgical expertise performed a laparoscopic Nissen fundoplication procedure on a porcine stomach explant. Video recordings were independently assessed by two blinded graders using global and TSM. An intraclass correlation coefficient (ICC) was used to assess interrater reliability (IRR). Performance scores were compared using a Kruskal-Wallis test. Spearman's rank correlation was used to evaluate the association between global and TSM. RESULTS: Phase I of the study consisted of 12 interviews with expert foregut surgeons. Phase II engaged 31 surgery residents, a fellow, and 6 attendings in the simulation. Phase II results showed high IRR for both global (ICC = 0.84, p < 0.001) and TSM (ICC = 0.75, p < 0.001). Significant between-group differences were detected for both global (χ2 = 24.01, p < 0.001) and TSM (χ2 = 18.4, p < 0.001). Post hoc analysis showed significant differences in performance between the three groups for both metrics (p < 0.05). There was a strong positive correlation between the global and TSM (rs = 0.86, p < 0.001). CONCLUSION: We developed task-specific metrics for LHHR and using a fundoplication model, we documented significant reliability and validity evidence. We anticipate that these LHHR task-specific metrics will be useful in our planned VR simulator.


Asunto(s)
Fundoplicación , Laparoscopía , Animales , Porcinos , Humanos , Fundoplicación/métodos , Laparoscopía/métodos , Reproducibilidad de los Resultados , Competencia Clínica , Estómago , Simulación por Computador
16.
J Surg Educ ; 81(4): 589-596, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38403503

RESUMEN

OBJECTIVE: Our institution recently implemented a virtual reality (VR) skills curriculum for general surgery residents using the SimNow simulator. Based on a content alignment study, we revised the curriculum to include only 20 of 33 VR tasks and we added 3 previously validated inanimate tasks. The purpose of this study was to establish expert-derived proficiency levels for all tasks and to evaluate the validity of the scoring for the VR tasks. DESIGN: Two expert robotic surgeons performed 5 repetitions of each VR and inanimate task. The trimmed mean (lowest scoring attempt and outliers [>2 standard deviations] were eliminated) was defined as the expert level for each task. For the VR tasks, expert levels were compared to resident performance to evaluate validity. SETTING: This study was conducted at the University of Texas Southwestern Medical Center (Dallas, TX), a tertiary care academic teaching hospital. PARTICIPANTS: Two expert robotic surgeons participated in this study. The data from 42 residents (PGY2-4) who completed the original curriculum was used to represent novice performance. RESULTS: Comparison of expert levels and resident performance was statistically significant for 15 VR tasks (supporting validity) and approached significance (p = 0.06, 0.09) for 2 VR tasks; expert levels were designated as proficiency levels for these 17 tasks. Group comparisons were clearly not significant (p = 0.2-0.8) for 3 VR tasks; 2 of these 3 tasks were retained as introductory exercises (with 3 repetitions required) and 1 was excluded. For the 3 inanimate tasks, expert levels minus 2 standard deviations were designated as proficiency levels. CONCLUSIONS: This analysis generated validity evidence for 15 VR tasks and established expert-derived proficiency levels for 17 VR tasks and 3 inanimate tasks. Our proposed curriculum now consists of 19 VR and 3 inanimate tasks using the selected proficiency levels. We anticipate that this design will maximize curriculum efficiency and effectiveness.


Asunto(s)
Procedimientos Quirúrgicos Robotizados , Realidad Virtual , Humanos , Procedimientos Quirúrgicos Robotizados/educación , Competencia Clínica , Simulación por Computador , Curriculum
17.
ACS Chem Neurosci ; 15(3): 671-684, 2024 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-38238043

RESUMEN

α1A-, α1B-, and α1D-adrenoceptors (α1-ARs) are members of the adrenoceptor G protein-coupled receptor family that are activated by adrenaline (epinephrine) and noradrenaline. α1-ARs are clinically targeted using antagonists that have minimal subtype selectivity, such as prazosin and tamsulosin, to treat hypertension and benign prostatic hyperplasia, respectively. Abundant expression of α1-ARs in the heart and central nervous system (CNS) makes these receptors potential targets for the treatment of cardiovascular and CNS disorders, such as heart failure, epilepsy, and Alzheimer's disease. Our understanding of the precise physiological roles of α1-ARs, however, and their involvement in disease has been hindered by the lack of sufficiently subtype-selective tool compounds, especially for α1B-AR. Here, we report the discovery of 4-[(2-hydroxyethyl)amino]-6-methyl-2H-chromen-2-one (Cpd1), as an α1B-AR antagonist that has 10-15-fold selectivity over α1A-AR and α1D-AR. Through computational and site-directed mutagenesis studies, we have identified the binding site of Cpd1 in α1B-AR and propose the molecular basis of α1B-AR selectivity, where the nonconserved V19745.52 residue plays a major role, with contributions from L3146.55 within the α1B-AR pocket. By exploring the structure-activity relationships of Cpd1 at α1B-AR, we have also identified 3-[(cyclohexylamino)methyl]-6-methylquinolin-2(1H)-one (Cpd24), which has a stronger binding affinity than Cpd1, albeit with reduced selectivity for α1B-AR. Cpd1 and Cpd24 represent potential leads for α1B-AR-selective drug discovery and novel tool molecules to further study the physiology of α1-ARs.


Asunto(s)
Prazosina , Receptores Adrenérgicos alfa 1 , Receptores Adrenérgicos alfa 1/metabolismo , Tamsulosina , Norepinefrina
18.
BMJ Open ; 14(1): e075821, 2024 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-38245009

RESUMEN

OBJECTIVE: To report participants' experiences of trial processes and use of the Neurofenix platform for home-based rehabilitation following stroke. The platform, consisting of the NeuroBall device and Neurofenix app, is a non-immersive virtual reality tool to facilitate upper limb rehabilitation following stroke. The platform has recently been evaluated and demonstrated to be safe and effective through a non-randomised feasibility trial (RHOMBUS). DESIGN: Qualitative approach using semistructured interviews. Interviews were audio recorded, transcribed verbatim and analysed using the framework method. SETTING: Participants' homes, South-East England. PARTICIPANTS: Purposeful sample of 18 adults (≥18 years), minimum 12 weeks following stroke, not receiving upper limb rehabilitation prior to the RHOMBUS trial, scoring 9-25 on the Motricity Index (elbow and shoulder), with sufficient cognitive and communicative abilities to participate. RESULTS: Five themes were developed which explored both trial processes and experiences of using the platform. Factors that influenced participant's decision to take part in the trial, their perceptions of support provided during the trial and communication with the research team were found to be important contextual factors effecting participants' overall experience. Specific themes around usability and comfort of the NeuroBall device, factors motivating persistence and perceived effectiveness of the intervention were highlighted as being central to the usability and acceptability of the platform. CONCLUSION: This study demonstrated the overall acceptability of the platform and identified areas for enhancement which have since been implemented by Neurofenix. The findings add to the developing literature on the interface between virtual reality systems and user experience. TRIAL REGISTRATION NUMBER: ISRCTN60291412.


Asunto(s)
Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Juegos de Video , Adulto , Humanos , Ejercicio Físico , Accidente Cerebrovascular/psicología , Rehabilitación de Accidente Cerebrovascular/métodos , Extremidad Superior , Ensayos Clínicos como Asunto , Investigación Cualitativa
19.
Lab Chip ; 24(6): 1616-1625, 2024 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-38288761

RESUMEN

Mechanosensitive proteins play a crucial role in a range of physiological processes, including hearing, tactile sensation and regulating blood flow. While previous work has demonstrated the mechanosensitivity of several proteins, the ability to apply precisely defined mechanical forces to cells in a consistent, replicable manner remains a significant challenge. In this work we present a novel 96-well plate-compatible plugin device for generating highly-controlled flow-based mechanical simulation of cells, which enables quantitative assessment of mechanosensitive protein function. The device is used to mechanically stimulate HEK 293T cells expressing the mechanosensitive protein GPR68, a G protein-coupled receptor. By assaying intracellular calcium levels during flow-based cell stimulation, we determine that GPR68 signalling is a function of the applied shear-force. As this approach is compatible with conventional cell culture plates and allows for simultaneous readout in a conventional fluorescence plate reader, this represents a valuable new tool to investigate mechanotransduction.


Asunto(s)
Técnicas de Cultivo de Célula , Mecanotransducción Celular , Mecanotransducción Celular/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Estrés Mecánico
20.
Nat Commun ; 14(1): 8155, 2023 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-38071229

RESUMEN

The conformational ensembles of G protein-coupled receptors (GPCRs) include inactive and active states. Spectroscopy techniques, including NMR, show that agonists, antagonists and other ligands shift the ensemble toward specific states depending on the pharmacological efficacy of the ligand. How receptors recognize ligands and the kinetic mechanism underlying this population shift is poorly understood. Here, we investigate the kinetic mechanism of neurotensin recognition by neurotensin receptor 1 (NTS1) using 19F-NMR, hydrogen-deuterium exchange mass spectrometry and stopped-flow fluorescence spectroscopy. Our results indicate slow-exchanging conformational heterogeneity on the extracellular surface of ligand-bound NTS1. Numerical analysis of the kinetic data of neurotensin binding to NTS1 shows that ligand recognition follows an induced-fit mechanism, in which conformational changes occur after neurotensin binding. This approach is applicable to other GPCRs to provide insight into the kinetic regulation of ligand recognition by GPCRs.


Asunto(s)
Neurotensina , Receptores de Neurotensina , Neurotensina/metabolismo , Receptores de Neurotensina/metabolismo , Ligandos , Receptores Acoplados a Proteínas G/metabolismo , Unión Proteica
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