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Useful monophosphorus products are obtained from both white and red phosphorus via a simple strategy involving initial oxidation by aryl disulfides followed by quenching with nucleophiles. Direct transformations of elemental phosphorus are usually very challenging, forcing chemists to instead rely on inefficient and hazardous multi-step methods. However, here they are achieved using inexpensive and easy-to-handle reagents, providing access to diverse P-C, P-N and P-O bonded products in good yields. By isolating the thiolate byproducts of these reactions, a simple, closed loop can be achieved that produces only minimal, benign waste byproducts, in contrast to other direct methods. This closed loop can even be elaborated into a true (electro)catalytic cycle, which is extremely rare in the field of elemental phosphorus functionalization., (© 2024 The Author(s). ChemSusChem published by Wiley-VCH GmbH.)

Background: This study systematically reviews the literature and reports on outcomes of total ankle arthroplasty (TAA) with the INBONE II fixed-bearing implant., Methods: PubMed, SCOPUS and CINAHL were searched for clinical studies reporting INBONE II specific outcomes from database inception through July 13th, 2024, according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines., Results: Seven primary TAA studies and 4 revision TAA studies were included with 406 and 114 patients respectively. Survivorship was 96.5 % (mean follow-up 44.8 months) and 93.9 % (mean follow-up=37.3 months) for primary and revision TAA, respectively. The mean reoperation rate was 11.4 % with a 3.2 % rate of major complications for primary TAA. Meanwhile, the reoperation rate was 9.1 % with a major complication rate of 12.2 % for revision TAA., Conclusions: Primary and revision TAA with this implant results in over 93 % survival at mid-term follow-up with an acceptable complication rate, supporting its continued use., Level of Evidence: Level IV: Systematic Review of Level I-IV Studies., (Copyright © 2024 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

This communication summarizes findings from the earliest encounters with extreme enthalpy‒entropy compensation, a phenomenon first detected in the 1950s by a reappraisal of isopiestic and calorimetric measurements on aqueous urea solutions in terms of solute self-association. Because concurrent studies of carboxylic acid association were confined to measurement of the equilibrium constant by conductance, IR spectrophotometry or potentiometric titration measurements, temperature-independence of the dimerization constant was mistakenly taken to signify a value of zero for Δ H o instead of (Δ H o  ‒ TΔ S o ). In those studies of small-solute self-association the extreme enthalpy‒entropy compensation was reflecting the action of water as a reactant whose hydroxyl groups were competing for the solute carbonyl involved in self-association. Such action gives rise to a positive temperature dependence of Δ H o that could well be operating in concert with that responsible for the commonly observed negative dependence for protein‒ligand interactions exhibiting extreme enthalpy‒entropy compensation, where the solvent contribution to the energetics reflects changes in the extent of ordered water structure in hydrophobic environments., Competing Interests: Declarations Conflict of interest The authors declare that they have no conflict of interest. Ethics approval This article does not contain any studies with human participants or animals performed by any of the authors., (© 2024. The Author(s).)

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., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

The hydrostannylation of white phosphorus (P 4 ) allows this crucial industrial precursor to be easily transformed into useful P 1 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 P 4 functionalization as a model for further reaction development. Here, we provide a deep and generalizable mechanistic picture for P 4 hydrostannylation by combining DFT calculations with in situ 31 P 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 P 4 activation., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Additive manufacturing is an expanding multidisciplinary field encompassing applications including medical devices 1 , aerospace components 2 , microfabrication strategies 3,4 and artificial organs 5 . Among additive manufacturing approaches, light-based printing technologies, including two-photon polymerization 6 , projection micro stereolithography 7,8 and volumetric printing 9-14 , 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., (© 2024. The Author(s).)

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Most albumin in blood plasma is thought to be monomeric with some 5% covalently dimerized. However, many reports in the recent biophysics literature find that albumin is reversibly dimerized or even oligomerized. We review data on this from X-ray crystallography and diverse biophysical techniques. The number-average molecular weight of albumin would be increased by dimerization, affecting size-dependent filtration processes of albumin such as at the glycocalyx of the capillary endothelium and the podocyte slit-diaphragm of the renal glomerulus. If correct, and depending on characteristics of the process, such as K d , reversible dimerization of albumin in plasma would have major implications for normal physiology and medicine. We present quantitative models of the impact of dimerization on albumin molecular forms, on the number-average molecular weight of albumin, and estimate the effect on the colloid osmotic pressure of albumin. Dimerization reduces colloid osmotic pressure as total albumin concentration increases below that expected in the absence of dimerization. Current models of albumin filtration by the renal glomerulus would need revision to account for the dynamic size of albumin molecules filtered. More robust biophysical data are needed to give a definitive answer to the questions posed and we suggest possible approaches to this., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Introduction: Next-generation DNA sequencing (NGS) technologies have increased the sensitivity for detecting the bacterial presence and have been used in other areas of orthopaedics to better understand the native microbiome of various joints. This study uses NGS to determine whether (1) a unique microbiome exists in human ankle tissues, (2) if components of the ankle microbiome affect patient outcomes, and (3) whether microbes found on the skin are a normal part of the ankle microbiome., Methods: A prospective study recruited 32 patients undergoing total ankle arthroplasty (n = 23) or ankle arthrodesis (n = 9) via direct anterior approach between November 2020 and October 2021. During surgery, five layers of the ankle were swabbed: skin (n = 32), retinaculum (n = 31), tibialis anterior tendon (n = 31), joint capsule (n = 31), and distal tibia (n = 32). These swabs (N = 157) were sent to MicroGen Diagnostics (Lubbock) for NGS. Demographics, medical comorbidities, surgical indication, postoperative complications, readmission, and revision surgery rates were collected from patient records., Results: The mean age was 60.7 (range, 19 to 85) years, and the mean follow-up duration was 10.2 (range, 4.8 to 20.6) months. Of 157 swabs sent for NGS, 19 (12.1%) indicated that bacteria were present (positive), whereas the remaining 138 (87.9%) had no bacteria present (negative). The most common organisms were Cutibacterium acnes in eight ankles (25.0%) and Staphylococcus epidermidis in two ankles (6.25%). Most bacteria were found in the retinaculum (29.6%). Complications, nonunions, infections, 90-day readmission, and revision surgery rates did not differ by NGS profile., Discussion: This study found that C acnes and S epidermidis were the most common bacteria in the ankle microbiome, with C acnes being present in 25% of ankles. Complication rates did not differ between patients with or without positive bacterial DNA remnants. Thus, we concluded that a unique ankle microbiome is present in some patients, which is unique from that of the skin of the ankle., Level of Evidence: Level II, Prospective cohort study., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

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., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

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., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright © 2024 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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](PF 6 ) 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 NEt 3 reductant, highlighting an alternative strategy for the future development of 3d metal-catalyzed PRC., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Integrin-mediated activation of the profibrotic mediator transforming growth factor-β1 (TGF-β1), plays a critical role in idiopathic pulmonary fibrosis (IPF) pathogenesis. Galectin-3 is believed to contribute to the pathological wound healing seen in IPF, although its mechanism of action is not precisely defined. We hypothesized that galectin-3 potentiates TGF-β1 activation and/or signaling in the lung to promote fibrogenesis. We show that galectin-3 induces TGF-β1 activation in human lung fibroblasts (HLFs) and specifically that extracellular galectin-3 promotes oleoyl-L-α-lysophosphatidic acid sodium salt-induced integrin-mediated TGF-β1 activation. Surface plasmon resonance analysis confirmed that galectin-3 binds to αv integrins, αvβ1, αvβ5, and αvβ6, and to the TGFβRII subunit in a glycosylation-dependent manner. This binding is heterogeneous and not a 1:1 binding stoichiometry. Binding interactions were blocked by small molecule inhibitors of galectin-3, which target the carbohydrate recognition domain. Galectin-3 binding to β1 integrin was validated in vitro by coimmunoprecipitation in HLFs. Proximity ligation assays indicated that galectin-3 and β1 integrin colocalize closely (≤40 nm) on the cell surface and that colocalization is increased by TGF-β1 treatment and blocked by galectin-3 inhibitors. In the absence of TGF-β1 stimulation, colocalization was detectable only in HLFs from IPF patients, suggesting the proteins are inherently more closely associated in the disease state. Galectin-3 inhibitor treatment of precision cut lung slices from IPF patients' reduced Col1a1, TIMP1, and hyaluronan secretion to a similar degree as TGF-β type I receptor inhibitor. These data suggest that galectin-3 promotes TGF-β1 signaling and may induce fibrogenesis by interacting directly with components of the TGF-β1 signaling cascade., Competing Interests: Conflict of interests R. G. J. is a trustee for Action for Pulmonary Fibrosis. A. E. J. is a founder and shareholder of Alevin Therapeutics. J. F. C., F. R. Z., A. C. M., and R. J. S. are Galecto employees with shares/options in the company. N. R. P. is a Roche employee. L. A. B. is a director and shareholder of FibroFind. G. H., R. M. L., P. S., S. B. C., D. J. S., and I. D. S. declare that they have no conflict of interests with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

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 ., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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 (χ 2  = 24.01, p < 0.001) and TSM (χ 2  = 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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

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 (α 1 ) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α 1 receptor variants, or wild-type human α 1 -adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α 1A adrenoceptor cryo-EM and α 1B 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 α 1 -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 α 1 -adrenoceptor antagonism by clioquinol., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DJS receives research support from Arthrex and Paragon 28. CEG receives research support from Wright Medical Technology and is a paid consultant for Medshape, Novastep, and Paragon 28.

α 1A -, α 1B -, and α 1D -adrenoceptors (α 1 -ARs) are members of the adrenoceptor G protein-coupled receptor family that are activated by adrenaline (epinephrine) and noradrenaline. α 1 -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 α 1 -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 α 1 -ARs, however, and their involvement in disease has been hindered by the lack of sufficiently subtype-selective tool compounds, especially for α 1B -AR. Here, we report the discovery of 4-[(2-hydroxyethyl)amino]-6-methyl-2H-chromen-2-one (Cpd1), as an α 1B -AR antagonist that has 10-15-fold selectivity over α 1A -AR and α 1D -AR. Through computational and site-directed mutagenesis studies, we have identified the binding site of Cpd1 in α 1B -AR and propose the molecular basis of α 1B -AR selectivity, where the nonconserved V197 45.52 residue plays a major role, with contributions from L314 6.55 within the α 1B -AR pocket. By exploring the structure-activity relationships of Cpd1 at α 1B -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 α 1B -AR. Cpd1 and Cpd24 represent potential leads for α 1B -AR-selective drug discovery and novel tool molecules to further study the physiology of α 1 -ARs.

Intraoperative complications during total ankle replacement (TAR) can be devastating. As surgeons' experience with total ankles grow and surgical techniques are refined, intraoperative complications, such as fractures, can still occur. Surgeons must be able to recognize a problem, identify the options to remediate, and then execute a solution readily. Unfortunately, given the heterogeneity of TAR outcome studies, it is difficult to garner the true incidence of complications in the peri-operative period following ankle replacements. The purpose of this review is to focus on perioperative fractures during TAR. Fractures can occur intraoperatively and postoperatively as stress fractures or post-operative trauma., (Copyright © 2023 Elsevier Inc. All rights reserved.)