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OBJECTIVE: To assess the association be tweencytomegalovirus (CMV) serology of donor and recipient and adverse outcomes afterliver transplantation in the era of effective antiviral chemoprophylaxis. PATIENTS AND METHODS: We performed a retrospective cohort study of 193 consecutive patients undergoing their first liver transplantation between February 1998 and July 2000 with targeted and preemptive ganciclovir chemoprophylaxis. Patients were divided into 4 groups by CMV serology of donor and recipient: donor-/recipient-; donor-/recipient+; donor+/recipient+; and donor+/recipient-. Survival to the end points of retransplantation, death, or survival to 1 year after transplantation (whichever occurred first) was assessed. Rates of bacterial, fungal, and CMV Infection and of CMV disease were recorded and compared. RESULTS: No significant differences were observed in the rates of retransplantation, death, or survival to 1 year among the 4 groups of patients. Despite significantly higher rates of CMV infection in the donor+ groups, there were no differences in the rates of bacterial or fungal Infection or of CMV disease. Rejection occurred least frequently in the donor-/recipient- group. CONCLUSION: The adverse effects of CMV on outcomes after liver transplantation have been diminished in the era of effective antiviral chemoprophylaxis. [ABSTRACT FROM AUTHOR]

The ability of analytical strategies to detect and positively identify molecules under extremely dilute conditions is important for the growth and expansion of analytical techniques and instrumentation. At present, few measurement science techniques can robustly approach the measurement of just a few thousand molecules. Here, we present an electrochemical platform for the detection and positive identification of fewer than 1000 molecules of decamethylferrocene ((Cp*) 2 Fe II ). We achieve this remarkable detection threshold by trapping (Cp*) 2 Fe II in a 1,2-dichloroethane microdroplet, which is allowed to dissolve into an aqueous continuous phase while on a gold microelectrode (radius ∼6.25 μm). Because electrochemistry is not sensitive enough to observe the charge of less than 1000 molecules, we dissolved μM amounts hexacyanoferrate(III) in the aqueous continuous phase. The biphasic reaction between hexacyanoferrate(III) and Cp 2 *(Fe) II allows for a feedback loop when the microelectrode is biased sufficiently negative to reduce Cp 2 *(Fe) III . This feedback loop, a typical EC' catalytic mechanism, amplifies the electrochemical signal of Cp 2 *(Fe) II when the droplet is of small enough dimensions for feedback to occur. Our results demonstrate that clever biphasic reactions can be coupled with dissolving microdroplets to access extremely low limits of quantitation in electroanalysis.

Environmental and genetic risk factors, and their interactions, contribute significantly to the etiology of neurodevelopmental disorders (NDDs). Recent epidemiology studies have implicated pyrethroid pesticides as an environmental risk factor for autism and developmental delay. Our previous research showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice caused male-biased changes in the brain and in NDD-relevant behaviors in adulthood. Here, we used a metabolomics approach to determine the broadest possible set of metabolic changes in the adult male mouse brain caused by low-dose pyrethroid exposure during development. Using a litter-based design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood and collected whole brain samples for untargeted high-resolution metabolomics analysis. Developmentally exposed mice had disruptions in 116 metabolites which clustered into pathways for folate biosynthesis, retinol metabolism, and tryptophan metabolism. As a cross-validation, we integrated metabolomics and transcriptomics data from the same samples, which confirmed previous findings of altered dopamine signaling. These results suggest that pyrethroid exposure during development leads to disruptions in metabolism in the adult brain, which may inform both prevention and therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: James P. Burkett reports financial support was provided by National Institute of Environmental Health Sciences. Gary W. Miller reports financial support was provided by National Institute of Environmental Health Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Purpose: Vision-degrading myodesopsia (VDM) from vitreous floaters significantly degrades vision and impacts visual quality of life (VQOL), but the relationship to light scattering is poorly understood. This study compared in vitro measures of light scatter and transmission in surgically excised human vitreous to preoperative indexes of vitreous structure, visual function, and VQOL., Methods: Pure vitreous collected during vitrectomy from 8 patients with VDM had wide-angle straylight measurements and dark-field imaging, performed within 36 hours of vitrectomy. Preoperative VQOL assessment with VFQ-25, contrast sensitivity (CS) measurements with Freiburg acuity contrast testing, and quantitative ultrasonography were compared to light scattering and transmission in vitro., Results: All indices of vitreous echodensity in vivo correlated positively with straylight at 0.5° (R = 0.708 to 0.775, P = 0.049 and 0.024, respectively). Straylight mean scatter index correlated with echodensity (R = 0.71, P = 0.04) and VQOL (R = -0.82, P = 0.0075). Dark-field measures in vitro correlated with degraded CS in vivo (R = -0.69, P = 0.04). VQOL correlated with straylight mean scatter index (R = -0.823, P = 0.012)., Conclusions: Increased vitreous echodensity in vivo is associated with more straylight scattering in vitro, validating ultrasonography as a clinical surrogate for light scattering. Contrast sensitivity in vivo is more degraded in the presence of dark-field scattering in vitro and VQOL is decreased in patients whose vitreous has increased light scattering. These findings could form the basis for the development of optical corrections for VDM or support new laser treatments, as well as novel pharmacotherapy.

Droplet evaporation has previously been used as a concentration enrichment strategy; however, the measurement technique of choice requires quantification in rather large volumes. Electrochemistry has recently emerged as a method to robustly probe volumes even down to the attoliter (10 -18 L) level. We present a concentration enrichment strategy based on the dissolution of a microdroplet placed on the surface of a Au ultramicroelectrode (radius ∼ 6.25 μm). By precisely positioning a 1,2-dichloroethane microdroplet onto the ultramicroelectrode with a microinjector, we are able to track the droplet's behavior optically and electrochemically. Because the droplet spontaneously dissolves over time, given the relative solubility of 1,2-dichloroethane in the water continuous phase, the change in volume with time enriches the concentration of the redox probe (Cp 2 *(Fe) II ) in the droplet. We demonstrate robust electrochemical detection down to sub-nM (800 pM) concentrations of Cp 2 *(Fe) II . For this droplet, 800 pM constitutes only about 10 6 molecules. We extend the strategy in a single-blind study to determine unknown concentrations, emphasizing the promise of the new methodology. These results take voltammetric quantification easily to the sub-μM regime.

The transition zone is a specialised gate at the base of cilia/flagella, which separates the ciliary compartment from the cytoplasm and strictly regulates protein entry. We identified a potential new regulator of the male germ cell transition zone, CEP76. We demonstrated that CEP76 was involved in the selective entry and incorporation of key proteins required for sperm function and fertility into the ciliary compartment and ultimately the sperm tail. In the mutant, sperm tails were shorter and immotile as a consequence of deficits in essential sperm motility proteins including DNAH2 and AKAP4, which accumulated at the sperm neck in the mutant. Severe annulus, fibrous sheath, and outer dense fibre abnormalities were also detected in sperm lacking CEP76. Finally, we identified that CEP76 dictates annulus positioning and structure. This study suggests CEP76 as a male germ cell transition zone protein and adds further evidence to the hypothesis that the spermatid transition zone and annulus are part of the same functional structure., (© 2024 Houston et al.)

Introduction: The anterior stove-in chest (ASIC) is a rare form of flail chest involving bilateral rib or sternal fractures resulting in an unstable chest wall that caves into the thoracic cavity. Given ASIC has only been described in a handful of case reports, this study sought to review our institution's experience in the surgical management of ASIC injuries., Methods: A retrospective review of patients with ASIC was conducted at our level I trauma center from 1//2021 to 3//2023. Information pertaining to patient demographics, fracture pattern, operative management, and outcomes was obtained and compared across patients in the case series., Results: 6 patients met inclusion criteria, all males aged 37-78 years. 5 suffered motor vehicle collisions, and 1 was a pedestrian struck by an automobile. The median injury severity score was 28. All received ORIF within 5 days of admission, most commonly for ongoing respiratory distress. Patients 2 and 4 underwent bilateral ORIF of the ribs and sternum while patients 1, 5, and 6 underwent left-sided repair. Patient 3 required ORIF of left ribs and the sternum to stabilize their injuries. 5 of 6 patients were liberated from the ventilator and survived to discharge., Conclusions: This study demonstrates successful operative management of 6 patients with ASIC and suggests that early operative intervention with ORIF for affected segments may improve respiratory mechanics, ability to wean from the ventilator, and overall survival. Further research is needed to generate standardized guidelines for the management of this uncommon and complex thoracic injury., 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: J Nguyen receives honoraria from Teleflex, Zimmer Biomet, and Pry-time Medical for educational lectures. Z Bauman receives honoraria from Biomet, AtriCure, and KLS for educational lectures.

Background: Cemiplimab (Libtayo ® ), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that C trough of extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W., Methods: In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review., Results: Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n = 14) achieving complete response and 40% (n = 25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue., Conclusions: Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit-risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen., Competing Interests: Competing interests: DR reports institutional research grants and funding from Bristol-Myers Squibb, GlaxoSmithKline, Kura Oncology, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc, ALX Oncology, Decibel Therapeutics and Roche; and uncompensated scientific committee and advisory board membership from GlaxoSmithKline, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc and Sanofi. BGMH reports consulting or advisory roles at AstraZeneca, Bristol-Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer and Roche; and institutional research funding from Amgen. NB-S declares no conflict of interest. DS reports institutional patients’ fees from Regeneron Pharmaceuticals, Inc; advisory board, speaker honoraria and patients’ fees from Bristol-Myers Squibb, EMD Serono, Merck Sharp & Dohme, Novarti and Pierre Fabre; steering committee honoraria from 4SC, Bristol-Myers Squibb, InflaRx, Merck Sharp & Dohme, Nektar and Novartis; advisory board fees from Daiichi Sanyo, OncoSec Medical, Pfizer and Replimune; advisory board and patients’ fees from Philogen and Sun Pharma; and research funding to their institution from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme and Novartis. SB reports an advisory board role or speaker bureau for Sanofi, Ipsen, Lilly, Bristol-Myers Squibb and Merck Sharp & Dohme Australia; and virtual meeting sponsorship from Bristol-Myers Squibb and Merck Sharp & Dohme Australia. ST reports speaker honoraria and advisory board fees from AbbVie, Bristol-Myers Squibb, Novartis, Pierre Fabre and Sun Pharma. FM reports travel support, speaker’s fees or advisor’s honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche and Sanofi; and research funding from Novartis and Roche. TE reports consulting or advisory roles at Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche and Sanofi Genzyme; speaker’s bureau roles at Merck Sharp & Dohme and Roche; and research funding from Bristol-Myers Squibb and Novartis. VCE reports advisory board honoraria from AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme and Pharmamar; and speaker honoraria from AstraZeneca and Merck Sharp & Dohme. BS reports advisory board membership for Bristol-Myers Squibb Australia and Merck Sharp & Dohme. MBB reports serving as a speaker without honoraria for Sanofi. SD reports advisory board honoraria and travel expenses from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, PFO Global and Sun Pharma. BD reports consultancy for Sanofi. MRM reports honoraria and travel expenses from Genentech, Eli Lilly, Novartis, Regeneron Pharmaceuticals, Inc, Sanofi and Sun Pharma; and institutional research funding from Genentech, Eli Lilly, Novartis and Regeneron Pharmaceuticals, Inc. AH reports institutional grants, speaker’s honoraria and consultancy fees from Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Provectus and Roche; institutional grants and consultancy fees from EMD Serono, Philogen and Regeneron Pharmaceuticals, Inc; and consultancy fees from OncoSec Medical. CDS reports steering committee membership for Castle Biosciences; steering committee membership and consultancy for Regeneron Pharmaceuticals, Inc; consultancy for Sanofi; research funding from Castle Biosciences, Genentech, Merck, Novartis and Regeneron Pharmaceuticals, Inc; and serving as a chair for the National Comprehensive Cancer Network. AML reports uncompensated advisory board participation from Merck Sharp & Dohme and Bristol-Myers Squibb with travel and accommodation expenses; and uncompensated consultancy for Eisai. S-YY, APaccaly, APapachristos, J-HN, EO, FS, JB and IL are employees of and shareholders in Regeneron Pharmaceuticals, Inc. MGF is an employee of, has patents pending with, and is a shareholder of Regeneron Pharmaceuticals, Inc. AG reports personal fees and nonfinancial support (advisory board and travel support) from Bristol-Myers Squibb and Sun Pharma; personal fees (advisory board) from Eisai, Merck KGaA and Pfizer; non-financial support (travel) from Astellas; and clinical trial unit support from PPD Australia., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Here, we report the clinical pharmacology data from LUMINA-1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in patients with fibrodysplasia ossificans progressiva. Forty-four patients were randomly assigned to intravenous 10 mg/kg of garetosmab or placebo every 4 weeks in a double-blind 28-week treatment period, followed by a 28-week open-label treatment period with garetosmab, and subsequent open-label extension. Serum samples were obtained to assess pharmacokinetics (PK), immunogenicity, and bone morphogenetic protein 9 (BMP9). Comparative exposure-response analyses for efficacy and safety were performed with trough concentrations (C trough ) of garetosmab prior to dosing. Steady-state PK was reached 12-16 weeks after the first dose of garetosmab, with mean (standard deviation) C trough of 105 ± 30.8 mg/L. Immunogenicity assessments showed anti-garetosmab antibody formation in 1 patient (1/43; 2.3%); titers were low, and did not affect PK or clinical efficacy. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. There were no meaningful differences in PK or BMP9 concentration-time profiles between patients who did and did not experience epistaxis or death. The comparative exposure-response analyses demonstrated no association between C trough and efficacy or safety. PK findings were consistent with prior data in healthy volunteers and were typical for a monoclonal antibody administered at doses sufficient to saturate target-mediated clearance. There were no trends that suggested patients with higher serum exposures to garetosmab were more likely to experience a reduction in heterotopic ossification or adverse events. Garetosmab is being further evaluated in the Phase 3 OPTIMA trial., (© 2023 Regeneron Pharmaceuticals, Inc and The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The classical Richtmyer-Meshkov instability (RMI) is a hydrodynamic instability characterizing the evolution of an interface following shock loading. In contrast to other hydrodynamic instabilities such as Rayleigh-Taylor, it is known for being unconditionally unstable: regardless of the direction of shock passage, any deviations from a flat interface will be amplified. In this article, we show that for negative Atwood numbers, there exist special sequences of shocks which result in a nearly perfectly suppressed instability growth. We demonstrate this principle computationally and experimentally with stepped fliers and phase transition materials. A fascinating immediate corollary is that in specific instances, a phase-transitioning material may self-suppress RMI.

In situ abdominal normothermic regional perfusion (A-NRP) has been used for liver transplantation (LT) with donation after circulatory death (DCD) liver grafts in Europe with excellent results; however, adoption of A-NRP in the United States has been lacking. The current report describes the implementation and results of a portable, self-reliant A-NRP program in the United States. Isolated abdominal in situ perfusion with an extracorporeal circuit was achieved through cannulation in the abdomen or femoral vessels and inflation of a supraceliac aortic balloon and cross-clamp. The Quantum Transport System by Spectrum was used. The decision to use livers for LT was made through an assessment of perfusate lactate (q15min). From May to November 2022, 14 A-NRP donation after circulatory death procurements were performed by our abdominal transplant team (N = 11 LT, N = 20 kidney transplants, and 1 kidney-pancreas transplant). The median A-NRP run time was 68 minutes. None of the LT recipients had post-reperfusion syndrome, nor were there any cases of primary nonfunction. All livers were functioning well at the time of maximal follow-up with zero cases of ischemic cholangiopathy. The current report describes the feasibility of a portable A-NRP program that can be used in the United States. Excellent short-term post-transplant results were achieved with both livers and kidneys procured from A-NRP., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Draining lymph nodes (DLNs) are implicated in alloimmunity and tolerance regulation. The role of DLNs in human organ transplant is unknown due to the lack of relevant clinical tissues., Methods: During a combined kidney and pancreas transplant, the distal vena cava and both right and left common and external iliac vessels were mobilized and exposed. Draining lymph nodes along these vessels were removed sequentially and archived before the pancreas transplant. Similarly, the DLNs along the left iliac vessels were removed and archived before implantation of the kidney allograft., Results: Among 13 patients undergoing kidney and pancreas transplants, 6 had pre- and postreperfusion DLNs clinically archived. The remaining 7 either had only prereperfusion DLNs archived or none. Clinical archiving of DLNs did not alter operative times or parameters., Conclusion: This study describes an approach for clinical archiving of DLNs obtained within the operative field during combined kidney-pancreas transplant in humans. The availability of relevant DLNs is essential for investigating fundamental initial primary immune responses potentially important in allograft alloimmunity and tolerance., Competing Interests: Declaration of Competing Interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Quantitative ultrasound (QUS) provides objective indices of Vision Degrading Myodesopsia (VDM) that correlate with contrast sensitivity (CS). To date, QUS methods were only tested on a single ultrasound machine. Here, we evaluate whether QUS measurements are machine independent., Methods: In this cross-sectional study, 47 eyes (24 subjects; age = 53.2 ± 14.4 years) were evaluated with Freiburg acuity contrast testing (%Weber), and ultrasonography using 2 machines: one with a 15-MHz single-element transducer and one with a 5-ring, 20-MHz annular-array. Images were acquired from each system in sequential scans. Artifact-free, log-compressed envelope data were processed to yield three parameters (mean amplitude, M; energy, E; and percentage filled by echodensities, P50) and a composite score (C). A B-mode normalization method was applied to the 20-MHz datasets to match QUS parameters at both frequencies. Statistical analyses were performed to evaluate correlations among CS, E, M, P50, and C for both machines., Results: QUS parameters from each machine correlated with CS (R ≥ 0.57, P < 0.001) and there was correlation between machines (R ≥ 0.84, P < 0.001). Correlations between CS and QUS parameters were statistically similar for both machines (P ≥ 0.14) except when the 20-MHz data were normalized (P = 0.04). Reproducibility of QUS parameters computed from 20-MHz data were satisfactory (52.3%-96.3%) with intraclass correlation values exceeding 0.80 (P < 0.001)., Conclusions: The high correlation between QUS parameters from both machines combined with a statistically similar correlation to CS suggests QUS is an effective, machine-independent, quantitative measure of vitreous echodensities., Translational Relevance: QUS may be applied across clinical ophthalmic ultrasound scanners and imaging frequencies to effectively evaluate VDM.

Purpose: Limited vitrectomy improves vision degrading myodesopsia, but the incidence of recurrent floaters postoperatively is not known. We studied patients with recurrent central floaters using ultrasonography and contrast sensitivity (CS) testing to characterize this subgroup and identify the clinical profile of patients at risk of recurrent floaters., Methods: A total of 286 eyes (203 patients, 60.6 ± 12.9 years) undergoing limited vitrectomy for vision degrading myodesopsia were studied retrospectively. Sutureless 25G vitrectomy was performed without intentional surgical posterior vitreous detachment (PVD) induction. CS (Freiburg Acuity Contrast test: Weber index, %W) and vitreous echodensity (quantitative ultrasonography) were assessed prospectively., Results: No eyes (0/179) with preoperative PVD experienced new floaters. Recurrent central floaters occurred in 14/99 eyes (14.1%) without complete preoperative PVD (mean follow-up = 39 months vs. 31 months in 85 eyes without recurrent floaters). Ultrasonography identified new-onset PVD in all 14 (100%) recurrent cases. Young (younger than 52 years; 71.4%), myopic (≥-3D; 85.7%), phakic (100%) men (92.9%) predominated. Reoperation was elected by 11 patients, who had partial PVD preoperatively in 5/11 (45.5%). At study entry, CS was degraded (3.55 ± 1.79 %W) but improved postoperatively by 45.6% (1.93 ± 0.86 %W, P = 0.033), while vitreous echodensity reduced by 86.6% ( P = 0.016). New-onset PVD postoperatively degraded CS anew, by 49.4% (3.28 ± 0.96 %W; P = 0.009) in patients electing reoperation. Repeat vitrectomy normalized CS to 2.00 ± 0.74%W ( P = 0.018)., Conclusion: Recurrent floaters after limited vitrectomy for vision degrading myodesopsia are caused by new-onset PVD, with younger age, male sex, myopia, and phakic status as risk factors. Inducing surgical PVD at the primary operation should be considered in these select patients to mitigate recurrent floaters., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Immune-mediated adverse effects of current systemic immunosuppression therapy compromise long-term survival of liver transplant recipients. Our recently observed results showed that intranodal delivery of sirolimus induced interleukin (IL)-10-driven CD4+ CD25+ Foxp3+ regulatory T cells. The present report investigated the feasibility of intra-nodal delivery of sirolimus ex vivo into a human liver common bile duct lymph node., Methods: We used a discarded donor human liver to directly administer sirolimus into a distal common bile duct lymph node. Sirolimus was injected once using an ultrasound-guided method., Results: The porta hepatis and its lymph node along the distal common bile duct were exposed. A handheld ultrasound probe (L15-7io, Koninklijke Philips N.V.) with a layer of standoff Aquasonic 100 Ultrasound Transmission Gel (Parker Laboratories, Inc) was applied to the exposed lymph node. Using a 1.0-mL 25G hypodermic needle, 0.05 mL of sirolimus solution was injected directly into the exposed lymph node., Conclusions: Under sonographic guidance, direct injection of sirolimus into a hepatic draining lymph node along the common bile duct is accomplished precisely and reliably. Direct administration of therapeutic agents into local lymph nodes is a viable approach for effective targeted immunotherapy., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare. Mayo Clinic does not endorse specific products or services included in this article., (Copyright © 2023. Published by Elsevier B.V.)

Our group previously defined a dissection gesture classification system that deconstructs robotic tissue dissection into its most elemental yet meaningful movements. The purpose of this study was to expand upon this framework by adding an assessment of gesture efficacy (ineffective, effective, or erroneous) and analyze dissection patterns between groups of surgeons of varying experience. We defined three possible gesture efficacies as ineffective (no meaningful effect on the tissue), effective (intended effect on the tissue), and erroneous (unintended disruption of the tissue). Novices (0 prior robotic cases), intermediates (1-99 cases), and experts (≥ 100 cases) completed a robotic dissection task in a dry-lab training environment. Video recordings were reviewed to classify each gesture and determine its efficacy, then dissection patterns between groups were analyzed. 23 participants completed the task, with 9 novices, 8 intermediates with median caseload 60 (IQR 41-80), and 6 experts with median caseload 525 (IQR 413-900). For gesture selection, we found increasing experience associated with increasing proportion of overall dissection gestures (p = 0.009) and decreasing proportion of retraction gestures (p = 0.009). For gesture efficacy, novices performed the greatest proportion of ineffective gestures (9.8%, p < 0.001), intermediates commit the greatest proportion of erroneous gestures (26.8%, p < 0.001), and the three groups performed similar proportions of overall effective gestures, though experts performed the greatest proportion of effective retraction gestures (85.6%, p < 0.001). Between groups of experience, we found significant differences in gesture selection and gesture efficacy. These relationships may provide insight into further improving surgical training., (© 2022. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objectives: Manually-collected suturing technical skill scores are strong predictors of continence recovery after robotic radical prostatectomy. Herein, we automate suturing technical skill scoring through computer vision (CV) methods as a scalable method to provide feedback., Methods: Twenty-two surgeons completed a suturing exercise three times on the Mimic™ Flex VR simulator. Instrument kinematic data (XYZ coordinates of each instrument and pose) were captured at 30 Hz. After standardized training, three human raters manually video segmented suturing task into four sub-stitch phases (Needle handling, Needle targeting, Needle driving, Needle withdrawal) and labeled the corresponding technical skill domains (Needle positioning, Needle entry, Needle driving, and Needle withdrawal). The CV framework extracted RGB features and optical flow frames using a pre-trained AlexNet. Additional CV strategies including auxiliary supervision (using kinematic data during training only) and attention mechanisms were implemented to improve performance., Results: This study included data from 15 expert surgeons (median caseload 300 [IQR 165-750]) and 7 training surgeons (0 [IQR 0-8]). In all, 226 virtual sutures were captured. Automated assessments for Needle positioning performed best with the simplest approach (1 s video; AUC 0.749). Remaining skill domains exhibited improvements with the implementation of auxiliary supervision and attention mechanisms when deployed separately (AUC 0.604-0.794). All techniques combined produced the best performance, particularly for Needle driving and Needle withdrawal (AUC 0.959 and 0.879, respectively)., Conclusions: This study demonstrated the best performance of automated suturing technical skills assessment to date using advanced CV techniques. Future work will determine if a "human in the loop" is necessary to verify surgeon evaluations., (© 2022. CARS.)

How well a surgery is performed impacts a patient's outcomes; however, objective quantification of performance remains an unsolved challenge. Deconstructing a procedure into discrete instrument-tissue "gestures" is a emerging way to understand surgery. To establish this paradigm in a procedure where performance is the most important factor for patient outcomes, we identify 34,323 individual gestures performed in 80 nerve-sparing robot-assisted radical prostatectomies from two international medical centers. Gestures are classified into nine distinct dissection gestures (e.g., hot cut) and four supporting gestures (e.g., retraction). Our primary outcome is to identify factors impacting a patient's 1-year erectile function (EF) recovery after radical prostatectomy. We find that less use of hot cut and more use of peel/push are statistically associated with better chance of 1-year EF recovery. Our results also show interactions between surgeon experience and gesture types-similar gesture selection resulted in different EF recovery rates dependent on surgeon experience. To further validate this framework, two teams independently constructe distinct machine learning models using gesture sequences vs. traditional clinical features to predict 1-year EF. In both models, gesture sequences are able to better predict 1-year EF (Team 1: AUC 0.77, 95% CI 0.73-0.81; Team 2: AUC 0.68, 95% CI 0.66-0.70) than traditional clinical features (Team 1: AUC 0.69, 95% CI 0.65-0.73; Team 2: AUC 0.65, 95% CI 0.62-0.68). Our results suggest that gestures provide a granular method to objectively indicate surgical performance and outcomes. Application of this methodology to other surgeries may lead to discoveries on methods to improve surgery., (© 2022. The Author(s).)

Purpose: Multifocal intraocular lenses (MFIOL) are associated with degradation in contrast sensitivity function (CSF); yet the contribution of vitreous is not known, nor is the benefit of vitrectomy., Design: Prospective, nonrandomized clinical study., Methods: A total of 180 eyes of 180 patients (55 MFIOL, 60 monofocal intraocular lenses [MIOL], 65 phakic) with symptomatic vitreous opacities were enrolled. Vitreous structure was assessed with quantitative ultrasonography (QUS). Vision was evaluated with visual acuity and CSF measurements., Results: Vitreous echodensity was the same in all lens cohorts, yet CSF was worse in MFIOL eyes (P < .001). In 86 patients who elected vitrectomy, there was 68% greater vitreous echodensity and 31% worse CSF than in observation controls (P < .0001 for each). Preoperatively, CSF was 25% worse in MFIOL than in MIOL (P = .014). Postoperatively, vitreous echodensity decreased by 55%, 51%, and 52%, whereas CSF improved by 37% 48% in and 43% in MFIOL, MIOL, and phakic eyes, respectively (P < .0001 for each). NEI Visual Function Questionnaire analyses showed improved visual well-being., Conclusions: Patients with vision degrading myodesopsia who elected vitrectomy had greater vitreous echodensity and worse CSF than controls, but no other differences in age, sex, or myopia. MFIOL eyes had worse CSF than MIOL and phakic eyes, very possibly due to combined effects of the MFIOL and vitreous opacification. Limited vitrectomy reduced vitreous echodensity and improved CSF in all eyes. All patients with CSF-degrading vitreous opacities benefited from limited vitrectomy, including those with MFIOL. As MFIOL eyes had 37% improvement in CSF, patients with MFIOL and vision degrading myodesopsia merit consideration of vitrectomy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To create a suturing skills assessment tool that comprehensively defines criteria around relevant sub-skills of suturing and to confirm its validity., Materials and Methods: 5 expert surgeons and an educational psychologist participated in a cognitive task analysis (CTA) to deconstruct robotic suturing into an exhaustive list of technical skill domains and sub-skill descriptions. Using the Delphi methodology, each CTA element was systematically reviewed by a multi-institutional panel of 16 surgical educators and implemented in the final product when content validity index (CVI) reached ≥0.80. In the subsequent validation phase, 3 blinded reviewers independently scored 8 training videos and 39 vesicourethral anastomoses (VUA) using EASE; 10 VUA were also scored using Robotic Anastomosis Competency Evaluation (RACE), a previously validated, but simplified suturing assessment tool. Inter-rater reliability was measured with intra-class correlation (ICC) for normally distributed values and prevalence-adjusted bias-adjusted Kappa (PABAK) for skewed distributions. Expert (≥100 prior robotic cases) and trainee (<100 cases) EASE scores from the non-training cases were compared using a generalized linear mixed model., Results: After two rounds of Delphi process, panelists agreed on 7 domains, 18 sub-skills, and 57 detailed sub-skill descriptions with CVI ≥ 0.80. Inter-rater reliability was moderately high (ICC median: 0.69, range: 0.51-0.97; PABAK: 0.77, 0.62-0.97). Multiple EASE sub-skill scores were able to distinguish surgeon experience. The Spearman's rho correlation between overall EASE and RACE scores was 0.635 (p=0.003)., Conclusions: Through a rigorous CTA and Delphi process, we have developed EASE, whose suturing sub-skills can distinguish surgeon experience while maintaining rater reliability.

A population pharmacokinetic (PopPK) model was previously developed for cemiplimab in patients with solid tumors, including advanced cutaneous squamous cell carcinoma (CSCC). Here, we update the existing PopPK model and characterize exposure-response relationships using efficacy and safety data obtained in patients with recurrent or metastatic cervical cancer (R/M CC). To improve model stability and robustness of the existing PopPK model in 1062 patients, the random-effect error model was revised, and structural covariates were removed from the base model to be tested in the covariate analysis. The updated model was used for external validation of cemiplimab pharmacokinetics (PK) in patients with R/M CC on cemiplimab monotherapy (350 mg every 3 weeks intravenously) from a phase III study (NCT03257267). Exposure-response relationships for cemiplimab efficacy (overall survival [OS], progression-free survival [PFS], duration of response [DOR], objective response rate [ORR]), and safety (immune-related adverse events [irAEs]) were analyzed in 295 patients with R/M CC from the aforementioned study. The updated PopPK model showed improved stability with 94.8% successful bootstrap runs vs. 47.6% in the prior model. Cemiplimab exposure was similar across tumor types, including basal cell carcinoma, CSCC, and non-small cell lung cancer. External validation showed the updated model adequately described cemiplimab PK in patients with R/M CC. In exposure-response efficacy analyses, Cox proportional hazard modeling (CPHM) showed no trend between exposure and OS, Kaplan-Meier plots showed no trend between exposure and PFS or DOR, and logistic regression analyses conducted on ORR showed no exposure-response relationship. In exposure-response safety analyses, CPHM showed no trend between exposure and irAEs., (© 2022 Regeneron Pharmaceuticals, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: There is no standard for the feedback that an attending surgeon provides to a training surgeon, which may lead to variable outcomes in teaching cases., Objective: To create and administer standardized feedback to medical students in an attempt to improve performance and learning., Design Setting and Participants: A cohort of 45 medical students was recruited from a single medical school. Participants were randomly assigned to two groups. Both completed two rounds of a robotic surgical dissection task on a da Vinci Xi surgical system. The first round was the baseline assessment. In the second round, one group received feedback and the other served as the control (no feedback)., Outcome Measurements and Statistical Analysis: Video from each round was retrospectively reviewed by four blinded raters and given a total error tally (primary outcome) and a technical skills score (Global Evaluative Assessment of Robotic Surgery [GEARS]). Generalized linear models were used for statistical modeling. According to their initial performance, each participant was categorized as either an innate performer or an underperformer, depending on whether their error tally was above or below the median., Results and Limitations: In round 2, the intervention group had a larger decrease in error rate than the control group, with a risk ratio (RR) of 1.51 (95% confidence interval [CI] 1.07-2.14; p  = 0.02). The intervention group also had a greater increase in GEARS score in comparison to the control group, with a mean group difference of 2.15 (95% CI 0.81-3.49; p  < 0.01). The interaction effect between innate performers versus underperformers and the intervention was statistically significant for the error rates, at F(1,38) = 5.16 ( p  = 0.03). Specifically, the intervention had a statistically significant effect on the error rate for underperformers (RR 2.23, 95% CI 1.37-3.62; p  < 0.01) but not for innate performers (RR 1.03, 95% CI 0.63-1.68; p  = 0.91)., Conclusions: Real-time feedback improved performance globally compared to the control. The benefit of real-time feedback was stronger for underperformers than for trainees with innate skill., Patient Summary: We found that real-time feedback during a training task using a surgical robot improved the performance of trainees when the task was repeated. This feedback approach could help in training doctors in robotic surgery., (© 2022 The Author(s).)

Introduction: Robotic surgical performance, in particular suturing, has been linked to postoperative clinical outcomes. Before attempting live surgery, virtual reality (VR) simulators afford opportunities for training surgeons to learn fundamental technical skills. Herein, we evaluate the association of suturing technical skill assessments between VR simulation and live surgery, and functional clinical outcomes. Materials and Methods: Twenty surgeons completed a VR suturing exercise on the Mimic™ Flex VR simulator and the anterior vesicourethral anastomosis during robot-assisted radical prostatectomy (RARP). Three independent and blinded graders provided technical skill scores using a validated assessment tool. Correlations between VR and live scores were assessed by Spearman's correlation coefficients (ρ). In addition, 117 historic RARP cases from participating surgeons were extracted, and the association between VR technical skill scores and urinary continence recovery was assessed by a multilevel mixed-effects model. Results: A total of 20 (6 training and 14 expert) surgeons participated. Statistically significant correlations for scores provided between VR simulation and live surgery were found for overall and needle driving scores (ρ = 0.555, p  = 0.011; ρ = 0.570, p  = 0.009, respectively). A subanalysis performed on training surgeons found significant correlations for overall scores between VR simulation and live surgery (ρ = 0.828, p  = 0.042). Expert cases with high VR needle driving scores had significantly greater continence recovery rates at 24 months after RARP (98.5% vs 84.9%, p  = 0.028). Conclusions: Our study found significant correlations in technical scores between VR and live surgery, especially among training surgeons. In addition, we found that VR needle driving scores were associated with continence recovery after RARP. Our data support the association of skill assessments between VR simulation and live surgery and potential implications for clinical outcomes.

The NIS synthetase family of enzymes responsible for the biosynthesis of siderophores is increasingly associated with bacterial virulence. Proteins in this class represent outstanding potential drug targets, assuming that basic biochemical and structural characterizations can be completed. Towards this goal, we have mated an improved synthesis of the non-commercial amino acid N -hydroxy- N -succinylcadaverine (HSC, 6 ) with an isothermal titration calorimetry (ITC) assay that profiles the iterative stages of HSC trimerization and macrocyclization by NIS synthetase DesD from Streptomyces coelicolor . HSC synthesis begins with multigram-scale Gabrielle and tert -butyl N -(benzyloxy)carbamate alkylations of 1-bromo-5-chloropentane following prior literature, but the end-game reported herein has two advantages for greater material throughput: (1) hydrogenolysis of benzyl ether and Cbz blocking groups is best accomplished with Pearlman's catalyst at 40 psi of H 2 and (2) purification of neutral (zwitterionic) HSC is effected by simple flash chromatography over silica gel in MeOH. HSC is subsequently shown to be a substrate for NIS synthetase DesD, which catalyzes three successive amide bond syntheses via adenyl monophosphate ester intermediates. We quantify and present the iterative and overall enzyme kinetic constants associated with formation of the cyclotrimeric siderophore desferrioxamine E (dfoE, 1 ).

Purpose: Automated performance metrics (APMs), derived from instrument kinematic and systems events data during robotic surgery, are validated objective measures of surgeon performance. Our previous studies showed that APMs are strong outcome predictors of urinary continence after robot-assisted radical prostatectomy (RARP). We now use machine learning to investigate how surgeon performance (i.e., APMs) and clinical factors can predict positive surgical margins (PSMs) after RARP. Methods: We prospectively collected data of patients undergoing RARP at our institution from 2016 to 2019. Random Forest model predicted PSMs based on 15 clinical factors and 38 APMs from 11 standardized RARP steps. Out-of-bag Gini impurity index determined the top 10 variables of importance (VOI). APMs in the top 10 VOI were assessed for confounding effects by extracapsular extension (ECE) and pathologic T (pT) through Poisson regression with Generalized Estimating Equation. Results: 55/236 (23.3%) cases had PSMs. Of the 55 cases with PSMs, 9 (16.4%) were pT2 and 46 (83.6%), pT3. The full model, including clinical factors and APMs, achieved area under the curve (AUC) 0.74. When assessing clinical factors or APMs alone, the model achieved AUC 0.72 and 0.64, respectively. The strongest PSM predictors were ECE and pT stage, followed by APMs in specific steps. After adjusting for ECE and pT stage, most APMs remained as independent predictors of PSM. Conclusion: Using machine learning methods, we found that the strongest predictors of PSMs after RARP are nonmodifiable, disease-driven factors (ECE and pT). While APMs provide minimal additional insight into when PSMs may occur, they are nonetheless capable of independently predicting PSMs based on objective measures of surgeon performance.

Objective: Morbidity and mortality rates associated with liver transplant are high for patients with concomitant heart disease. Traditionally, such cases were considered contraindications for transplant. The objective of our study was to assess the outcome of combined surgical approaches., Methods: A prospectively maintained database was analyzed of patients undergoing cardiac surgery and liver transplant at our institution. Twelve identified patients underwent combined cardiac operation and liver transplant. A control group was created (n = 24) with the same selection criteria., Results: Median patient age was 64.94 years in the combined group vs 63.80 in the control, and in both groups, 58% were male. Left ventricular ejection fraction (0.60), body mass index (30.1), and median (range) score of the Model for End-stage Liver Disease (18 [9-33]) were the same in both groups. The cardiac operations combined with liver transplant were coronary artery bypass grafting, valve replacement procedures, and ascending thoracic aortic aneurysm repair. Piggyback liver transplant was performed for all patients. Survival periods of 1, 5, and 10 years for control vs combined cases were 90 vs 62%, 79 vs 55%, and 70 vs 45%, respectively (P = 0.03)., Conclusion: Concomitant cardiac procedure and liver transplant is a valid treatment option and should be considered with risk stratification criteria of the patient with end-stage liver disease and cardiac surgical pathologic characteristics., (© 2022. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Purpose: Previously, we identified 8 objective suturing performance metrics highly predictive of urinary continence recovery after robotic-assisted radical prostatectomy. Here, we aimed to test the feasibility of providing tailored feedback based upon these clinically relevant metrics and explore the impact on the acquisition of robotic suturing skills., Materials and Methods: Training surgeons were recruited and randomized to a feedback group or a control group. Both groups completed a baseline, midterm and final dry laboratory vesicourethral anastomosis (VUA) and underwent 4 intervening training sessions each, consisting of 3 suturing exercises. Eight performance metrics were recorded during each exercise: 4 automated performance metrics (derived from kinematic and system events data of the da Vinci® Robotic System) representing efficiency and console manipulation competency, and 4 suturing technical skill scores. The feedback group received tailored feedback (a visual diagram+verbal instructions+video examples) based on these metrics after each session. Generalized linear mixed model was used to compare metric improvement (Δ) from baseline to the midterm and final VUA., Results: Twenty-three participants were randomized to the feedback group (11) or the control group (12). Demographic data and baseline VUA metrics were comparable between groups. The feedback group showed greater improvement than the control group in aggregate suturing scores at midterm (mean Δ feedback group 4.5 vs Δ control group 1.1) and final VUA (Δ feedback group 5.3 vs Δ control group 4.9). The feedback group also showed greater improvement in the majority of the included metrics at midterm and final VUA., Conclusions: Tailored feedback based on specific, clinically relevant performance metrics is feasible and may expedite the acquisition of robotic suturing skills.

Purpose: We attempt to understand the relationship between surgeon technical skills, cognitive workload, and errors during a simulated robotic dissection task. Materials and Methods: Participant surgeons performed a robotic surgery dissection exercise. Participants were grouped based on surgical experience. Technical skills were evaluated utilizing the validated Global Evaluative Assessment of Robotic Skills (GEARS) assessment tool. The dissection task was evaluated for errors during active dissection or passive retraction maneuvers. We quantified cognitive workload of surgeon participants as an index of cognitive activity (ICA), derived from task-evoked pupillary response metrics; ICA ranged 0 to 1, with 1 representing maximum ICA. Generalized estimating equation (GEE) was used for all modelings to establish relationships between surgeon technical skills, cognitive workload, and errors. Results: We found a strong association between technical skills as measured by multiple GEARS domains (depth perception, force sensitivity, and robotic control) and passive errors, with higher GEARS scores associated with a lower relative risk of errors (all p  < 0.01). For novice surgeons, as average GEARS scores increased, the average estimated ICA decreased. In contrast, as average GEARS increased for expert surgeons, the average estimated ICA increased. When exhibiting optimal technical skill (maximal GEARS scores), novices and experts reached a similar range of ICA scores (ICA: 0.47 and 0.42, respectively). Conclusions: This study found that there is an optimal cognitive workload level for surgeons of all experience levels during our robotic surgical exercise. Select technical skill domains were strong predictors of errors. Future research will explore whether an ideal cognitive workload range truly optimizes surgical training and reduces surgical errors.

We describe the management of bullet embolism from a penetrating cardiac injury, including the clinical, radiographic, and operative considerations in this challenging trauma scenario. Bullet embolism represents a rare but complex subset of ballistic penetrating trauma, and highlights the importance of radiographic correlation with intraoperative findings.

Objective: To automate surgeon skills evaluation using robotic instrument kinematic data. Additionally, to implement an unsupervised mislabeling detection algorithm to identify potentially mislabeled samples that can be removed to improve model performance., Methods: Video recordings and instrument kinematic data were derived from suturing exercises completed on the Mimic FlexVR robotic simulator. A structured human consensus-building process was developed to determine Robotic Anastomosis Competency Evaluation technical scores across 3 human graders. A 2-layer long short-term memory-based classification model used instrument kinematic data to automate suturing skills assessment. An unsupervised label analyzer (NoiseRank) was used to identify potential mislabeling of skills data. Performance of the long short-term memory model's technical skill score prediction was measured by best area under the curve over the training runs. NoiseRank outputted a ranked list of rated skills assessments based on likelihood of mislabeling., Results: 22 surgeons performed 226 suturing attempts, which were broken down into 1,404 individual skill assessment points. Automation of needle entry angle, needle driving, and needle withdrawal technical skill scores performed better (area under the curve 0.698-0.705) than needle positioning (0.532) at baseline using all available data. Potential mislabels were subsequently identified by NoiseRank and removed, improving model performance across all domains (area under the curve 0.551-0.766)., Conclusion: Using ground truth labels from human graders and robotic instrument kinematic data, machine learning models have automated assessment of detailed suturing technical skills with good performance. Further, an unsupervised mislabeling detection algorithm projected mislabeled data, allowing for their removal and subsequent improvement of model performance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: It has been shown that metrics recorded for instrument kinematics during robotic surgery can predict urinary continence outcomes., Objective: To evaluate the contributions of patient and treatment factors, surgeon efficiency metrics, and surgeon technical skill scores, especially for vesicourethral anastomosis (VUA), to models predicting urinary continence recovery following robot-assisted radical prostatectomy (RARP)., Design, Setting, and Participants: Automated performance metrics (APMs; instrument kinematics and system events) and patient data were collected for RARPs performed from July 2016 to December 2017. Robotic Anastomosis Competency Evaluation (RACE) scores during VUA were manually evaluated. Training datasets included: (1) patient factors; (2) summarized APMs (reported over RARP steps); (3) detailed APMs (reported over suturing phases of VUA); and (4) technical skills (RACE). Feature selection was used to compress the dimensionality of the inputs., Outcome Measurements and Statistical Analysis: The study outcome was urinary continence recovery, defined as use of 0 or 1 safety pads per day. Two predictive models (Cox proportional hazards [CoxPH] and deep learning survival analysis [DeepSurv]) were used., Results and Limitations: Of 115 patients undergoing RARP, 89 (77.4%) recovered their urinary continence and the median recovery time was 166 d (interquartile range [IQR] 82-337). VUAs were performed by 23 surgeons. The median RACE score was 28/30 (IQR 27-29). Among the individual datasets, technical skills (RACE) produced the best models (C index: CoxPH 0.695, DeepSurv: 0.708). Among summary APMs, posterior/anterior VUA yielded superior model performance over other RARP steps (C index 0.543-0.592). Among detailed APMs, metrics for needle driving yielded top-performing models (C index 0.614-0.655) over other suturing phases. DeepSurv models consistently outperformed CoxPH; both approaches performed best when provided with all the datasets. Limitations include feature selection, which may have excluded relevant information but prevented overfitting., Conclusions: Technical skills and "needle driving" APMs during VUA were most contributory. The best-performing model used synergistic data from all datasets., Patient Summary: One of the steps in robot-assisted surgical removal of the prostate involves joining the bladder to the urethra. Detailed information on surgeon performance for this step improved the accuracy of predicting recovery of urinary continence among men undergoing this operation for prostate cancer., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Robotic surgical performance, in particular suturing, has been associated with postoperative clinical outcomes. Suturing can be deconstructed into substep components ( needle positioning , needle entry angle , needle driving , and needle withdrawal ) allowing for the provision of more specific feedback while teaching suturing and more precision when evaluating suturing technical skill and prediction of clinical outcomes. This study evaluates if the technical skill required for particular substeps of the suturing process is associated with the execution of subsequent substeps in terms of technical skill, accuracy, and efficiency. Materials and Methods: Training and expert surgeons completed standardized sutures on the Mimic™ Flex virtual reality robotic simulator. Video recordings were deidentified, time annotated, and provided technical skill scores for each of the four suturing substeps. Hierarchical Poisson regression with generalized estimating equation was used to examine the association of technical skill rating categories between substeps. Results: Twenty-two surgeons completed 428 suturing attempts with 1669 individual technical skill assessments made. Technical skill scores between substeps of the suturing process were found to be significantly associated. When needle positioning was ideal, needle entry angle was associated with a significantly greater chance of being ideal ( risk ratio [RR] = 1.12, p  = 0.05). In addition, ideal needle entry angle and needle driving technical skill scores were each significantly associated with ideal needle withdrawal technical skill scores (RR = 1.27, p  = 0.03; RR = 1.3, p  = 0.03, respectively). Our study determined that ideal technical skill was associated with increased accuracy and efficiency of select substeps. Conclusions: Our study found significant associations in the technical skill required for completing substeps of suturing, demonstrating inter-relationships within the suturing process. Together with the known association between technical skill and clinical outcomes, training surgeons should focus on mastering not just the overall suturing process, but also each substep involved. Future machine learning efforts can better evaluate suturing, knowing that these inter-relationships exist.

Background: This study compares surgical performance during analogous vesico-urethral anastomosis (VUA) tasks in two robotic training environments, virtual reality (VR) and dry laboratory (DL), to investigate transferability of skill assessment across the two platforms. Utilizing computer-generated performance metrics and pupillary data, we evaluated the two environments to distinguish surgical expertise and ultimately whether performance in the VR simulation correlates with performance in live robotic surgery in the DL. Materials and Methods: Experts (≥300 cases) and trainees (<300 cases) performed analogous VUAs during VR and DL sessions on a da Vinci robotic console following an Institutional Review Board (IRB) approved protocol (HS-16-00318). Twenty-two metrics were generated in each environment (kinematic metrics, tissue metrics, and biometrics). The DL included 18 previously validated automated performance metrics (APMs) (kinematics and event metrics) captured by an Intuitive system data recorder. In both settings, Tobii Pro Glasses 2 recorded the task-evoked pupillary response (reported as Index of Cognitive Activity [ICA]) to indicate cognitive workload, analyzed by EyeTracking cognitive workload software. Pearson correlation, Mann-Whitney, and independent t -tests were used for the comparative analyses. Results: Our study included six experts (median caseload 1300 [interquartile range 400-3000]) and 11 trainees (25 [0-250]). A total of 8/9 metrics directly comparable between VR and DL showed significant positive correlation ( r  ≥ 0.554, p  ≤ 0.032); 5/22 VR metrics distinguished expertise, including task time ( p  = 0.031), clutch usage ( p  = 0.040), unnecessary needle piercing ( p  = 0.026), and suspected injury to the endopelvic fascia ( p  = 0.040). This contrasts with 14/22 APMs in DL ( p  ≤ 0.038), including linear velocities of all three instruments ( p  ≤ 0.038) and dominant-hand instrument wrist articulation ( p  = 0.013). Trainees experienced higher cognitive workload (ICA) in both environments when compared with experts ( p  < 0.036). Conclusions: Most performance metrics between VR and DL exhibited moderate to strong correlations, showing transferability of skills across the platforms. Comparing training environments, APMs during DL tasks are better able to distinguish expertise than VR-generated metrics.

Purpose: Evaluation of surgical competency has important implications for training new surgeons, accreditation, and improving patient outcomes. A method to specifically evaluate dissection performance does not yet exist. This project aimed to design a tool to assess surgical dissection quality., Methods: Delphi method was used to validate structure and content of the dissection evaluation. A multi-institutional and multi-disciplinary panel of 14 expert surgeons systematically evaluated each element of the dissection tool. Ten blinded reviewers evaluated 46 de-identified videos of pelvic lymph node and seminal vesicle dissections during the robot-assisted radical prostatectomy. Inter-rater variability was calculated using prevalence-adjusted and bias-adjusted kappa. The area under the curve from receiver operating characteristic curve was used to assess discrimination power for overall DART scores as well as domains in discriminating trainees (≤100 robotic cases) from experts (>100)., Results: Four rounds of Delphi method achieved language and content validity in 27/28 elements. Use of 3- or 5-point scale remained contested; thus, both scales were evaluated during validation. The 3-point scale showed improved kappa for each domain. Experts demonstrated significantly greater total scores on both scales (3-point, p < 0.001; 5-point, p < 0.001). The ability to distinguish experience was equivalent for total score on both scales (3-point AUC= 0.92, CI 0.82-1.00, 5-point AUC= 0.92, CI 0.83-1.00)., Conclusions: We present the development and validation of Dissection Assessment for Robotic Technique (DART), an objective and reproducible 3-point surgical assessment to evaluate tissue dissection. DART can effectively differentiate levels of surgeon experience and can be used in multiple surgical steps., Competing Interests: Conflicts of interest/Competing interests: M Aron has financial disclosures with Intuitive. JW Davis is a consultant for Intuitive Surgical and Janssen. MM Desai is a consultant for Auris Health, PROCEPT BioRobotics. AC Goh is a consultant for Medtronic. R Kimmig has financial disclosures with Intuitive Surgical Inc., Medtronic, Avatera, CMR and Medicaroid. J Porter is a consultant for Medtronic, Ceevra, Proximie, Intuitive. I Gill is an unpaid advisor for Steba Biotech. AJ Hung is a consultant for Mimic Technologies, Quantagene, and Johnson & Johnson. The study was not funded by any of these companies. Other authors have no conflict of interest.

Background: Our previous work classified a taxonomy of suturing gestures during a vesicourethral anastomosis of robotic radical prostatectomy in association with tissue tears and patient outcomes. Herein, we train deep learning-based computer vision to automate the identification and classification of suturing gestures for needle driving attempts., Methods: Using two independent raters, we manually annotated live suturing video clips to label timepoints and gestures. Identification (2,395 videos) and classification (511 videos) datasets were compiled to train computer vision models to produce 2- and 5-class label predictions, respectively. Networks were trained on inputs of raw red/blue/green pixels as well as optical flow for each frame. Each model was trained on 80/20 train/test splits., Results: In this study, all models were able to reliably predict either the presence of a gesture (identification, area under the curve: 0.88) as well as the type of gesture (classification, area under the curve: 0.87) at significantly above chance levels. For both gesture identification and classification datasets, we observed no effect of recurrent classification model choice (long short-term memory unit versus convolutional long short-term memory unit) on performance., Conclusion: Our results demonstrate computer vision's ability to recognize features that not only can identify the action of suturing but also distinguish between different classifications of suturing gestures. This demonstrates the potential to utilize deep learning computer vision toward future automation of surgical skill assessment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Automated performance metrics objectively measure surgeon performance during a robot-assisted radical prostatectomy. Machine learning has demonstrated that automated performance metrics, especially during the vesico-urethral anastomosis of the robot-assisted radical prostatectomy, are predictive of long-term outcomes such as continence recovery time. This study focuses on automated performance metrics during the vesico-urethral anastomosis, specifically on stitch versus sub-stitch levels, to distinguish surgeon experience. During the vesico-urethral anastomosis, automated performance metrics, recorded by a systems data recorder (Intuitive Surgical, Sunnyvale, CA, USA), were reported for each overall stitch (C total ) and its individual components: needle handling/targeting (C 1 ), needle driving (C 2 ), and suture cinching (C 3 ) (Fig 1, A). These metrics were organized into three datasets (GlobalSet [whole stitch], RowSet [independent sub-stitches], and ColumnSet [associated sub-stitches] (Fig 1, B) and applied to three machine learning models (AdaBoost, gradient boosting, and random forest) to solve two classifications tasks: experts (≥100 cases) versus novices (<100 cases) and ordinary experts (≥100 and <2,000 cases) versus super experts (≥2,000 cases). Classification accuracy was determined using analysis of variance. Input features were evaluated through a Jaccard index. From 68 vesico-urethral anastomoses, we analyzed 1,570 stitches broken down into 4,708 sub-stitches. For both classification tasks, ColumnSet best distinguished experts (n = 8) versus novices (n = 9) and ordinary experts (n = 5) versus super experts (n = 3) at an accuracy of 0.774 and 0.844, respectively. Feature ranking highlighted Endowrist articulation and needle handling/targeting as most important in classification. Surgeon performance measured by automated performance metrics on a granular sub-stitch level more accurately distinguishes expertise when compared with summary automated performance metrics over whole stitches., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: During robotic surgeries, kinematic metrics objectively quantify surgeon performance., Objective: To determine whether clinical factors confound the ability of surgeon performance metrics to anticipate urinary continence recovery after robot-assisted radical prostatectomies (RARPs)., Design Setting and Participants: Clinical data (patient characteristics, continence recovery, and treatment factors) and surgeon data from RARPs performed between July 2016 and November 2018 were prospectively collected. Surgeon data included 40 automated performance metrics (APMs) derived from robot systems (instrument kinematics and events) and summarized over each standardized RARP step. The data were collected from two high-volume robotic centers in the USA and Germany. Surgeons from both institutions performed RARPs. The inclusion criteria were consecutive RARPs having both clinical and surgeon data., Intervention: RARP with curative intent to treat prostate cancer., Outcome Measurements and Statistical Analysis: The outcome was 3- and 6-mo urinary continence recovery status. Continence was defined as the use of zero or one safety pad per day. Random forest (SAS HPFOREST) was utilized., Results and Limitations: A total of 193 RARPs performed by 20 surgeons were included. Of the patients, 56.7% (102/180) and 73.3% (129/176) achieved urinary continence by 3 and 6 mo after RARP, respectively. The model anticipated continence recovery (area under the curve = 0.74, 95% confidence interval [CI] 0.66-0.81 for 3-mo, and area under the curve = 0.67, 95% CI 0.58-0.76 for 6 mo). Clinical factors, including pT stage, confounded APMs during prediction of continence recovery at 3 mo after RARP (Δβ median -13.3%, interquartile range [-28.2% to -6.5%]). After adjusting for clinical factors, 11/20 (55%) top-ranking APMs remained significant and independent predictors (ie, velocity and wrist articulation during the vesicourethral anastomosis). Limitations included heterogeneity of surgeon/patient data between institutions, although it was accounted for during multivariate analysis., Conclusions: Clinical factors confound surgeon performance metrics during the prediction of urinary continence recovery after RARP. Nonetheless, many surgeon factors are still independent predictors of early continence recovery., Patient Summary: Both patient factors and surgeon kinematic metrics, recorded during robotic prostatectomies, impact early urinary continence recovery after robot-assisted radical prostatectomy., Competing Interests: Financial disclosures: Andrew J. Hung certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Andrew J. Hung is a consultant for Mimic Technologies, Quantgene, and Johnson & Johnson. Christian Wagner has a financial relationship with Intuitive Surgical (speaker, proctor, and consultant).

Background: Building surgical capacity through global surgery partnerships (GSPs) between high and low- and middle-income countries (LMICs) is a rising global health focus. Our aim was to conduct a systematic review to characterize strategies employed by GSPs to build capacity and promote sustainability and to propose a novel reproducible model for sustainability., Methods: We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched PubMed, EMBASE, Medline and African Journals Online to identify all peer-reviewed articles published between 2000 and 2016 that described GSPs between partners from the United States or Canada or both and partners from LMICs. We excluded papers that described nonsurgical GSPs, unilateral GSPs (e.g., humanitarian missions) or military initiatives. Descriptive features were analyzed, with a focus on attributes that promote sustainability. We then proposed criteria for sustainability on the basis of the themes that emerged from our review., Results: Our search retrieved 3580 abstracts, which were then independently reviewed by 4 authors. A total of 128 papers (3.6%) met the inclusion criteria. They described GSPs in 68 countries on 5 continents. Among the GSPs, 21.9% demonstrated community engagement and 51.6% included multidisciplinary collaboration. Surgical training or education was provided in 81.3% of GSPs. Although 64.8% of GSPs collected data, only 53.1% reported project-related outcomes. A total of 55.5% had bilateral authorship for publications, and 28.9% had multisource funding. Only 1 GSP fulfilled all 6 of our criteria for sustainability., Conclusion: In this systematic review we identified 6 pillars that are indicators of sustainability: community engagement, multidisciplinary collaboration, education and training, outcomes reporting, bilateral authorship and multisource funding. We propose that future GSPs should build on a foundation of bilateral ideas and expertise exchange, that they should have defined and measurable objectives, that they should engage in continuous evaluation of program outcomes and that they should take a thoughtful and transparent approach to sustained capacity building., Competing Interests: None declared., (© 2021 CMA Joule Inc. or its licensors)